Ultrasound-Promoted One-Pot Synthesis of Mono- or Bis-Substituted Organylselanyl Pyrroles

Article abstract of DOI:10.1021/acs.joc.9b00405

A simple method for the direct mono- and bis-organylselenylation of N-substituted pyrroles through a multicomponent reaction promoted by ultrasonic radiation was described. These sonochemical promoted reactions were performed between different primary amines, 2,5-hexanedione and dialkyl, diheteroaryl, or diaryl diselenides, using catalytic amounts of copper iodide. Depending on the amount of copper iodide and diorganyl diselenide used in the reactions, mono- or bis-organylselenylation products were efficiently synthesized in high yields.

Full text of DOI:10.1021/acs.joc.9b00405

Article
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Ultrasound-Promoted One-Pot Synthesis of Mono- or Bis-
Substituted Organylselanyl Pyrroles
Thiago J. Peglow, Gabriel P. da Costa, Luis Fernando B. Duarte, Mar
́
cio S. Silva, Thiago Barcellos,‡
†
†
†
†
,
†
,†
Gelson Perin,* and Diego Alves*
†
Laborator
́
io de Síntese Organ
̂
ica LimpaLASOL, CCQFA, Universidade Federal de PelotasUFPel, P.O. Box 354, 96010-900
Pelotas, RS, Brazil
‡
Laborator
RS, Brazil
́
io de Biotecnologia de Produtos Naturais e Sintet
́
icos, Universidade de Caxias do SulUCS, 95070-560 Caxias do Sul,
*
S Supporting Information
ABSTRACT: A simple method for the direct mono- and bis-
organylselenylation of N-substituted pyrroles through a
multicomponent reaction promoted by ultrasonic radiation
was described. These sonochemical promoted reactions were
performed between different primary amines, 2,5-hexanedione
and dialkyl, diheteroaryl, or diaryl diselenides, using catalytic
amounts of copper iodide. Depending on the amount of
copper iodide and diorganyl diselenide used in the reactions,
mono- or bis-organylselenylation products were efficiently
synthesized in high yields.
INTRODUCTION
considered as an essential nutrient for all mammals and it plays
■
13
important roles in metabolic pathways. Additionally, the
Nitrogen-containing heterocycles represent important struc-
14
15
1
interest in the “selenium” pharmacology and chemistry has
increased in this century, and the development of new and
efficient methods to synthesize these scaffolds is a growing area
tural units that display a large spectrum of biological
2
3
2,3
activities, drugs under development, pharmaceuticals,
4
5
agrochemicals, and functional materials. In this sense, we
can highlight pyrroles as versatile heteroaromatic compounds,
which serve a range of applications in different fields of
16
in organic synthesis.
Numerous methodologies have been reported for the
17
6
selective C−Se bond formation. Direct organylselenylation
of N-heterocycles is an economic, practical, and useful method
to introduce different substituted organylselanyl units to these
chemical/pharmaceutical sciences. Research works on the
synthesis of pyrrole scaffolds are being performed because their
derivatives show several pharmacological activities, including
antibiotics, cholesterol-reducing drugs, anti-inflammatory
drugs, fungicides, and antitumor agents. Also, it is well
known that pyrrole derivatives inhibit reverse transcriptase
HIV-1), as well as are present in dyes, fluorescent
compounds, and conductive materials, among others.
example, atorvastatin, nonsteroidal anti-inflammatory drug
tolmetin (marketed as Tolectin), and the anticancer agent
tallimustine contain pyrrole in their structure (Figure 1).
Although a variety of methods were described to synthesize
pyrroles, Paal−Knorr reaction has received considerable
attention due to the applicability of simple starting materials,
1
7a−l
scaffolds.
For the C−Se bond formation starting from
18
7
diaryl diselenides, our research group has recently described
the copper(I)-catalyzed synthesis of selanyl pyrazoles starting
from hydrazines, 1,3-diketones, and diorganyl diselenides by a
multicomponent reaction (Scheme 1, eq 1). In addition, Zhu
and co-workers described a method for C5-selanylation of 8-
amidoquinoline scaffolds using copper(II) bromide in
(
18
7
a,8
For
18b
6
stoichiometric amounts (Scheme 1, eq 2).
In another
study, Cera and Ackermann developed an effective method in
which copper(I) acetate promoted the C−H selenylation of
the 1H-1,2,3-triazole-4-carboxamides with diaryl diselenides
9
1
8c
(
Scheme 1, eq 3).
Thus, in view of the above explanation and combining the
efficiency, and greener characteristics, and it is one of the most
10
classical approaches. Some synthetic methods to function-
alize pyrroles have some disadvantages, such as high temper-
19
versatility of multicomponent reactions with the sonochem-
istry, we describe our results on the synthesis of a range of
20
11
ature and requirement of excess reagents.
On the other hand, N-heterocycles containing selanyl
moieties have attracted interest in different areas of research,
including the design of new drug candidates. Selenium is
Received: February 14, 2019
12
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00405
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Examples of drugs containing pyrrole in their structure.
Scheme 1. Examples of Direct Arylselenylation of N-
Heterocycles by C−H Bond Cleavage
4a, and a set of optimization reactions were performed (Table
1).
Thus, we carried out the one-pot reaction of aniline 1a (0.5
mmol), 2,5-hexanedione 2a (0.5 mmol), and diphenyl
diselenide 3a (0.25 mmol) under identical reaction conditions
shown in Scheme 2, and 2,5-dimethyl-1-phenyl-3-(phenyl-
selanyl)-1H-pyrrole 4a was obtained in 55% yield after 1.0 h
(
Table 1, entry 1). A small increase in the yield of product 3a
occurs in the reaction carried out under microwave irradiation;
however, 2.0 h of reaction is needed (Table 1, entry 2). The
effect of different temperatures was studied, and decreasing the
temperature to 80 °C yielded the product 4a in a similar yield
(
Table 1, entries 1 vs 3). In another experiment, a slight
increase in the yield of the product 4a was observed on gentle
heating (50 °C) (Table 1, entry 4). Reaction conducted at
room temperature gave only traces of the product 4a, even
after 24.0 h (Table 1, entry 5).
These results led us to explore an alternative procedure to
obtain selectively the product 4a in higher yield. In this sense,
21
we choose ultrasound (US) as an alternative energy source to
provide the selective reactions. Thus, the same reaction
conditions were applied for the reaction under US irradiation
(
40% of amplitude); however, product 4a was not obtained
mono- and bis-substituted organylselanyl pyrroles by one-pot
copper-catalyzed Paal−Knorr condensation and C−H bond
selenylation reactions.
(Table 1, entry 6). A notable enhancement in yield was
observed in the reaction carried out using US irradiation with
60% of amplitude, and the mono-arylselenylated pyrrole 4a
was obtained in 70% yield after 0.5 h (Table 1, entry 7). When
the reaction was performed under US irradiation with an
amplitude of 80%, the starting materials were consumed in
only 0.25 h (Table 1, entry 8). Nevertheless, the reaction was
not selective because in this case, both mono- and bis-
arylselenylation products 4a and 5a were obtained in 52 and
24% yields, respectively (Table 1, entry 8).
RESULTS AND DISCUSSION
Based on a study conducted in 2012 by our research group,
in which we performed sulfenylation of pyrroles with disulfides
or thiols, we start our studies by reacting 2,5-dimethyl-1-
phenyl-1H-pyrrole A (0.5 mmol) with diphenyl diselenide 3a
■
17i
(
0.25 mmol), using CuI (10 mol %) as a catalyst in dimethyl
sulfoxide (DMSO) at 110 °C (Scheme 2).
