Solventless selective phosgene-free N-carbonylation of N-heteroaromatics (pyrrole, indole, carbazole) under mild conditions

Article abstract of DOI:10.1039/c2gc36103e

N-Heteroaromatics HetNH, such as pyrrole (1), indole (2) and carbazole (3), have been selectively N-carbonylated by a direct reaction with diphenyl carbonate (DPC), used as an environmental friendly carbonyl active species in place of toxic and hazardous phosgene. The carbonylation reaction can be effectively catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which can act as a base catalyst by activating the HetNH substrate, and as a nucleophile catalyst by activating the organic carbonate. The influence of reaction parameters (temperature, reaction time, DBU load, DPC/HetNH molar ratio) on the productivity of the process has been also investigated. The synthetic methodology does not require severe temperature conditions, is solventless, simple (only one step), efficient and selective, and offers a new solution to the synthesis of synthetically versatile HetNCO₂Ph derivatives through a route alternative to the current traditional phosgenation methods.

Full text of DOI:10.1039/c2gc36103e

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PAPER
Solventless selective phosgene-free N-carbonylation of N-heteroaromatics
(pyrrole, indole, carbazole) under mild conditions
Marianna Carafa, Francesco Iannone, Valentina Mele and Eugenio Quaranta*
Received 16th July 2012, Accepted 26th September 2012
DOI: 10.1039/c2gc36103e
N-Heteroaromatics HetNH, such as pyrrole (1), indole (2) and carbazole (3), have been selectively
N-carbonylated by a direct reaction with diphenyl carbonate (DPC), used as an environmental friendly
carbonyl active species in place of toxic and hazardous phosgene. The carbonylation reaction can be
effectively catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which can act as a base catalyst by
activating the HetNH substrate, and as a nucleophile catalyst by activating the organic carbonate. The
influence of reaction parameters (temperature, reaction time, DBU load, DPC/HetNH molar ratio) on the
productivity of the process has been also investigated. The synthetic methodology does not require severe
temperature conditions, is solventless, simple (only one step), efficient and selective, and offers a new
solution to the synthesis of synthetically versatile HetNCO2Ph derivatives through a route alternative to
the current traditional phosgenation methods.
compounds,5 which are useful precursors of the corresponding
Introduction
N-alkyl derivatives HetNR (R = alkyl).4c,d,6a,13
Organic carbonates (RO)2CO (R = alkyl, aryl), nowadays avail-
able through phosgeneless routes even on an industrial scale,1
are arousing greater and greater interest as environmentally
friendly carbonylating agents.2 So far, a lot of studies have
explored the synthetic potential of these compounds in carbony-
lation reactions of amines for the synthesis of carbamates, iso-
cyanates, ureas.2,3 Much less, however, is known about their
utilization in carbonylation reactions of N-heteroaromatic com-
pounds HetNH, such as pyrrole (1), indole (2), and carbazole
(3), to HetNCO2R (R = alkyl, aryl) derivatives (eqn (1)).4–6
The methods of synthesis of heterocarbamates HetNCO2R
(R = alkyl, aryl) are still based on harmful and risky phosgene,14
whose use in the chemical industry meets, nowadays, growing
restrictions due to governmental policies for environmental pro-
tection, and, in fact, imply the use of phosgene-derivatives like
dicarbonates,9a,15 alkyl-azidoformates,16 1,1′-carbonyldiimid-
azole,17 chloroformates18 as sources of the carbonyl moiety
(Scheme 1). In most cases the preliminary conversion of HetNH
into a more nucleophilic HetNM (M = alkali metal) salt is
required.16,18a–c,e,f
A
relatively more recent protocol
(Scheme 2)19a,b is based on the activation of carbamic acid
HetNCO2H (HetNH = pyrrole, indole) to (HetNC(O))2O anhy-
dride. However, this method, which requires a stoichiometric
amount of the phosgene-derivative EDCI·HCl ([(3-dimethyl-
amino)propyl]-3-ethylcarbodiimide hydrochloride)19c for the
activation step, is atomically uneconomical as it involves a multi-
step procedure and needs two moles of HetNH (for preforming
the anhydride) per mol of product.
HetNH þ ðROÞ2CO ! HetNCO2R þ ROH
ð1Þ
HetNCO2R carbamates are important synthetic intermediates
for the preparation of a variety of chemicals, because of wide-
spread use of “CO2R” (R = alkyl, aryl) functionality as a protec-
tive group of the N-atom of HetNH substrates.7 Pyrrole-
carbamates are useful starting materials for C-functionalisation
of the pyrrole ring and the synthesis of pharmaceutically relevant
substances or biologically active compounds.8,9 Carbonyl indole
derivatives HetNCO2R (R = alkyl, aryl) have been utilized as
precursors of bromoindole alkaloids10 and as reagents for the
synthesis of more complex heterocyclic systems.11,12 Under suit-
able conditions, N-phenoxocarbonyl derivatives HetNCO2Ph
(HetNH = pyrrole, indole, carbazole) can act as carbonylating
agents and be converted into unsymmetrical ureas HetNC(O)-
3a
NR2 or undergo transesterification with alcohols to HetNCO2R
Dipartimento di Chimica, Università degli Studi di Bari “Aldo Moro”,
Campus Universitario, Via E. Orabona, 4, 70126 Bari, Italy.
E-mail: eugenio.quaranta@uniba.it; Fax: (+39)-080-544-2129
Scheme 1 Conventional phosgene-based synthetic routes to
HetNCO2R carbamates.
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more severe temperature conditions (433 K). Moreover, we
excluded the use of any organic solvent as the reaction medium,
and used low-melting DPC (mp: 353 K), which was reacted in
excess with respect to HetNH, as the reactant and solvent. Gener-
ally, under the working catalytic conditions, a homogeneous
reacting system was obtained within variable times, depending
on reaction temperature, loading of DBU, DPC/HetNH molar
ratio, and the nature of the investigated substrate (1, mp: 250 K;
2, mp: 326 K; 3, mp: 520 K).
Scheme 2 Synthesis of HetNCO2R carbamates via HetNCO2H
activation.
In the absence of any catalyst, substrates 1–3 exhibited very
poor reactivity towards DPC (Table 1). Addition of DBU to the
reaction mixture modified the reactivity of the system and pro-
moted the selective formation of HetNCO2Ph derivatives 4–6
(eqn (1), R = Ph) with yields which depended on the working
conditions.
Influence of reaction parameters. At a temperature as mild as
343 K, using a DPC/HetNH molar ratio close to 4, pyrrole,
indole and carbazole were respectively carbonylated to 4, 5 and
6 in the presence of sub-stoichiometric amounts of DBU (entries
Scheme 3 Phosgeneless route to heterocarbamates HetNCO2Ph.
1–3, Table 2). The TON (molHetNCO Ph/molDBU) values higher
2
The reaction of HetNH substrates with carbonic acid diesters
(eqn (1)) may provide a potential direct route to the synthesis of
N-carbonyl derivatives HetNCO2R (R = alkyl, aryl) and offer an
intriguing alternative to the classic phosgenation methods. A few
pioneering studies described the synthesis of heteroaromatic car-
bamates HetNCO2R (HetNH = pyrrole, indole; R = alkyl) by the
reaction of preformed pyrryl or indolyl HetNM salts (M = K,
Na, Li, MgBr) with (MeO)2CO20a or (EtO)2CO18a,20a or tBuOC-
(O)OPh.20b Only recently a few studies4–6 have reported on the
direct N-alkoxycarbonylation of N-heteroaromatics as pyrrole or
carbazole or indoles with dialkyl carbonates (dimethyl carbonate
(DMC),4a–c,e,5,6 dibenzyl carbonate4d,5) or alkyl aryl carbonates
(methyl phenyl carbonate,5 t-butyl phenyl carbonate5) with vari-
able selectivity depending on the catalyst used (tetrabutylammo-
nium bromide,4b 4-dimethylaminopyridine,4c 1,4-diazabicyclo-
[2.2.2]octane,4a,c,d amidine4c,d,5,6a or phosphazene5,6a superbases,
solid bases (CaO),6b ionic liquids6c) and the working conditions.
To date, the direct reaction of diaryl carbonates with HetNH
substrates has received very poor attention. In this paper, as part
of our efforts devoted to developing a phosgene-free chemistry
based on safe non-toxic carbonyl active species which can serve
as phosgene substitutes,2,3a,f–h,5,6a we focus on industrially rel-
evant diphenyl carbonate (DPC)1a,b and explore its potential as a
carbonylating agent of pyrrole (1), indole (2) and carbazole (3)
in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
the catalyst of the carbonylation process (Scheme 3). A few very
preliminary results of this research have been described in a
short account elsewhere.5 Herein, we report a detailed study of
the carbonylation reaction (eqn (1), R = Ph) and shed light on
the possible mechanistic pathways by probing the role played
by the amidine catalyst in the process.
than unity (entry 1: TON ≈ 6; entry 2: TON ≈ 50; entry 3: TON
≈ 9) established unambiguously that DBU acts as a catalyst for
the carbonylation process. In experiments 1–3 (Table 2) a homo-
geneous reaction mixture was obtained at the working temp-
erature (343 K), differently from what was observed, at 333 K,
Table 1 Reactivity of HetNH (1–3) towards DPC in the absence of
any catalysta
HetNH
(mmol)
DPC/HetNH
(mol/mol)
HetNCO2Ph
GC-yield [%]
Entry
T/K
t/h
1
2
3
4
5
1(3.60)
1(3.60)
2(1.20)
2(1.25)
3(1.21)
3.89
3.89
3.97
3.82
3.90
343
393
343
393
393
9
12
24
15
15
—
—
—
5b
2b
a Under the working conditions a homogeneous system was rapidly
obtained, except for entry 5. In the latter case, the reaction mixture
remained heterogeneous throughout the reaction time because of non-
complete solubilization of solid 3 in melted DPC at the working
temperature (393 K). b The GC analysis of the reaction mixture did not
show any significant presence of other products besides minor amounts
of HetNCO2Ph and phenol.