Inspired by the result described in entry 7, we followed the
additional experiments using US irradiation (60% of
amplitude). We also studied the effects of few copper salts,
solvents, and stoichiometry of the starting materials. Different
solvents such as dimethylformamide (DMF), N-methyl
pyrrolidone (NMP), N,N-dimethylacetamide (DMA),
Under these reaction conditions, after 1.0 h, both products
mono-phenylselenylation 4a and bis-phenylselenylation 5a
were obtained in 80 and 10% yield, respectively. With this
result, we turn our efforts to a one-pot Paal−Knorr
condensation and successive C−H bond selenylation reaction
for the selective formation of mono-substituted selanyl pyrrole
CH CN, PEG-400, and EtOH were evaluated and very poor
3
Scheme 2
B
DOI: 10.1021/acs.joc.9b00405
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a
Table 1. Optimization of the Reaction Conditions for the One-Pot Synthesis of Compound 4a
entry
CuX (mol %)
solvent
temp. (°C)
time (h)
yield of 4a (%)
yield of 5a (%)
1
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuBr (10)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
110
110
80
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
1.0
2.0
2.0
3.0
24.0
0.5
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
55
67
50
69
traces
traces
70
52
9
9
8
11
4
b
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
c
d
e
5
24
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
NMP
DMA
63
4
traces
traces
traces
CH CN
3
PEG-400
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
52
62
8
7
CuBr (10)
2
Cu O (10)
2
Cu(OAc) (10)
22
40
62
31
63
80
15
2
CuCl (10)
CuI (15)
CuI (5)
CuI (10)
CuI (10)
CuI (10)
11
4
,
,
,
f
8
5
g
g
,
h
a
Reactions were carried out with aniline 1a (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), and diphenyl diselenide 3a (0.25 mmol) in solvent (2.0
b
mL). The reaction progress was followed by thin layer chromatography (TLC) until the total consumption of the starting materials. Reaction
performed under microwave irradiation. Temperature was measured with an IR sensor on the outer surface of the reaction vial. Reaction
performed under ultrasound (US) irradiation (40% of amplitude). Reaction performed under ultrasound irradiation (60% of ampitude). Reaction
performed under ultrasound irradiation (80% of amplitude). Reaction was performed with 0.3 mmol of diphenyl diselenide 3a. Reaction
c
d
e
f
g
h
performed with 0.6 mmol of the aniline 1a and 0.6 mmol of the 2,5-hexanedione 2a. Reaction performed under argon atmosphere.
results were obtained (Table 1, entries 9−14). When the
reaction was carried out using both copper(I) and copper(II)
species such as CuBr, CuBr , Cu O, Cu(OAc) , and CuCl as
catalyst, product 4a was obtained in lower yields (Table 1,
compare entries 15−19 and 7). Furthermore, on increasing the
catalyst charge from 10 to 15 mol %, a slight decrease in the
yield of compound 4a was observed (Table 1, entry 20). On
reducing the catalyst charge from 10 to 5 mol %, no gain in the
yield of 4a was obtained, and in this case, there was incomplete
consumption of starting materials (Table 1, entry 21).
use of aniline 1a (0.6 mmol), 2,5-hexanedione 2a (0.6 mmol),
diphenyl diselenide 3a (0.25 mmol), CuI as a catalyst (10 mol
%), and 2.0 mL of DMSO as solvent under US irradiation
(60% of amplitude).
2
2
2
After reaction optimization, to demonstrate the generality of
this method, we synthesized a series of mono-arylselenylated
pyrroles 4a−p using different amines and diorganyl diselenides
substituted with aryl, heteroaryl, benzyl, or alkyl groups.
The presence of electron-donating methyl or methoxy group
in para position of the phenyl ring of the diaryl diselenides, as
in 3b and 3c, affords products 4b and 4c in 57 and 64% yields
after 1.5 and 1.0 h, respectively (Table 2, compounds 4b and
4c). On the other hand, the electron-withdrawing effect
exerted by fluoro or chloro in the ring of the diaryl diselenides
4d and 4e was considerable. In these cases, the reaction
required more time (3.0 h) to obtain even slightly lower yields
than the electron-donating groups (Table 2, compounds 4b-c
vs 4d-e).
We verified the use of an excess of diphenyl diselenide 3a
(
0.3 mmol) in this reaction, and it did not seem to significantly
influence the yield (Table 1, entry 22). Instead, when we use
.6 mmol of both starting materials 1a and 2a, the mono-
0
arylselenylated pyrrole 4a was obtained in 80% yield, showing
that a little excess of these starting materials is required to
obtain better results (Table 1, entry 23). To check the
influence of inert atmosphere, we performed a reaction under
argon atmosphere, which generated only 15% of the desired
product 4a, proving the importance of the atmosphere of air
for this reaction (Table 1, entry 24).
To extend the scope, the di(thiophen-2-yl)diselenide 3f was
reacted giving the desired compound 4f in 36% after 1.5 h
(Table 2, compound 4f). When we used dibutyl diselenide 3g
to give the desired product 4g, an unsatisfactory result was
obtained. The reaction was maintained for 2.0 h and furnished
Analyzing Table 1, we judge that the optimal reaction
condition to obtain the mono-arylselenylated pyrrole 4a is the
C
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a
Table 2. Reaction Scope for Synthesis of Mono-Organylselenylated Pyrroles 4a−p
a
Reaction conditions: amine 1a−j (0.6 mmol), 2,5-hexanedione 2a (0.6 mmol), diorganyl diselenide 3a−g (0.25 mmol), CuI (10 mol %) as
b
catalyst, in DMSO (2.0 mL) as solvent under US irradiation (60% of amplitude). The reaction progress was followed by TLC. The yield was
determined by H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
1
Scheme 3
D
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a
Table 3. Optimization of the Reaction Conditions for the One-Pot Synthesis of Compound 5a
entry
CuI (mol %)
time (h)
3a (mmol)
yield 4a (%)
yield 5a (%)
b
1
10
10
15
20
15
15
15
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.50
0.50
0.50
0.50
0.60
0.50
0.50
12
7
traces
traces
traces
6
79
79
91
89
86
84
83
2
3
4
5
b
6
c
7
8
a
Reactions were carried out with aniline 1a (0.5 mmol) and 2,5-hexanedione 2a (0.5 mmol), using DMSO (2.0 mL) as solvent under US
b
irradiation (60% of amplitude). The reaction progress was followed by TLC until the total consumption of the starting materials. Reaction
performed with 0.6 mmol of the aniline 1a and 0.6 mmol of the 2,5-hexanedione 2a. Reaction performed under ultrasound irradiation (80% of
c
amplitude).
an inseparable mixture of the 2,5-dimethyl-1-phenyl-1H-
pyrrole A and mono-selenylation product (Table 2, compound
diselenide 3a (0.5 mmol). Gratifyingly, after 1.0 h, the bis-
arylselenated product was obtained in 79% yield, however
together with the mono-arylselenylation product 4a (Table 3,
entry 1). A similar result was obtained when the amount of
aniline 1a and 2,5-hexanedione 2a was decreased to 0.5 mmol
(Table 3, entry 2). To our satisfaction, excellent results for the
selective synthesis of bis-selenylated pyrrole 5a were obtained
in reactions using 15 and 20 mol % of CuI, giving the product
5a in 91 and 89% yields, respectively (Table 3, entries 3 and
4). In these reactions, only traces of mono-selenylated pyrrole
4a were observed.
Additional tests were performed in reactions using 15 mol %
of catalyst, with different amounts of diphenyl diselenide 3a
and also of the starting materials 1a and 2a, however without a
substantial increment in the reaction yield (Table 3, entries 5
and 6 vs 3). Identical result was observed when the reaction
was realized under US irradiation with an amplitude of 80%
(Table 3, entry 7 vs 3).
Hence, the suitable conditions for the selective synthesis of
bis-selenylated pyrroles 5 were defined was follows: aniline 1a
(0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), diphenyl
diselenide 3a (0.5 mmol), CuI as a catalyst (15 mol %), and
2.0 mL of DMSO as solvent under US irradiation (60% of
amplitude), which could afford 5a in 91% yield.
The generality of this protocol was expanded for the
synthesis of different bis-selenylated pyrrole 5a−p. First, the
scope was extended to diorganyl diselenides containing
different electronic demands (3b−e), and according to our
results, reactions were not sensitive to electron-donating and
-withdrawing groups at the phenyl ring on the diselenide 3
(Table 4, compounds 5b−e).
4
g). This reaction was not maintained for a long time because
we noted a significant increase in byproduct formation.
In the next series of experiments, we extend the applicability
of the optimized reaction conditions to other substituted
anilines, benzylamine and butylamine. Thus, different sub-
stituted anilines were screened, and the electronic effects
presented an influence on the yield of mono-arylselenylated
pyrroles. For instance, substituted anilines having a 4-methoxy
(
1b) or a 4-methyl group (1c) provided better yields than
para-substituted anilines bearing clorine (1e) and fluorine (1g)
Table 2, compounds 4h-i vs 4k and 4m). In addition, it is
(
interesting to note that when substituents at the ortho-position
are evaluated in the substituted anilines 1d and 1f, moderated
yields of mono-arylselenylated pyrroles 4j and 4l were
obtained and when nitro substituent is used in the meta-
position of the aniline, the desired product 4n was obtained in
moderate yield (50%). We also examined the reactivity of the
butyl and benzylamine 1i and 1j, respectively, in this reaction,
and under the same reaction conditions, the desired products
4
o and 4p were obtained in satisfactory yields (56 and 79%,
respectively).