Table 2 Carbonylation of HetNH (1–3) to HetNCO2Ph (4–6) with
DPC in the presence of DBU at different temperaturesa
HetNH
Entry (mmol) (mol/mol)
DPC/HetNH DBUb
(mol%) T/K t/h
GC-yieldc
[%]
1
2
3
4
5
6
1(3.60)
2(1.20)
3(1.23)
1(3.60)
2(1.24)
3(1.20)
3.89
3.96
3.98
3.89
3.98
3.79
9.3
1.1
9.3
9.3
1.1
9.4
343
343
343
393
393
393
24
24
22
1
62
55
89
57
75
6
Results and discussion
0.5 87
Carbonylation of pyrrole, indole, and carbazole with diphenyl
carbonate: catalytic activity of DBU
a At the working temperature a homogeneous mixture was obtained.
b Vs. HetNH. c Of HetNCO2Ph. The GC analysis of the reaction mixture
did not show any significant formation of other products besides
HetNCO2Ph and PhOH.
In this study we avoided drastic working temperatures (generally,
≤393 K) and only for the case of pyrrole we explored relatively
3378 | Green Chem., 2012, 14, 3377–3385
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Fig. 2 Carbonylation of carbazole with DPC (DPC/3 ≈ 4 : 1 mol/mol)
in the presence of DBU, at 393 K: influence of catalyst loading.21 (a)
DPC/3 = 3.8 0.1 mol/mol; DBU/3 = 9.3 0.1 mol%. (b) DPC/3 = 3.9
0.1 mol/mol; DBU/3 = 3.9 0.1 mol%. (c) DPC/3 = 3.9 0.1 mol/
mol; DBU/3 = 1.1 0.1 mol%. Selectivity to 6: ≥99%.
Fig. 1 Carbonylation of HetNH (1–3) with DPC (DPC/HetNH ≈
4 : 1 mol/mol) in the presence of DBU (≈10 mol% vs. HetNH).21 (a)
DPC/3 = 3.8 0.1 mol/mol; DBU/3 = 9.3 0.1 mol%; 393 K. (b) DPC/
2 = 3.9 0.1 mol/mol; DBU/2 = 10.3 0.8 mol%; 393 K. (c) DPC/1 =
3.9 0.1 mol/mol; DBU/1 = 9.3 mol%; 393 K. (d) DPC/1 = 3.9
0.1 mol/mol; DBU/1 = 9.3 mol%; 433 K.
for an ≈ 4 : 1 : 0.1 (mol/mol) DPC/3/DBU mixture. In the latter
case, most of DPC and 3 remained in the solid state throughout
the reaction time (24 h). This may explain why, at 333 K, the
latter system showed poor reactivity. At the higher temperature
of 393 K the productivity of the carbonylation reaction was
markedly higher and conversions to carbamate interesting from a
synthetic point of view were achieved selectively within signifi-
cantly shorter reaction times (entries 4–6, Table 2).
Curves (a)–(c) in Fig. 1 show the conversion of the different
substrates as a function of time, at 393 K, when using a DPC/
HetNH/DBU molar ratio close to 4 : 1 : 0.1. The curves indicate
that 1 is less reactive than 2 and 3. Under the working con-
ditions, indole and carbazole reacted selectively (≥99%) and
quantitatively (100%) within comparable short times (2–3 h). At
393 K, under otherwise analogous conditions, the quantitative
conversion of pyrrole (98%) needed a longer time (24 h), which,
however, reduced markedly at the working temperature of 433 K
(curve (d), Fig. 1; 98% conversion after 5 h). Remarkably, the
use of the higher temperature (433 K) did not produce any dim-
inution of carbamate selectivity, which remained very high
(≥99%) even at 433 K.
Fig. 3 Carbonylation of HetNH (1–3) with DPC (DPC/HetNH ≈
4 : 1 mol/mol) in the presence of DBU (≈1 mol% vs. HetNH), at
393 K.21 (a) HetNH: carbazole; DPC/3 = 3.9 0.1 mol/mol; DBU/3 =
1.1 0.1 mol%. (b) HetNH: indole; DPC/2 = 3.9 0.1 mol/mol; DBU/2
= 1.1 0.1 mol%. (c) HetNH: pyrrole; DPC/1 = 3.9 0.1 mol/mol;
DBU/1 = 0.93 mol%.
The carbonylation process was studied, at 393 K, in the pres-
ence of lower catalyst loadings. Fig. 2 illustrates the results
obtained for the carbonylation of carbazole. At the working
temperature (393 K), a catalyst load as low as 1.1 mol% pro-
moted selectively (>99%) the phenoxycarbonylation of 3 in
quantitative yield within 25 h. Fig. 3 (curve (b)) shows that,
under analogous experimental conditions, also indole was selec-
tively (≥99%) carbonylated satisfactorily (94%, after 25 h),
while the conversion of pyrrole to 1-phenoxycarbonyl pyrrole
was modest and did not exceed 52% (≈99% selectivity) after
24 h (curve (c)). At 393 K, keeping unchanged the DPC/HetNH
molar ratio (≈4), 1, the least reactive of the substrates investi-
gated, can be carbonylated more effectively by employing higher
catalyst loadings (Fig. 4, curves (b) and (c)). In general, the use
of higher catalyst loads allowed us to shorten the conversion
times and to work very efficiently at lower temperatures. Accord-
ingly, using a stoichiometric amount of DBU (1 equiv.), all the
substrates 1–3 were quantitatively and selectively carbonylated
Fig. 4 Reaction of pyrrole with DPC (DPC/1 ≈ 4 : 1 mol/mol) in the
presence of DBU, at 393 K: influence of catalyst loading.21 (a) DPC/1 =
3.9 0.1 mol/mol; DBU/1 = 0.93 mol%. (b) DPC/1 = 3.9 0.1 mol/
mol; DBU/1 = 3.5 mol%. (c) DPC/1 = 3.9 0.1 mol/mol; DBU/1 =
9.3 mol%.
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Table 3 Carbonylation of HetNH (1–3) to HetNCO2Ph (4–6) with
C-carbonylation. C-Carbonylation products may form in variable
yield, depending on the working conditions, when HetNM (Li,
Na, K, MgX) salts are allowed to react stoichiometrically with
carbonylating agents, such as organic carbonates, chlorofor-
mates, or isocyanates.18a,20a,23
In principle, the reaction of HetNH with DPC might also
result in the side-generation of (HetN)2CO ureas (eqn (2))
through consecutive processes involving (i) the preliminary for-
mation of
DPC in the presence of 1 equiv. of DBU, at 333 Ka,b
HetNH
(mmol)
DPC/HetNH
(mol/mol)
DBUc
(mol%)
HetNH
conversion [%]
Entry
t/h
1
2
3
1(3.60)
2(3.69)
3(3.59)
3.92
3.81
3.91
102
100
102
3
3
3
97
100
100
a HetNCO2Ph selectivity was ≥99%. b At the working temperature a
homogeneous mixture was obtained. c Vs. HetNH.
2HetNH þ ðPhOÞ2CO ! ðHetNÞ2CO þ 2PhOH
ð2Þ
HetNCO2Ph (eqn (1), R = Ph) and (ii) the further conversion of
the latter species into (HetN)2CO (eqn (3)).
HetNCO2Ph þ HetNH ! ðHetNÞ2CO þ PhOH
ð3Þ
Under the above catalytic conditions, (HetN)2CO species, if
any, formed in very minor amounts. However, the formation of
ureidic derivatives may become more important, even at ambient
temperature, when using a larger amount of HetNH relative to
DPC, as has been found for the specific case of pyrrole. For
instance, at 293 K, in the presence of DBU, a homogeneous
mixture of 1 and DPC (1/DBU/DPC = 1 : 1 : 0.5 mol/mol) con-
verted into 4 and 1,1′-carbonyldipyrrole. After 9 h the conver-
sion of 1 was around 50%, and 4 and 1,1′-carbonyldipyrrole
formed in an ≈3 : 1 molar ratio. The composition of the reaction
mixture did not undergo any appreciable change by prolonging
the reaction time for a further 15 h, suggesting that an equili-
brium state was likely reached. Accordingly, using a greater
excess of 1 led to a significant increase of 1,1′-carbonyldipyrrole
yield relative to 4. For instance, after 24 h at 293 K, 4 and 1,1′-
carbonyldipyrrole were obtained in approximately equimolar
Fig. 5 Carbonylation of HetNH (1 or 3) with DPC in the presence of
DBU at 393 K: influence of DPC/HetNH molar ratio.21 (a) HetNH: carb-
azole; DBU = 1.1 0.1 mol% vs. 3; reaction time = 2 h. In the range
1.3–2 mol/mol the reaction mixture remained heterogeneous throughout
the reaction time (2 h), as 3 did not dissolve completely in the reaction
medium (melted DPC). In all the runs selectivity was higher than 99%.
(b) HetNH: pyrrole; DBU = 3.53 mol% vs. 1; reaction time = 4 h. In all
the runs selectivity was close to 99%.
amounts, when 1, DBU and DPC were reacted in
a
5 : 1 : 0.5 molar ratio. Through this way, which allowed us to
bypass the traditional synthetic routes to (HetN)2CO ureas based
on the direct use of phosgene24 or 1,1′-carbonyldiimidazole
(a phosgene-derivative),25 we succeeded in isolating 1,1′-carbo-
nyldipyrrole with yields close to 50% (vs. DPC).
within very short times (3 h) at the temperature of 333 K (entries
1–3, Table 3).