We try to extend the reaction scope to other dicarbonyl
compounds such as 1-(4-chlorophenyl)-4-phenylbutane-1,4-
dione 2b. Thus, a mixture of aniline 1a (0.5 mmol), dicarbonyl
compound 2b (0.5 mmol), diphenyl diselenide 3a (0.5 mmol),
CuI as a catalyst (15 mol %), and 2.0 mL of DMSO as solvent
was sonicated for 2.0 h under US irradiation (60% of
amplitude) (Scheme 3). In this reaction, we neither observed
the formation of desired selanylation products 4q or 4q′ nor
the formation of the Paal−Knorr condensation product. In this
reaction, all of the starting materials were recovered.
In all reactions performed, small amounts of bis-substituted
organylselanyl pyrroles were obtained. Thus, with the aim of
direct reaction for the selective formation of bis-selenylated
pyrroles 5, we turned our attention to optimize the reaction
conditions to these products (Table 3).
Additionally, when the di(thiophen-2-yl)diselenide 3f was
reacted under optimized conditions, the product 5f was
obtained in 31% yield after 3.5 h (Table 4, compound 5f). We
also used dibutyl diselenide 3g, and in this case, the reaction
did not occur satisfactorily. In the same way as the reaction for
the synthesis of mono-butylselenylated pyrrole 4g, we
maintained the reaction time of 2.0 h and obtained a mixture
1
In this sense, under the optimal conditions (Table 1, entry
of compounds A, 4g, and 5g. Analysis of H NMR showed the
2
2
3), we performed the reaction of aniline 1a (0.6 mmol) and
,5-hexanedione 2 (0.6 mmol) with an excess of diphenyl
formation of the bis-selenylation product 5g in 9% yield and
the mono-selenylated compound 4g in 19% yield. We
E
DOI: 10.1021/acs.joc.9b00405
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a
Table 4. Reaction Scope for Synthesis of Bis-Organylselenylated Pyrroles 5a−p
a
Reaction conditions: amine 1a−j (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), diorganyl diselenide 3a−g (0.5 mmol), CuI (15 mol %) as catalyst,
b
and DMSO (2.0 mL) as solvent under US irradiation (60% of amplitude). The reaction progress was followed by TLC. The yield was determined
by H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
1
attributed these poor results to the low reactivity of the dibutyl
diselenide 3g relative to the aryl analogues.
Good results were obtained using substituted anilines, and
this approach tolerates different electronic demands on the
aniline. When we used 4-anisidine 1b, the product 5h in was
obtained in 85% yield (Table 4, compound 5h). A similar
result was observed when para-toluidine 1c or ortho-toluidine
pyrroles were obtained in 68 and 75% yields, respectively
(Table 4, compounds 5o and 5p).
In addition, we also try to obtain nonsymmetric bis-
substituted products by the reaction of 2,5-dimethyl-1-phenyl-
3-(phenylselanyl)-1H-pyrrole 4a with 1,2-di-p-tolyldiselenide
3b or 1,2-bis(4-chlorophenyl)diselenide 3e under the previous
optimized conditions (Scheme 4). Thus, after 1.5 h of the
reaction between pyrrole 4a with diselenide 3b, an inseparable
mixture of compounds was obtained. The components of this
mixture and their ratio were identified by gas chromatog-
raphy−mass spectrometry (GC−MS) analyses, and the desired
nonsymmetric compound 5q was obtained in a ratio of 52%.
Surprisingly, the symmetric pyrroles 5a and 5b were also
obtained in ratios of 17 and 31%, respectively (Scheme 4). A
similar result was obtained in the reaction between pyrrole 4a
with diselenide 3e, giving the nonsymmetric bis-substituted
product 5r preferably (59%), however with the formation of
1
d were used, yielding products 5i and 5j in 90 and 95% yields,
respectively (Table 4, compounds 5i and 5j).
Reactions performed with 4-chloroaniline 1e and 4-
fluoroaniline 1g provided the respective products 5k and 5m
in 80 and 86% yields, whereas 2-chloroaniline 1f and 3-
nitroaniline 1h gave the products in moderated yields (50 and
5
5%, respectively) (Table 4, compounds 5l and 5n).
Inspired by the positive result of mono-arylselenylation
using butylamine 1i and benzylamine 1j, the reactions were
performed with these substrates and the bis-selenylated
F
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Scheme 4
Figure 2. Plausible mechanism of the reaction from synthesis of compounds 4 and 5.
the other symmetrical products 5a and 5e (ratios of 16 and
substituted organylselanyl pyrroles 4 instead of pyrrole A
2
5%, respectively) (Scheme 4).
Based on these results and previous reported studies,
(cycle II).
17f,g
we
believe that, first, the reaction between amine 1 and the 2,5-
hexanedione 2a generates the Paal−Knorr condensation
product (pyrrole A). In parallel, the interaction of CuI with
diorganyl diselenide 3 could occur, leading to the intermediate
B (Figure 2). After that, the nucleophilic attack of the pyrrole
A in the intermediate B delivers the intermediates C and D.
Subsequently, intermediate C loses a proton to form product 4,
releases the CuI to the catalytic cycle, giving the organylselenol
E, which was oxidized to diorganyl diselenide 3 (cycle I). For
the synthesis of bis-substituted organylselanyl pyrroles 5, the
catalytic cycle is almost the same, however starting from mono-
CONCLUSIONS
■
Summarizing, we developed a simple method for the direct
mono- and bis-organylselenylation of N-substituted pyrroles
through a multicomponent reaction promoted by ultrasonic
radiation. In this new copper(I)-catalyzed multicomponent
methodology, mono- or bis-substituted organylselanyl pyrroles
could be obtained in moderate to excellent yields starting from
primary amines, 2,5-hexanedione and diorganyl diselenides.
The selectivity of the products depends of the amount of
copper catalyst and diorganyl diselenide employed in the
reactions.
G
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2
,5-Dimethyl-1-phenyl-3-(phenylselanyl)-1H-pyrrole 4a. Yield:
EXPERIMENTAL SECTION
■
1
0
(
1
(
1
(
(
.131 g (80%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
General Information. The reactions were monitored by TLC
carried out on Merck silica gel (60 F254) by using UV light as
visualization agent and the mixture of 5% vanillin and 10% H SO
ppm) = 7.50−7.40 (m, 3H); 7.29−7.17 (m, 6H); 7.13−7.09 (m,
13 1
H); 6.102−6.10 (m, 1H); 2.09 (s, 3H); 2.04 (s, 3H). C{ H} NMR
2
4
CDCl , 100 MHz) δ (ppm) = 138.9, 135.0, 134.1, 130.0, 129.2,
3
under heating conditions as developing agents. Merck silica gel
77
28.9, 128.3, 128.1, 128.07, 125.2, 113.0, 100.6, 12.9, 12.2. Se NMR
CDCl , 76 MHz) δ (ppm) = 238.1. MS (rel. int., %) m/z: 327
34.7), 247 (100.0), 170 (16.1), 77 (28.9). HRMS (APCI-QTOF)
calculated mass for C H NSe [M + H] : 328.0604, found:
(
particle size 0.040−0.063 mm) was used for flash chromatography.
Hydrogen nuclear magnetic resonance ( H NMR) spectra were
obtained on a Bruker Avance III HD 400 spectrometer at 400 MHz.
1
3
+
1
8
17
The spectra were recorded in CDCl solutions. The chemical shifts
3
3
28.0614.
,5-Dimethyl-1-phenyl-3-(4-tolylselanyl)-1H-pyrrole 4b. Yield:
are reported in ppm, referenced to tetramethylsilane as the internal
reference. Coupling constants (J) are reported in hertz. Abbreviations
to denote the multiplicity of a particular signal are s (singlet), d
doublet), ddd (doublet of doublet of doublets), t (triplet), quint
quintet), sext (sextet), and m (multiplet). C NMR spectra were
obtained on a Bruker Avance III HD 400 spectrometer at 100 MHz.