We have also investigated the influence of the DPC/HetNH
molar ratio (Fig. 5). Curve (a) in Fig. 5 shows the change of
carbazole conversion against the DPC/HetNH (HetNH = 3)
molar ratio, when the reaction was carried out at 393 K for 2 h
with a DBU load close to 1 mol% (vs. 3). Curve (b) in Fig. 5
illustrates the analogous change in the case of less reactive
pyrrole (HetNH = 1), when the latter substrate was reacted with
DPC at 393 K for 4 h in the presence of 3.5 mol% of DBU
(vs. 1). In both cases, the use of a DPC/HetNH molar ratio
higher than 4 did not offer any substantial advantage as it pro-
duced only a little variation of substrate conversion to carbamate.
Conversely, substrate conversion decreased upon using DPC/
HetNH molar ratios lower than 4. The above results justify the
DPC/HetNH molar ratios close to 4 used in the present work.
The excess of DPC can be recovered in a pure form with high
yield, as we have demonstrated for the specific cases of carbony-
lation of indole and pyrrole.22
Role of DBU
The catalytic role played by DBU in the carbonylation process
(eqn (1), R = Ph) was probed. We focused on the reactivity of
the amidine catalyst not only as a base, but also as a
nucleophile.26
HetNH activation: base catalysis. In principle, by acting as a
proton acceptor DBU can activate the substrate and convert
HetNH into the more nucleophilic HetN− anion according to
reaction (4) (Scheme 4). The effectiveness of equilibrium (4) has
Carbamate selectivity. Formation of HetNCO2Ph heterocarb-
amate was very selective. The N-carbonylation reaction
proceeded regioselectively without any significant incidence of
Scheme 4 Base catalysis.
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Fig. 6 1H NMR (500 MHz; (CD3)2SO (1 mL); 293 K): (a) pyrrole
(15 μL, 0.216 mmol); (b) pyrrole (15 μL, 0.216 mmol)/DBU (35 μL,
0.234 mmol) mixture.
Scheme 5 Reactivity of DBU with carbonic acid diesters.26b
been documented experimentally by 1H NMR (500 MHz,
(CD3)2SO, 293 K) spectroscopy for the specific case of pyrrole,
the least acidic of the N-heteroaromatic substrates considered in
this study.27,28 As a matter of fact, DBU promotes the “exchange
decoupling”29 between the pyrrolic protons Hα and Hβ and the
N–H proton of the heteroaromatic substrate. Accordingly, in the
proton spectrum of an equimolar 1/DBU mixture (Fig. 6, spec-
trum (b)) the resonances of Hα and Hβ protons of pyrrole were
no longer quartets, but triplets (J = 2), as a result of the fact that,
in the presence of the base (eqn (4)), the expected coupling of
Hα and Hβ with the N–H proton was washed out. This behaviour
is reminiscent of that exhibited by 1 in the presence of piper-
idine,30 a weaker base than DBU.
corresponding N-alkoxycarbonyl amidinium cations 8 by the
amidine base, as we have demonstrated experimentally by isolat-
ing and characterizing a few 8 chloride salts, such as (8a)Cl and
(8b)Cl·H2O (eqn (7)), and studying their reactivity towards the
organic base (eqn (8)).26b Ketene aminals 7 are more active car-
bonylating species than amidinium ions 8 and organic carbonates
from which they derive (Scheme 5), and can function as “CO2R”
carriers, as they can transfer the alkoxycarbonyl group to a
nucleophile as methanol, for instance, and regenerate the
amidine base.26b
The above findings make plausible the hypothesis that a base
catalysis may be operative (Scheme 4). A base catalysis has been
proposed by Sun for the N-methoxycarbonylation of 1 with
DMC over solid base (CaO) catalysts.6b In our case, the pKa
values of the HetNH substrates (1–3) and DBUH+ suggest that
equilibrium (4) lies to the left.31 Although the HetN− anion is
expected to be present in the reaction medium at low concen-
tration, it may be reactive enough, under the working conditions,
as to react with the organic carbonate and to generate the relevant
N-phenoxycarbonylation product (Scheme 4, eqn (5)). In this
regard, it is worth reminding that HetNM (M = Li, Na, K, MgX)
salts of pyrrole and indole can react with organic carbonates,
such as dimethyl, diethyl, tert-butyl phenyl carbonate, to give
the corresponding methyl, ethyl, tert-butyl carbamates.18a,20
The catalyst (DBU) can be regenerated according to equili-
brium (6). The pKa values of PhOH and DBUH+ in different
media (H2O or DMSO)27 suggest that the position of equilibrium
(6) may depend markedly on the nature of the solvent. In
DMSO, a polar aprotic medium (like melted DPC), equilibrium
(6) may lie to the right.27 Moreover, under our catalytic con-
ditions, the location of equilibrium (6) is expected to vary with
time as a result of phenol co-production. This may affect the
activity of the catalytic system in the long run.
ð7Þ
ð8Þ
The above findings raise the question whether, in the catalytic
process here investigated (eqn (1), R = Ph), the formation of hetero-
carbamates HetNCO2Ph (4–6) may involve DBU-promoted
DPC activation: nucleophilic catalysis. The ability of DBU to
act as a nucleophile towards a variety of electrophiles has been
long recognized.26 In a recent study,26b we have demonstrated
that organic carbonates, such as DPC itself, can be activated
nucleophilically by DBU through the formation of an N-alkoxy-
carbonyl ketene aminal 7 as the ultimate product (Scheme 5).
The latter species may form through deprotonation of the
Scheme 6 Reactivity of (8)Cl salts with pyrrole in the absence and in
the presence of DBU.
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Fig. 7 Reaction of 7b with pyrrole (1/7b = 2 mol/mol), in CDCl3, at
293 K. Yield of 1-methoxycarbonyl pyrrole versus time.
Scheme 7 Nucleophilic catalysis.
nucleophilic activation of DPC (Scheme 5) as an additional reac-
tion pathway. In tackling this issue, once more we selected
pyrrole as the reference substrate and investigated the reactivity
of 1 towards N-alkoxycarbonyl amidinium salts (8a)Cl and (8b)
Cl·H2O and ketene aminal 7b.
intermediacy of (8a)OPh, into ketene aminal 7a, which, then,
transfers the CO2Ph moiety to HetNH and regenerates the cata-
lyst (step II).33
At ambient temperature, in CDCl3, pyrrole did not react with
either (8a)Cl or (8b)Cl·H2O (Scheme 6). However, addition of
DBU altered the reactivity of the system. For instance, at 293 K,
in CDCl3 and in the presence of DBU (20 mol% vs. the salt),
pyrrole reacted with (8a)Cl (eqn (9)) to give DBU·HCl and 4,
albeit slowly under the working conditions (≈20% vs. 8a, after
65 h). In principle, the change of reactivity observed upon
addition of DBU might be ascribed to the formation of a pyrryl
anion (eqn (4)), a more nucleophilic species than pyrrole (see
above). However, soon after adding DBU to the CDCl3 solution
of (8a)Cl and 1, we noted that the NMR spectrum of the reaction
mixture (see Experimental) also showed the presence, in solu-
tion, of ketene aminal 7a (eqn (8)). The resonances of both 7a
and 8a remained clearly distinguishable in the spectrum through-
out the reaction time (65 h).
Conclusions
DPC has been investigated as a carbonylating agent of pyrrole,
indole and carbazole. The carbonylation of these substrates with
DPC provides a solution to the synthesis of heterocarbamates
HetNCO2Ph (HetNH = pyrrole, indole, carbazole) through a
phosgene- and halogen-free synthetic route (Scheme 3), which is
safe and avoids the heavy cogeneration of wastes (salts, etc.)
typical of classic phosgenation protocols. The developed syn-
thetic methodology is solventless, direct (only one step), selec-
tive and high yield. The carbonylation reaction can be effectively
catalyzed, under usually non severe temperature conditions, by
DBU, acting not only as a base, by activating the substrate
HetNH to HetN−, but also as a nucleophile towards DPC.
The latter fact suggested that reaction (9) may proceed through
the intermediate formation of 7a (eqn (8)) and involve, as a sub-
sequent step, the reaction of 7a with pyrrole (eqn (10), R = Ph).
Substantial support for this hypothesis has been obtained by
Experimental
General methods
All solvents were dried according to conventional methods
(P2O5; Na–benzophenone)34 and stored under N2. DPC, DBU,
1, 2 and 3 were commercial products (Fluka, Aldrich, Carlo
Erba). Pyrrole was dried over CaH2, filtered, distilled in vacuo
over fresh CaH2, stored and manipulated under N2. DBU was
used as received and manipulated under an inert atmosphere to
prevent contamination by atmospheric CO2 or moisture. Ketene
aminal 7b and salts (8a)Cl and (8b)Cl·H2O were prepared as pre-
viously described.26b GC analyses were performed with an HP
5890 Series II gas-chromatograph (capillary column: Heliflex
AT-5, 30 m × 0.25 mm, 0.25 μm film thickness). GC-MS
analyses were carried out with a Shimadzu GC-17A linked to a
Shimadzu GC-MS QP5050 selective mass detector (capillary
column: Supelco MDN-5S, 30 m × 0.25 mm, 0.25 μm film
thickness). IR spectra were taken on a Shimadzu FTIR Prestige
21 spectrophotometer. NMR spectra were run with a Bruker
AM 500 spectrometer or with a Varian Inova 400 instrument.
Chemical shifts are in δ (ppm) vs. Me4Si. Coupling constants
are in Hz.