The chemical shifts are reported in ppm, referenced to the solvent
peak of CDCl3. 77Se NMR spectra were obtained on a Bruker Avance
2
1
0
(
.097 g (57%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
ppm) = 7.43−7.32 (m, 3H); 7.16−7.11 (m, 4H); 6.95 (d, J = 7.9 Hz,
(
(
2
H); 6.02−6.01 (m, 1H); 2.20 (s, 3H); 2.01 (s, 3H); 1.95 (s, 3H).
1
3
13
1
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 138.9, 135.0, 133.8,
3
1
31.0, 129.7, 129.4, 129.2, 128.8, 128.1, 128.0, 112.9, 101.1, 20.9,
12.9, 12.2.
int., %) m/z: 341 (24.2), 261 (100.0), 170 (12.3), 77 (22.8). HRMS
APCI-QTOF) calculated mass for C H NSe [M + H] : 342.0761,
found: 342.0759.
3
c. Yield: 0.114 g (64%); yellowish oil. H NMR (CDCl , 400 MHz)
δ (ppm) = 7.41−7.32 (m, 3H); 7.20 (d, J = 8.6 Hz, 2H); 7.13 (d, J =
.4 Hz, 2H); 6.71 (d, J = 8.6 Hz, 2H); 6.00 (s, 1H); 3.68 (s, 3H);
.02 (s, 3H); 1.94 (s, 3H). C{ H} NMR (CDCl , 100 MHz) δ
ppm) = 158.1, 138.8, 133.4, 130.9, 129.3, 129.2, 128.1, 128.0, 124.6,
14.7, 112.7, 102.0, 55.3, 12.9, 12.2. Se NMR (CDCl , 76 MHz) δ
ppm) = 228.2. MS (rel. int., %) m/z: 357 (24.5), 277 (100.0), 170
9.9), 77 (21.0). HRMS (APCI-QTOF) calculated mass for
7
7
Se NMR (CDCl , 76 MHz) δ (ppm) = 232.1. MS (rel.
3
III HD 400 spectrometer at 76 MHz using CDCl as the solvent and
3
+
(
19 19
diphenyl diselenide as an internal standard. High-resolution electro-
spray ionization mass spectrometry analysis was performed on a
Bruker Daltonics micrOTOF-Q II instrument in positive mode. The
samples were solubilized in high-performance liquid chromatography-
grade acetonitrile and injected into the APCI source by means of a
syringe pump at a flow rate of 5.0 μL min . The following instrument
parameters were applied: capillary and cone voltages, +3500 and
500 V, respectively; desolvation temperature, 180 °C. For data
acquisition and processing, Compass 1.3 for micrOTOF-Q II software
Bruker Daltonics) was used. The data were collected in the m/z
range of 50−1200 at the speed of two scans per second. Low-
resolution mass spectra were obtained with a Shimadzu GC-MS-
QP2010 mass spectrometer. Melting point (mp) values were
measured in a Marte PFD III instrument with a 0.1 °C precision.
The ultrasound-promoted reactions were performed using a Cole
Parmer-ultrasonic processor Model CPX 130, with a maximum power
of 130 W, operating at an amplitude of 60% and a frequency of 20
kHz. The temperature of the reaction under US was monitored using
a Incoterm digital infrared thermometer Model Infraterm (Brazil).
General Procedure for Synthesis 2,5-Dimethyl-1-phenyl-
H-pyrrole A. Aniline 1a (0.093 g; 1.0 mmol), 2,5-hexanedione 2a
0.114 g; 1.0 mmol), and DMSO (2.0 mL) were added to a 10.0 mL
glass tube. An ultrasound probe was placed in the glass tube
containing the reaction mixture. The amplitude of the ultrasound
waves was fixed at 60%. Then, the reaction mixture was sonicated for
-[(4-Methoxyphenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole
1
4
3
7
2
(
1
(
(
−
1
13
1
3
−
7
7
3
(
+
C H NOSe [M + H] : 358.0710, found: 358.0708.
1
9
3
19
-[(4-Fluorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole
1
4
d. Yield: 0.095 g (55%); yellowish oil. H NMR (CDCl , 400 MHz)
3
δ (ppm) = 7.42−7.32 (m, 3H); 7.19−7.12 (m, 4H); 6.82 (t, J = 8.7
Hz, 2H); 6.00 (s, 1H); 2.00 (s, 3H); 1.95 (s, 3H). C{ H} NMR
CDCl , 100 MHz) δ (ppm) = 161.4 (d, J = 242.4 Hz), 138.7, 134.8
d, J = 8.0 Hz), 133.8, 130.3 (d, J = 7.4 Hz), 129.6, 129.2, 128.11,
28.07, 115.9 (d, J = 21.4 Hz), 112.8, 101.1, 12.8, 12.2. Se NMR
CDCl , 76 MHz) δ (ppm) = 236.6. MS (rel. int., %) m/z: 345
31.5), 265 (100.0), 170 (15.7), 77 (30.9). HRMS (APCI-QTOF)
calculated mass for C H FNSe [M + H] : 346.0510, found:
13
1
(
(
1
(
(
3
77
3
1
(
+
1
8
16
3
46.0511.
3
-[(4-Chlorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole
1
4
e. Yield: 0.088 g (49%); yellowish oil. H NMR (CDCl , 400 MHz)
3
δ (ppm) = 7.44−7.33 (m, 3H); 7.16−7.06 (m, 6H); 6.01−6.0 (m,
H); 2.00 (s, 3H); 1.96 (s, 3H). C{ H} NMR (CDCl , 100 MHz) δ
ppm) = 138.7, 134.1, 133.4, 131.1, 129.7, 129.6, 129.3, 128.9, 128.2,
28.1, 112.8, 100.4, 12.9, 12.2. Se NMR (CDCl , 76 MHz) δ (ppm)
241.0. MS (rel. int., %) m/z: 361 (46.9), 281 (100.0), 170 (25.5),
7 (44.9). HRMS (APCI-QTOF) calculated mass for C H ClNSe
M + H] : 362.0215, found: 362.0208.
2
1
0 min. The crude product obtained was subsequently purified by
column chromatography using hexane as eluent.
13
1
1
(
1
=
7
[
3
General Procedure for Synthesis of Mono-Organylseleny-
77
3
lated Pyrroles 4a−p. Amines 1a−j (0.6 mmol), 2,5-hexanedione 2a
(
0
0.068 g; 0.6 mmol), diselenides 3a−g (0.25 mmol), CuI (10 mol %,
1
8
16
.0095 g), and DMSO (2.0 mL) were added to a 10.0 mL glass tube.
+
An ultrasound probe was placed in the glass tube containing the
reaction mixture. The amplitude of the ultrasound waves was fixed at
0%. Then, the reaction mixture was sonicated for 0.5−3.0 h. The
crude product obtained was subsequently purified by column
chromatography using hexane as eluent.
General Procedure for Synthesis of Bis-Organylselenylated
Pyrroles 5a−p. Amines 1a−j (0.5 mmol), 2,5-hexanedione 2 (0.057
g; 0.5 mmol), diselenides 3a−g (0.5 mmol), CuI (15 mol %, 0.0142
g), and DMSO (2.0 mL) were added to a 10.0 mL glass tube. An
ultrasound probe was placed in the glass tube containing the reaction
mixture. The amplitude of the ultrasound waves was fixed at 60%.
Then, the reaction mixture was sonicated for 1.0−4.0 h. The crude
product obtained was subsequently purified by column chromatog-
raphy using hexane/ethyl acetate (99/1%) as eluent.
,5-Dimethyl-1-phenyl-3-(thiophen-2-ylselanyl)-1H-pyrrole 4f.
1
Yield: 0.060 g (36%); yellow solid, mp: 69−70 °C. H NMR
6
(
1
6
CDCl , 400 MHz) δ (ppm) = 7.47−7.38 (m, 3H); 7.27−7.26 (m,
3
H); 7.18−7.16 (m, 2H); 7.14−7.13 (m, 1H); 6.92−6.90 (m, 1H);
13 1
.11 (s, 1H); 2.16 (s, 3H); 1.98 (s, 3H). C{ H} NMR (CDCl , 100
3
MHz) δ (ppm) = 138.7, 132.8, 131.7, 129.2, 129.11, 129.08, 128.7,
28.1, 128.0, 127.7, 112.0, 103.8, 12.8, 12.3. Se NMR (CDCl , 76
MHz) δ (ppm) = 179.2. MS (rel. int., %) m/z: 333 (10.1), 253
68.1), 170 (11.5), 77 (100.0), 51 (54.7). HRMS (APCI-QTOF)
calculated mass for C H NSSe [M + H] : 334.0169, found:
34.0173.