ð10Þ
reacting pyrrole with ketene aminal 7b. In fact, at 293 K, in
CDCl3, 7b and pyrrole reacted to afford 1-methoxycarbonyl
pyrrole (eqn (10), R = Me) with 78% yield after 56 h (Fig. 7).
The formation of HetNCO2Me (HetNH = pyrrole) was ascer-
tained not only by means of NMR spectroscopy (1H, 13C), but
also by GC/MS (see Experimental).
These results provide further evidence supporting the fact that
ketene aminal 7 can behave as a carrier of the CO2R group.26b
Moreover, the above findings substantiate the pathway concisely
illustrated in Scheme 7 as an additional accessible mechanistic
route for the catalytic process under study. Scheme 7 summarizes
a nucleophile catalysis, whose key steps, I and II, have been
documented experimentally. In step I the organic carbonate is
nucleophilically activated by DBU and converted, through the
3382 | Green Chem., 2012, 14, 3377–3385
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Carbonylation of HetNH (1–3) with DPC in the presence of
DBU: general procedure
of 7a and (8a)Cl), in addition to the signals of pyrrole (δH 6.14
(q, J = 2.0, Hβ), 6.76 (q, J = 2, Hα), 9.34 (br s, NH)) and
unreacted (8a)Cl (δH 1.74 (unresolved br, 3-H, 4-H, 5-H), 2.20
(quint, J = 6, 10-H), 3.24 (unresolved br, 6-H), 3.80 (t, J = 6.2,
9-H or 11-H), 3.96 (unresolved br, 2-H), 4.11 (pseudo-t, J = 6,
9-H or 11-H), 7.13 (dm, Hortho), 7.26 (m, Hpara), 7.38 (m,
Into a 30 mL Schlenk tube, containing the heteroaromatic sub-
strate HetNH (typically ≈1.2 mmol for 2 and 3; 1.8 or 3.6 mmol
for 1) and the organic carbonate, the catalyst (DBU) was added.
The reaction mixture was heated in an oil bath to the working
temperature and allowed to react for a given time (for further
details see Tables 2 and 3, and the legends of Fig. 1–5). The
mixture was cooled to room temperature, dissolved in diethyl
ether and analyzed by GC (internal standard: n-dodecane) or
GC/MS.
H
meta)).26b A triplet of very low intensity at 6.28 ppm (J = 2),
assigned to the Hβ protons of 4,5,19a was distinguishable in the
spectrum after a few hours (3.5 h). The other proton resonances
of 4 were masked by the other signals in the aromatic region.
The intensity of this triplet increased slowly in the long run. The
formation of 4 was further confirmed by GC and GC/MS (m/z
(EI) 187 (M+), 143, 115, 94, 77, 66, 51, 39).
The isolation and spectroscopic characterization of com-
pounds 4–6 as well as 1,1′-carbonyl dipyrrole have been
described elsewhere.5,22
Reaction of 7b with pyrrole
HetNH activation: 1H and 13C NMR spectra of the pyrrole/DBU
system in (CD3)2SO
Pyrrole (34 μL; 0.490 mmol) was added to a CDCl3 (1 mL)
solution of 7b (52.4 mg; 0.249 mmol). The mixture was allowed
to react at ambient temperature and monitored by means of
NMR spectroscopy. In addition to the signals of pyrrole (δH 6.14
(t, J = 2.0, Hβ), 6.72 (t, J = 2, Hα), 9.87 (br s, NH)) and 7b
(characteristic signals at δH 4.81 (slightly br t, J = 6.2, 6-H),
3.63 (s, OMe), 3.49 (t, J = 6.6, 9-H or 11-H), 2.99 (m, 2-H),
2.89 (m, 9-H or 11-H), 2.06 (t, J ≈ 6, 5-H); proton 6-H under-
went H/D exchange, under the working conditions), the proton
spectrum (400 MHz) showed the progressive increase of the
signals due to the formation of 1-methoxycarbonyl pyrrole (δH
7.20 (t, J = 2.2, Hα), 6.17 (t, J = 2, Hβ), 3.88 (s, OMe))19a and
DBU (δH 3.22 (t, 9-H), 3.15 and 3.14 (overlapped signals prob-
ably due to 2-H and 11-H), 2.36 (m, 6-H); the other signals at
higher field overlapped with the resonances of 7b). In the 13C
spectrum (100 MHz) the resonances of 1-methoxycarbonyl
pyrrole were observed at δC 53.65 (OMe), 112.12 (Cβ), 117.18
(Cα), 150.58 (COO). The 13C spectrum also indicated the pres-
ence of partially deuterated DBU, probably formed by H/D
exchange with CDCl3.35 The conversion of 7b into 1-methoxy-
carbonyl pyrrole was around 78% after 56 h. The GC/MS analy-
sis of the reaction mixture further confirmed the formation of 1-
methoxycarbonyl pyrrole (m/z (EI) 125 (M+), 90, 80, 66, 59, 55,
53, 42, 39) and partially deuterated DBU (153 m/z) and 7b (211
m/z). The FT-IR spectrum of the deuterochloroform solution
showed the characteristic strong absorption of the carbonyl
The 1H and 13C NMR spectra of an equimolar mixture of
pyrrole (15 μL, 0.216 mmol) and DBU (35 μL, 0.234 mmol) in
(CD3)2SO (1 mL) were measured and compared with those of
DBU (35 μL, 0.234 mmol) and pyrrole (15 μL, 0.216 mmol), in
the same solvent (1 mL), under otherwise similar experimental
conditions.