3
7
7
1
3
(
+
16 15
3
-(Butylselanyl)-2,5-dimethyl-1-phenyl-1H-pyrrole 4g. Yield by
1
H NMR (14%); yellowish oil. Mixture of compounds 4g and pyrrole
A (ratio 1:3). Asterisk denotes the chemical shifts of the pyrrole A. H
1
Spectral Data of the Compounds. 2,5-Dimethyl-1-phenyl-1H-
2
2
1
pyrrole A. Yield: 0.164 g (96%); white solid, mp: 49−51 °C. H
NMR (CDCl , 400 MHz) δ (ppm) = 7.46−7.35 (m, 3H); 7.21−7.16
3
NMR (CDCl , 400 MHz) δ (ppm) = 7.46−7.35 (m, 3H); 7.21−7.18
(m, 2H); 6.04 (s, 1H); 5.90* (s, 2H); 2.65 (t, J = 7.4 Hz, 2H); 2.11
(s, 3H); 2.02* (s, 6H); 2.0 (s, 3H); 1.65 (quint, J = 7.4 Hz, 2H); 1.42
3
1
3
1
(
m, 2H); 5.90 (s, 2H); 2.03 (s, 6H). C{ H} NMR (CDCl , 100
3
1
3
1
MHz) δ (ppm) = 139.0, 129.0, 128.7, 128.2, 127.6, 105.6, 12.9. MS
(sext, J = 7.4 Hz, 2H); 0.90 (t, J = 7.4 Hz, 3H). C{ H} NMR
(
(
rel. int., %) m/z: 171 (86.2), 170 (100.0), 154 (15.6), 128 (11.8), 77
27.8), 51 (17.3).
(CDCl , 100 MHz) δ (ppm) = 139.0, 138.9*, 132.3, 129.0, 128.9*,
3
128.71, 128.65*, 128.2*, 128.1, 127.8, 127.5*, 112.5, 105.6*, 101.8,
H
DOI: 10.1021/acs.joc.9b00405
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
2.4, 28.8, 22.8, 13.6, 12.9*, 12.7, 12.3. 77Se NMR (CDCl , 76 MHz)
7.22−7.19 (m, 2H); 7.16−7.11 (m, 2H); 7.08−7.04 (m, 1H); 6.077−
3
1
3
1
δ (ppm) = 119.4. MS (rel. int., %) m/z: 307 (37.0), 250 (27.2), 171
100.0), 170 (83.2), 77 (25.9). HRMS (APCI-QTOF) calculated
6.075 (m, 1H); 2.05 (s, 3H); 1.99 (s, 3H). C{ H} NMR (CDCl ,
3
(
100 MHz) δ (ppm) = 148.7, 139.9, 134.4, 134.2, 133.7, 130.2, 129.3,
+
77
mass for C H NSe [M + H] : 308.0917, found: 308.0906.
129.0, 128.6, 125.5, 123.2, 123.0, 114.2, 102.4, 12.9, 12.3. Se NMR
16
21
1
-(4-Methoxyphenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole
(CDCl , 76 MHz) δ (ppm) = 240.9. MS (rel. int., %) m/z: 372
3
1
4
h. Yield: 0.164 g (92%); yellowish oil. H NMR (CDCl , 400 MHz)
3
(32.8), 292 (100.0), 215 (4.8), 122 (1.6), 77 (8.6). HRMS (APCI-
+
δ (ppm) = 7.20−7.17 (m, 2H); 7.13−7.00 (m, 5H); 6.92−6.88 (m,
QTOF) calculated mass for C H N O Se [M + H] : 373.0455,
1
8
16
2
2
2
H); 6.003−6.001 (m, 1H); 3.78 (s, 3H); 2.00 (s, 3H); 1.95 (s, 3H).
found: 373.0437.
13
1
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 159.1, 135.1, 134.3,
3
1-Butyl-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4o. Yield:
1
1
1
31.6, 129.8, 129.1, 128.8, 128.3, 125.1, 114.3, 112.7, 100.2, 55.5,
0.086 g (56%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
2.8, 12.2. 77Se NMR (CDCl , 76 MHz) δ (ppm) = 238.3. MS (rel.
3
(ppm) = 7.18−7.12 (m, 4H); 7.09−7.04 (m, 1H); 5.97 (s, 1H); 3.79
(t, J = 7.3 Hz, 2H); 2.28 (s, 3H); 2.23 (s, 3H); 1.62 (quint, J = 7.3
Hz, 2H); 1.37 (sext, J = 7.3 Hz, 2H); 0.96 (t, J = 7.3 Hz, 3H).
int., %) m/z: 357 (36.9), 277 (100.0), 200 (11.1), 107 (2.9), 77
12.7). HRMS (APCI-QTOF) calculated mass for C H NOSe [M
(
+
19 19
+
1
3
1
H] : 358.0710, found: 358.0706.
,5-Dimethyl-3-(phenylselanyl)-1-(4-tolyl)-1H-pyrrole 4i. Yield:
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 135.5, 132.8, 128.8,
3
2
77
1
28.1, 127.9, 124.9, 112.7, 99.4, 44.5, 32.9, 20.1, 13.8, 12.3, 11.4. Se
1
0
(
3
.142 g (83%); yellowish oil. H NMR (CDCl , 400 MHz) δ
ppm) = 7.20−7.18 (m, 4H); 7.12−7.09 (m, 2H); 7.04−7.00 (m,
H); 6.01 (s, 1H); 2.34 (s, 3H); 2.00 (s, 3H); 1.95 (s, 3H). C{ H}
NMR (CDCl , 100 MHz) δ (ppm) = 137.9, 136.2, 135.1, 134.1,
29.8, 129.5, 128.8, 128.3, 127.8, 125.1, 112.8, 100.3, 21.1, 12.9, 12.2.
Se NMR (CDCl , 76 MHz) δ (ppm) = 238.3. MS (rel. int., %) m/z:
41 (29.3), 261 (100.0), 184 (13.2), 91 (17.1), 77 (3.9). HRMS
APCI-QTOF) calculated mass for C H NSe [M + H] : 342.0761,
found: 342.0758.
2
3
NMR (CDCl , 76 MHz) δ (ppm) = 235.1. MS (rel. int., %) m/z: 307
3
(
67.9), 227 (79.4), 185 (63.8), 150 (10.0), 108 (100.0), 77 (13.4).
13 1
+
HRMS (APCI-QTOF) calculated mass for C H NSe [M + H] :
1
6
21
3
308.0917, found: 308.0920.
1
1
-Benzyl-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4p. Yield:
77
1
3
0.135 g (79%); colorless oil. H NMR (CDCl , 400 MHz) δ
3
3
(
(
ppm) = 7.33−7.14 (m, 7H); 7.10−7.06 (m, 1H); 6.90 (d, J = 7.4 Hz,
+
13 1
1
9
19
2H); 6.08 (s, 1H); 5.08 (s, 2H); 2.20 (s, 3H); 2.16 (s, 3H). C{ H}
NMR (CDCl , 100 MHz) δ (ppm) = 137.8, 135.4, 133.6, 128.8,
3
,5-Dimethyl-3-(phenylselanyl)-1-(2-tolyl)-1H-pyrrole 4j. Yield:
77
1
28.0, 127.2, 125.5, 125.0, 113.2, 100.1, 47.7, 12.3, 11.4. Se NMR
1
0
(
3
(
1
1
.107 g (63%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
(CDCl , 76 MHz) δ (ppm) = 236.4. MS (rel. int., %) m/z: 341
3
ppm) = 7.28−7.20 (m, 3H); 7.17−7.15 (m, 2H); 7.12−7.08 (m,
(
10.7), 261 (19.8), 170 (5.7), 91 (100.0), 77 (10.7). HRMS (APCI-
H); 7.04−6.99 (m, 1H); 6.044−6.042 (m, 1H); 1.90 (s, 3H); 1.89
+
QTOF) calculated mass for C H NSe [M + H] : 342.0761, found:
1
3
1
19 19
s, 3H); 1.86 (s, 3H). C{ H} NMR (CDCl , 100 MHz) δ (ppm) =
3
3
42.0755.
37.9, 136.7, 135.4, 133.7, 130.9, 129.0, 128.8, 128.7, 128.6, 127.9,
26.8, 125.0, 112.8, 100.1, 17.0, 12.4, 11.7. Se NMR (CDCl , 76
MHz) δ (ppm) = 236.0. MS (rel. int., %) m/z: 341 (41.1), 261
100.0), 184 (15.2), 91 (20.3), 77 (5.9). HRMS (APCI-QTOF)
calculated mass for C H NSe [M + H] : 342.0761, found:
2
,5-Dimethyl-1-phenyl-3,4-bis(phenylselanyl)-1H-pyrrole 5a.
7
7
1
3
Yield: 0.220 g (91%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
(
4
ppm) = 7.52−7.42 (m, 3H); 7.26−7.24 (m, 2H); 7.19−7.16 (m,
(
13 1
H); 7.11−7.02 (m, 6H); 2.17 (s, 6H). C{ H} NMR (CDCl , 100
+
3
1
9
19
MHz) δ (ppm) = 138.8, 135.4, 134.4, 129.4, 128.7, 128.67, 128.5,
1
3
42.0762.
-(4-Chlorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole
77
27.9, 125.2, 109.3, 13.3. Se NMR (CDCl , 76 MHz) δ (ppm) =
3
1
1
234.8. MS (rel. int., %) m/z: 483 (56.8), 326 (84.8), 246 (43.6), 170
14.2), 77 (100.0). HRMS (APCI-QTOF) calculated mass for
4
k. Yield: 0.108 g (60%); yellowish oil. H NMR (CDCl , 400 MHz)
3
(
δ (ppm) = 7.37−7.34 (m, 2H); 7.19−7.17 (m, 2H); 7.11−7.05 (m,
+
C H NSe [M] : 483.0004, found: 483.0010.
2
4
21
2
4
H); 7.03−6.99 (m, 1H); 6.01 (s, 1H); 1.99 (s, 3H); 1.94 (s, 3H).
13
1
2,5-Dimethyl-1-phenyl-3,4-bis(4-tolylselanyl)-1H-pyrrole 5b.
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 137.3, 134.8, 134.0,
3
1
Yield: 0.141 g (55%); yellow solid, mp: 86−88 °C. H NMR
7
7
1
33.8, 129.4, 129.3, 128.8, 128.4, 125.2, 113.4, 101.1, 12.8, 12.2. Se
NMR (CDCl , 76 MHz) δ (ppm) = 239.3. MS (rel. int., %) m/z: 361
43.1), 281 (100.0), 204 (10.0), 111 (21.0), 77 (8.7). HRMS (APCI-
QTOF) calculated mass for C H ClNSe [M + H] : 362.0215,
(
2
CDCl , 400 MHz) δ (ppm) = 7.41−7.31 (m, 3H); 7.14−7.12 (m,
3
3
H); 7.50 (d, J = 8.0 Hz, 4H); 6.81 (d, J = 8.0 Hz, 4H); 2.14 (s, 6H);
(
1
3
1
+
2.08 (s, 6H). C{ H} NMR (CDCl
, 100 MHz) δ (ppm) = 138.8,
3
1
8
16
1
1
35.0, 134.9, 130.5, 129.4, 129.3, 129.2, 128.4, 127.9, 109.7, 20.9,
found: 362.0208.
-(2-Chlorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole
7
7
3.2. Se NMR (CDCl , 76 MHz) δ (ppm) = 228.3. MS (rel. int., %)
3
1
1
m/z: 511 (57.6), 340 (100.0), 260 (38.1), 170 (12.2), 77 (67.0).
4
l. Yield: 0.090 g (50%); yellowish oil. H NMR (CDCl , 400 MHz)
3
+
HRMS (APCI-QTOF) calculated mass for C H NSe [M] :
2
6
25
2
δ (ppm) = 7.51−7.47 (m, 1H); 7.37−7.30 (m, 2H); 7.28−7.23 (m,
5
11.0317, found: 511.0343.
3,4-Bis[(4-methoxyphenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-
pyrrole 5c. Yield: 0.160 g (59%); yellowish solid, mp: 104−106 °C.
1
6
(
H); 7.18−7.15 (m, 2H); 7.12−7.09 (m, 2H); 7.04−7.00 (m, 1H);
13 1
.052−6.051 (m, 1H); 1.94 (s, 3H); 1.91 (s, 3H). C{ H} NMR
CDCl , 100 MHz) δ (ppm) = 136.6, 135.1, 134.3, 133.7, 130.4,
3
1
7
7
H NMR (CDCl
3
, 400 MHz) δ (ppm) = 7.41−7.32 (m, 3H); 7.18−
1
30.0, 129.4, 128.9, 127.9, 127.7, 125.0, 113.1, 100.6, 12.4, 11.7. Se
NMR (CDCl , 76 MHz) δ (ppm) = 236.7. MS (rel. int., %) m/z: 361
59.0), 281 (100.0), 204 (17.9), 111 (24.1), 77 (18.3). HRMS
APCI-QTOF) calculated mass for C H ClNSe [M + H] :
7.12 (m, 2H); 7.07 (d, J = 8.5 Hz, 4H); 6.56 (d, J = 8.5 Hz, 4H); 3.63
3
1
3
1
(s, 6H); 2.09 (s, 6H). C{ H} NMR (CDCl , 100 MHz) δ (ppm) =
(
(
3
3
+
158.0, 138.8, 134.7, 131.4, 129.3, 128.4, 127.9, 124.2, 114.4, 110.4,
1
8
16
7
7
5
5.1, 13.2. Se NMR (CDCl , 76 MHz) δ (ppm) = 222.7. MS (rel.
62.0215, found: 362.0205.
-(4-Fluorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole
3
int., %) m/z: 543 (49.7), 356 (100.0), 276 (28.9), 170 (8.2), 77
1
1
4
m. Yield: 0.114 g (66%); yellowish oil. H NMR (CDCl , 400 MHz)
(63.6). HRMS (APCI-QTOF) calculated mass for C26
[M] : 543.0216, found: 543.0217.
H
25NO
2
Se
2
3
+
δ (ppm) = 7.19−7.17 (m, 2H); 7.12−6.98 (m, 7H); 6.005−6.003 (m,
H); 1.98 (s, 3H); 1.93 (s, 3H). C{ H} NMR (CDCl , 100 MHz) δ
ppm) = 162.0 (d, J = 246.6 Hz), 134.9, 134.8 (d, J = 3.2 Hz), 134.0,
29.7 (d, J = 8.6 Hz), 129.5, 128.8, 128.3, 125.2, 116.1 (d, J = 22.6
Hz), 113.1, 100.8, 12.8, 12.1. Se NMR (CDCl , 76 MHz) δ (ppm)
239.0. MS (rel. int., %) m/z: 345 (35.0), 265 (100.0), 188 (17.6),
5 (25.4), 77 (3.6). HRMS (APCI-QTOF) calculated mass for
C H FNSe [M + H] : 346.0510, found: 346.0508.
8
1
3
1
1
(
1
3,4-Bis[(4-fluorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyr-
3
1
role 5d. Yield: 0.117 g (45%); yellowish solid, mp: 118−120 °C. H
NMR (CDCl , 400 MHz) δ (ppm) = 7.43−4.34 (m, 3H); 7.16−7.14
3
7
7
(
m, 2H); 7.06−7.03 (m, 4H); 6.70 (t, J = 8.8 Hz, 4H); 2.09 (s, 6H).
3
1
3
1
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 161.4 (d, J = 243.0
=
9
3
Hz), 138.6, 135.4, 130.9 (d, J = 7.6 Hz), 129.5, 128.6, 128.5 (d, J =
+
77
2.3 Hz), 127.9, 115.7 (d, J = 21.5 Hz), 109.7, 13.2. Se NMR
1
16
2
,5-Dimethyl-1-(3-nitrophenyl)-3-(phenylselanyl)-1H-pyrrole 4n.