Pyrrole/DBU mixture in (CD3)2SO. δH (500 MHz, 293 K)
1.44–159 (6 H, m, 3-H, 4-H, 5-H), 1.64 (2 H, quint, J = 5.9,
10-H), 2.24 (2 H, m, 6-H), 3.07 (2 H, t, J = 5.5, 2-H), 3.13 (4 H,
m, 9-H and 11-H), 6.01 (2 H, t, J = 2.0, Hβ,pyrr), 6.72 (2 H, t, J =
2.0, Hα,pyrr), 10.93 (1 H, br s, NHpyrr). δC (125 MHz, 293 K)
22.34 (10-C), 25.79 (4-C), 28.10 (3-C), 29.08 (5-C), 36.37
(6-C), 43.48 (9-C), 47.48 (2-C), 51.78 (11-C), 159.66 (7-C),
107.01 (Cβ,pyrr), 117.27 (Cα,pyrr).
Pyrrole in (CD3)2SO. δH (500 MHz, 293 K) 6.01 (2 H, q, J =
2.0, Hβ), 6.73 (2 H, q, J = 2, Hα), 10.75 (1 H, br s, NH). δC
(125 MHz, 293 K) 107.10 (Cβ), 117.35 (Cα).
DBU in (CD3)2SO. δH (500 MHz, 293 K) 1.44–158 (6 H, m,
3-H, 4-H, 5-H), 1.63 (2 H, quint, J = 5.9, 10-H), 2.23 (2 H, m,
6-H), 3.05 (2 H, t, J = 5.7, 2-H), 3.12 (4 H, m, 9-H and 11-H).
δC (125 MHz, 293 K): δ = 22.36 (10-C), 25.80 (4-C), 28.11
(3-C), 29.07 (5-C), 36.40 (6-C), 43.52 (9-C), 47.46 (2-C), 51.76
(11-C), 159.48 (7-C).
group of 1-methoxycarbonyl pyrrole at 1713 cm−1
.
Acknowledgements
Reaction of (8a)Cl with pyrrole in the presence of DBU
Università degli Studi “Aldo Moro” di Bari (Fondi di Ateneo)
and Ministero dell’Istruzione, dell’Università e della Ricerca
(PRIN 2008A7P7YJ_002) are acknowledged for financial
support.
To a solution of (8a)Cl (39.7 mg, 0.129 mmol) and 1 (18 μL,
0.259 mmol) in CDCl3 (1 mL), DBU (4 μL, 0.0268 mmol) was
added. The reaction solution was analyzed, at 293 K, by 1H
(400 MHz) and 13C (100 MHz) NMR. The proton spectrum of
the reaction mixture showed the instantaneous formation of
ketene aminal 7a (characteristic signals at δH 4.99 (slightly br t,
J = 6.2, 6-H), 3.62 (br t, J = 6, 9-H or 11-H), 3.05 (m, 2-H),
2.99 (m, 9-H or 11-H), 2.11 (pseudo-quartet, J = 6, 5-H); the
remaining absorptions of 7a were masked by other signals) and
the resonances of DBU/DBU·HCl (δH 2.85 (m, 6-H), 3.27 (t, J =
6, 9-H), 3.34 (t, J = 6, 11-H), 3.39 (m, 2-H), 11.16 (s br, NH);
the other signals at higher field overlapped with the resonances
Notes and references
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31 Accordingly, the 13C NMR spectrum (125 MHz, 293 K) of an equimolar
mixture of 1 and DBU in (CD3)2SO practically corresponds to the super-
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DBU) in the same solvent, at similar concentrations and temperature,
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3384 | Green Chem., 2012, 14, 3377–3385
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protonation of the N(sp2) atom of DBU and is found around 165 ppm in
DBUH+.26b Analogously, in the proton spectrum (500 MHz, (CD3)2SO)
of the equimolar mixture, the observed resonances do not show any
significant shift with respect to the signals found in the proton spectra
of the pure components measured under similar experimental conditions
(solvent, concentration, temperature), with the exception of the
broad signal assigned to the pyrrole N–H proton, whose resonance is
slightly shifted downfield (+0.18 ppm), probably as a consequence of a
hydrogen-bond interaction (HetNH⋯N) between the substrate and the
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(eqn (4)), may play some role in the formation of product (see also
above, in the main text).
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base.32
.
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