(CDCl , 76 MHz) δ (ppm) = 232.2. MS (rel. int., %) m/z: 519
3
1
Yield: 0.093 g (50%); yellow oil. H NMR (CDCl , 400 MHz) δ
ppm) = 8.24 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H); 8.07 (t, J = 2.1 Hz,
H); 7.63 (t, J = 8.1 Hz, 1H); 7.52 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H);
(67.4), 344 (95.0), 264 (47.8), 170 (14.4), 77 (100.0). HRMS
3
+
(
1
(APCI-QTOF) calculated mass for C H F NSe [M] : 518.9816,
2
4
19
2
2
found: 518.9814.
I
DOI: 10.1021/acs.joc.9b00405
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
,4-Bis[(4-chlorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyr-
m/z: 517 (70.8), 360 (100.0), 280 (29.2), 204 (13.2), 111 (49.5), 77
1
role 5e. Yield: 0.138 g (50%); yellowish solid, mp: 135−137 °C. H
(16.7). HRMS (APCI-QTOF) calculated mass for C H ClNSe
24
20
2
+
NMR (CDCl , 400 MHz) δ (ppm) = 7.47−7.37 (m, 3H); 7.19−7.16
[M] : 516.9615, found: 516.9626.
1-(2-Chlorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyr-
3
1
3
1
(
m, 2H); 7.00−6.95 (m, 8H); 2.10 (s, 6H). C{ H} NMR (CDCl ,
3
1
1
1
2
00 MHz) δ (ppm) = 138.6, 135.7, 132.5, 131.4, 130.2, 129.5, 128.75,
role 5l. Yield: 0.129 g (50%); yellowish oil. H NMR (CDCl
, 400
3
7
7
28.69, 127.9, 109.1, 13.2. Se NMR (CDCl , 76 MHz) δ (ppm) =
37.5. MS (rel. int., %) m/z: 551 (52.1), 360 (46.2), 325 (100.0), 280
15.9), 170 (10.5), 77 (80.0). HRMS (APCI-QTOF) calculated mass
for C H Cl NSe [M] : 550.9225, found: 550.9216.
MHz) δ (ppm) = 7.54−7.49 (m, 1H); 7.40−7.28 (m, 3H); 7.10−7.05
3
1
3
1
(m, 4H); 7.03−6.95 (m, 6H); 2.04 (s, 6H). C{ H} NMR (CDCl
,
3
(
100 MHz) δ (ppm) = 136.6, 135.5, 134.4, 133.5, 130.5, 130.4, 130.1,
128.7, 128.4, 127.9, 125.1, 109.3, 12.8. Se NMR (CDCl , 76 MHz)
3
+
77
24
19
2
2
2
,5-Dimethyl-1-phenyl-3,4-bis(thiophen-2-ylselanyl)-1H-pyrrole
δ (ppm) = 233.8. MS (rel. int., %) m/z: 517 (73.3), 360 (100.0), 280
1
5
(
7
5
f. Yield: 0.077 g (31%); yellow oil. H NMR (CDCl , 400 MHz) δ
(32.7), 204 (13.9), 111 (40.0), 77 (23.4). HRMS (APCI-QTOF)
3
+
ppm) = 7.48−7.39 (m, 3H); 7.21 (dd, J = 5.2 and 1.1 Hz, 2H);
calculated mass for C H ClNSe [M] : 516.9615, found: 516.9617.
2
4
20
2
.17−7.14 (m, 2H); 7.12 (dd, J = 3.5 and 1.1 Hz, 2H); 6.86 (dd, J =
1-(4-Fluorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyr-
1
3
1
1
.2 and 3.5 Hz, 2H); 2.20 (s, 6H). C{ H} NMR (CDCl , 100
role 5m. Yield: 0.215 g (86%); yellowish oil. H NMR (CDCl
, 400
3
3
MHz) δ (ppm) = 138.6, 134.4, 132.0, 129.34, 129.30, 128.5, 128.4,
28.0, 127.5, 111.1, 13.2. Se NMR (CDCl , 76 MHz) δ (ppm) =
69.1. MS (rel. int., %) m/z: 495 (5.6), 332 (17.8), 252 (28.8), 77
100.0). HRMS (APCI-QTOF) calculated mass for C H NS Se
MHz) δ (ppm) = 7.10−7.02 (m, 8H); 6.98−6.90 (m, 6H); 2.05 (s,
7
7
13
1
1
1
(
[
6H). C{ H} NMR (CDCl
, 100 MHz) δ (ppm) = 162.1 (d, J =
3
3
247.3 Hz), 135.3, 134.6 (d, J = 3.2 Hz), 134.2, 129.6 (d, J = 8.6 Hz),
7
7
128.7, 128.6, 125.2, 116.3 (d, J = 22.5 Hz), 109.5, 13.2. Se NMR
2
0
17
2
2
+
(
(
CDCl , 76 MHz) δ (ppm) = 235.8. MS (rel. int., %) m/z: 501
M + H] : 495.9211, found: 495.9201.
,4-Bis(butylselanyl)-2,5-dimethyl-1-phenyl-1H-pyrrole 5g. Yield
3
70.3), 344 (100.0), 264 (45.6), 188 (16.8), 95 (69.7), 77 (14.3).
3
+
1
HRMS (APCI-QTOF) calculated mass for C H FNSe [M] :
by H NMR (9%); yellowish oil. Mixture of compounds 4g, 5g, and
pyrrole A (ratio 5:2:2). Asterisk denotes the chemical shifts of the
24 20
2
5
00.9910, found: 500.9924.
2
,5-Dimethyl-1-(3-nitrophenyl)-3,4-bis(phenylselanyl)-1H-pyr-
pyrrole A. Double asterisk denotes the chemical shifts of the
1
1
role 5n. Yield: 0.145 g (55%); yellow solid, mp: 93−95 °C. H NMR
compound 4g. H NMR (CDCl , 400 MHz) δ (ppm) = 7.48−7.37
3
(CDCl , 400 MHz) δ (ppm) = 8.21 (ddd, J = 8.1, 2.1 and 1.1 Hz,
(
m, 3H); 7.21−7.18 (m, 2H); 6.03** (s, 1H); 5.90* (s, 2H); 2.70 (t,
3
1
8
H); 8.07 (t, J = 2.1 Hz, 1H); 7.60 (t, J = 8.1 Hz, 1H); 7.51 (ddd, J =
.1, 2.1 and 1.1 Hz, 1H); 7.10−7.07 (m, 4H); 7.02−6.94 (m, 6H);
J = 7.4 Hz, 4H); 2.65** (t, J = 7.4 Hz, 2H); 2.16 (s, 6H); 2.10** (s,
3
(
(
1
1
2
(
4
H); 2.03* (s, 6H); 2.0** (s, 3H); 1.68−1.57 (m, 2H); 1.47−1.37
1
3
1
1
3
1
2.11 (s, 6H). C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 148.6,
3
m, 2H); 0.92−0.88 (m, 3H). C{ H} NMR (CDCl , 100 MHz) δ
3
1
1
39.7, 135.0, 134.0, 133.8, 130.4, 128.9, 128.7, 125.5, 123.4, 123.0,
ppm) = 139.2, 139.0**, 138.9*, 133.5, 132.3**, 129.2, 129.1**,
7
7
10.8, 13.3. Se NMR (CDCl , 76 MHz) δ (ppm) = 238.1. MS (rel.
3
29.0*, 128.73**, 128.68*, 128.2*, 128.1**, 128.0, 127.8**, 127.5*,
int., %) m/z: 528 (70.4), 371 (100.0), 291 (18.8), 215 (10.0), 122
12.5**, 109.2, 105.6*, 101.8**, 32.5**, 32.2, 29.1, 28.9**, 22.9,
7
7
(0.9), 77 (32.4). HRMS (APCI-QTOF) calculated mass for
2.8**, 13.64, 13.61**, 13.2, 12.9*, 12.8**, 12.3**. Se NMR
CDCl , 76 MHz) δ (ppm) = 119.3**, 110.7. MS (rel. int., %) m/z:
+
C H N O Se [M] : 527.9855, found: 527.9861.
2
4
20
2
2
2
3
1
-Butyl-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5o.
43 (49.2), 305 (26.0), 250 (70.2), 171 (100.0), 170 (56.4), 77
37.5). HRMS (APCI-QTOF) calculated mass for C H NSe [M] :
1
+
Yield: 0.157 g (68%); yellowish oil. H NMR (CDCl
, 400 MHz) δ
3
(
4
20 29 2
(
1
ppm) = 7.09−6.98 (m, 10H); 3.87 (t, J = 7.4 Hz, 2H); 2.37 (s, 6H);
43.0630, found: 443.0650.
-(4-Methoxyphenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-
.65 (quint, J = 7.4 Hz, 2H); 1.38 (sext, J = 7.4 Hz, 2H); 0.97 (t, J =
1
13 1
1
7.4 Hz, 3H). C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 134.8,
1
pyrrole 5h. Yield: 0.218 g (85%); yellowish oil. H NMR (CDCl ,
3
3
77
34.1, 128.5, 128.3, 125.0, 108.5, 45.6, 32.7, 20.0, 13.8, 12.5. Se
4
6
00 MHz) δ (ppm) = 7.08−7.05 (m, 4H); 7.05−7.01 (m, 2H);
NMR (CDCl , 76 MHz) δ (ppm) = 231.8. MS (rel. int., %) m/z: 463
3
.98−6.89 (m, 6H); 6.88−6.84 (m, 2H); 3.70 (s, 3H); 2.06 (s, 6H).
13
1
(70.4), 306 (100.0), 226 (19.2), 150 (8.7), 108 (10.2), 77 (22.7).
C{ H} NMR (CDCl , 100 MHz) δ (ppm) = 159.3, 135.6, 134.4,
3
+
7
7
HRMS (APCI-QTOF) calculated mass for C22
63.0317, found: 463.0333.
-Benzyl-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5p.
H
25NSe
2
[M] :
1
(
(
31.3, 128.8, 128.6, 128.58, 125.1, 114.4, 108.8, 55.4, 13.2. Se NMR
CDCl , 76 MHz) δ (ppm) = 234.8. MS (rel. int., %) m/z: 513
63.7), 356 (100.0), 276 (28.5), 200 (11.1), 107 (12.1), 77 (40.8).
HRMS (APCI-QTOF) calculated mass for C H NOSe [M] :
4
3
1
1
+
Yield: 0.186 g (75%); white solid, mp: 114−115 °C. H NMR
2
5
23
2
(
1
CDCl , 400 MHz) δ (ppm) = 7.35−7.25 (m, 3H); 7.13−7.01 (m,
3
5
13.0110, found: 513.0125.
,5-Dimethyl-3,4-bis(phenylselanyl)-1-(4-tolyl)-1H-pyrrole 5i.
13 1
0H); 6.91 (d, J = 7.3 Hz, 2H); 5.18 (s, 2H); 2.31 (s, 6H). C{ H}
2
1
NMR (CDCl
28.6, 128.4, 127.5, 125.5, 125.1, 109.3, 48.9, 12.5. Se NMR
CDCl , 76 MHz) δ (ppm) = 233.4. MS (rel. int., %) m/z: 497 (9.5),
3
, 100 MHz) δ (ppm) = 137.1, 135.0, 134.7, 128.9,
Yield: 0.224 g (90%); yellowish oil. H NMR (CDCl , 400 MHz) δ
77
3
1
(
(
1
ppm) = 7.22−7.18 (m, 2H); 7.10−6.94 (m, 12H); 2.35 (s, 3H); 2.09
(
s, 6H). 13C{1H} NMR (CDCl , 100 MHz) δ (ppm) = 138.5, 136.2,
3
3
3
40 (10.1), 260 (1.4), 91 (100.0), 77 (4.9). HRMS (APCI-QTOF)
7
7
35.5, 134.5, 130.0, 128.7, 128.66, 127.6, 125.2, 109.0, 21.2, 13.3. Se
NMR (CDCl , 76 MHz) δ (ppm) = 234.5. MS (rel. int., %) m/z: 497
64.1), 340 (100.0), 260 (39.2), 184 (12.5), 91 (57.4), 77 (12.4).
HRMS (APCI-QTOF) calculated mass for C H NSe [M] :
+
calculated mass for C H NSe [M + H] : 498.0239, found:
2
5
23
2
3
498.0238.
(
+
2
5
23
2
4
97.0161, found: 497.0176.
,5-Dimethyl-3,4-bis(phenylselanyl)-1-(2-tolyl)-1H-pyrrole 5j.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00405.
■
2
S
1
*
Yield: 0.236 g (95%); yellowish oil. H NMR (CDCl , 400 MHz) δ
3
(
6
ppm) = 7.28−7.18 (m, 3H); 7.10−7.05 (m, 5H); 7.00−6.91 (m,
13 1
H); 1.97 (s, 6H); 1.90 (s, 3H). C{ H} NMR (CDCl , 100 MHz) δ
3
(
1
=
ppm) = 137.8, 136.1, 134.9, 134.6, 131.0, 129.0, 128.6, 128.3, 128.2,
1H, 13C{ H}, and 77Se NMR spectra of all compounds
1
7
7
27.0, 125.1, 108.9, 17.0, 12.7. Se NMR (CDCl , 76 MHz) δ (ppm)
3
(PDF)
233.1. MS (rel. int., %) m/z: 497 (69.4), 340 (100.0), 260 (35.7),
1
84 (13.9), 91 (57.7), 77 (16.4). HRMS (APCI-QTOF) calculated
+
mass for C H NSe [M] : 497.0161, found: 497.0171.
25
23
2
1
-(4-Chlorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyr-
AUTHOR INFORMATION
■
*
1
role 5k. Yield: 0.207 g (80%); yellowish oil. H NMR (CDCl , 400
3
Corresponding Authors
E-mail: gelson_perin@ufpel.edu.br (G.P.).
*E-mail: diego.alves@ufpel.edu.br. Tel/Fax: +55 5332757533
(D.A.).
MHz) δ (ppm) = 7.42−7.38 (m, 2H); 7.14−7.08 (m, 6H); 7.03−6.95
m, 6H); 2.09 (s, 6H). C{ H} NMR (CDCl , 100 MHz) δ (ppm) =
1
3
1
(
1
1
3
37.2, 135.2, 134.5, 134.2, 129.7, 129.2, 128.8, 128.7, 125.3, 109.8,
3.3. 77Se NMR (CDCl , 76 MHz) δ (ppm) = 236.0. MS (rel. int., %)
3
J
DOI: 10.1021/acs.joc.9b00405
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ORCID
(8) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P.
Pyrrole: A resourceful small molecule in key medicinal hetero-
aromatics. RSC Adv. 2015, 5, 15233.
Thiago Barcellos: 0000-0001-9872-4602
Diego Alves: 0000-0002-1074-0294
Notes
(
9) (a) Knorr, L. Einwirkung des diacetbernsteinsau
ammoniak und primare aminbasen. Ber. Dtsch. Chem. Ges. 1885, 18,
99. (b) Paal, C. Synthese von thiophen- und pyrrolderivaten. Ber.
Dtsch. Chem. Ges. 1885, 18, 367.
10) (a) Aghapoor, K.; Mohsenzadeh, F.; Darabi, H. R.; Rastgar, S.
̈
reesters auf
̈
2
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
Microwave-induced calcium(II) chloride-catalyzed Paal−Knorr pyr-
role synthesis: A safe, expeditious, and sustainable protocol. Res.
Chem. Intermed. 2018, 44, 4063. (b) Liu, Y.; Hu, Y. L. Novel and
highly efficient preparation of pyrroles using supported ionic liquid
ILCF SO @SiO as a heterogeneous catalyst. J. Iran. Chem. Soc. 2018,
The authors are grateful for the financial support and
scholarships from the Brazilian agencies CNPq and FAPERGS
(
PRONEM 16/2551-0000240-1). CNPq is also acknowledged
for the fellowship for G.P. and D.A. This study was partially
financed by the Coordenaca de Aperfeicoamento de Pessoal
3
3
2
1
5, 1033. (c) Wozniak, B.; Li, Y.; Hinze, S.; Tin, S.; Vries, J. G.
Efficient synthesis of biomass-derived N-substituted 2-hydroxymethyl-
-methyl-pyrroles in two steps from 5-hydroxymethylfurfural. Eur. J.
̧
o
̃
̧
de Nivel SuperiorBrasil (CAPES)Finance Code 001.
5
Org. Chem. 2018, 2009. (d) Wu, X.; Zhao, P.; Geng, X.; Wang, C.;
Wu, Y.-D.; Wu, A.-X. Synthesis of pyrrole-2-carbaldehyde derivatives
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