Copper-Promoted Regioselective Synthesis of Polysubstituted Pyrroles from Aldehydes, Amines, and Nitroalkenes via 1,2-Phenyl/Alkyl Migration

Article abstract of DOI:10.1021/acs.joc.7b03051

The facile copper-catalyzed synthesis of polysubstituted pyrroles from aldehydes, amines, and β-nitroalkenes is reported. Remarkably, the use of α-methyl-substituted aldehydes provides efficient access to a series of tetra- and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration. The present methodology is also accessible to non α-substituted aldehydes, yielding the corresponding trisubstituted pyrroles. On the contrary, the use of ketones, in place of aldehydes, does not promote the organic transformation, signifying the necessity of α-substituted aldehydes. The reaction proceeds under mild catalytic conditions with low catalyst loading (0.3-1 mol %), a broad scope, very good functional-group tolerance, and high yields and can be easily scaled up to more than 3 mmol of product, thus highlighting a useful synthetic application of the present catalytic protocol. Based on formal kinetic studies, a possible radical pathway is proposed that involves the formation of an allylic nitrogen radical intermediate, which in turn reacts with the nitroalkene to yield the desired pyrrole framework via a radical 1,2-phenyl or alkyl migration.

Full text of DOI:10.1021/acs.joc.7b03051

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Article
Copper-promoted regioselective synthesis of polysubstituted pyrroles
from aldehydes, amines and nitroalkenes via 1,2-phenyl/alkyl migration
Dimitrios Andreou, Michael G. Kallitsakis, Edward Loukopoulos,
Catherine Gabriel, George E Kostakis, and Ioannis N. Lykakis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03051 • Publication Date (Web): 22 Jan 2018
Downloaded from http://pubs.acs.org on January 22, 2018
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CopperꢀPromoted Regioselective Synthesis of
Polysubstituted Pyrroles from Aldehydes, Amines
and Nitroalkenes via1,2ꢀPhenyl/Alkyl Migration
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Dimitrios Andreou,† Michael G. Kallitsakis,† Edward Loukopoulos, ‡ Catherine Gabriel, §
George E. Kostakis,*,‡ and Ioannis N. Lykakis*,†
†Department of Chemistry, Aristotle University of Thessaloniki, University Campus,
Thessaloniki 54124, Greece; lykakis@chem.auth.gr
§Center for Research of the Structure of Matter, Magnetic Resonance Laboratory, Department of
Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
‡Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN19QJ,
United Kingdom; G.Kostakis@sussex.ac.uk
KEYWORDS: Copper catalysis • 1,2ꢀmigration • pyrroles • nitrostyrenes • αꢀmethyl substituted
aldehydes
ABSTRACT: The facile Copperꢀcatalyzed synthesis of polysubstituted pyrroles from aldehydes,
amines and βꢀnitroalkenesis reported. Remarkably, the use of αꢀmethyl substituted aldehydes
provide efficient access to a series of tetraꢀ and pentasubstituted pyrroles via an overwhelming
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1,2ꢀphenyl/alkyl migration. The present methodology is also accessible to non αꢀsubstituted
aldehydes yielding the corresponding trisubstituted pyrroles. On the contrary, the use of ketones,
in place of aldehydes, does not promote the organic transformation signifying the necessity of αꢀ
substituted aldehydes. The reaction proceeds under mild catalytic conditions with low catalyst
loading (0.3 – 1 mol %), a broad scope, very good functionalꢀgroup tolerance, high yields and
can be easily scaled up to more than 3 mmol of product, thus highlighting a useful synthetic
application of the present catalytic protocol. Based on formal kinetic studies, a possible radical
pathway is proposed that involves the formation of an allylic nitrogen radical intermediate,
which in turn reacts with the nitroalkene to yield the desired pyrrole framework via a radical 1,2ꢀ
phenyl or alkyl migration.
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INTRODUCTION
Pyrroles represent one of the most important fiveꢀmembered Nꢀcontaining heterocyclic
scaffolds and key structural cores in natural products with bioactive and therapeutic properties.1
Several synthetic strategies including the wellꢀknown Hantzsch, Knorr, and PaalꢀKnorr synthesis
have been developed to harvest the pyrrole framework.2 At present, emphasis is given on the
development of 3d transition metal based catalysts as well multicomponent reactions (MCRs) for
high atom economy, bondꢀforming efficiency as well minimization of waste, time, and cost.2,3
An interesting approach towards the synthesis of pyrroles is based on MCRs incorporating βꢀ
nitrostyrenes; the latter are versatile electrophiles and have extensively been used in heterocycle
synthesis.4,5 To date, four methodologies report the use of the nitrostyrene scaffold to produce
pyrroles; the CrobꢀCamenisch includes βꢀenaminoꢀcarbonyl compounds as key intermediates
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(Scheme 1, i),6,7 the BartonꢀZard incorporates the formation of αꢀisocyanide carbonyl enolate
(Scheme 1, ii),8 the “Lego method” uses βꢀbromo nitrostyrenes under enamine catalysis (Scheme
1, iii)9 and the [3+2] cycloaddition protocol of azomethineylide intermediates with nitrostyrenes
(Scheme 1, iv).10 Consequently, the efficient and versatile synthesis of polyꢀsubstituted pyrroles,
by easily accessible precursors, wide diversity and precise introduction of substituents into a
certain position on the pyrrole ring, remains a great challenge.
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Our groups have developed successful protocols for organic transformations promoted by a
family of one dimensional (1D) Copper based coordination polymers (CPs).11 These CPs are
made from commercial available starting materials, in two steps and excellent yields and
promote the chemical transformations with catalyst loadings of one order of magnitude lower
when compared to metal salts, in better yields and, most importantly, absence of byꢀproducts.11
Herein, we employ this catalytic library in the MCR of αꢀsubstituted aldehydes, amines and βꢀ
nitroalkenes (Scheme 1, v) that yields polysubstituted pyrroles in a fast and regioselective
manner via an 1,2ꢀphenyl/alkyl migration. Notwithstanding, few similar MCR protocols have
been reported, however our current methodology has significant variations and benefits. For
12a
example, the MCR studies that involved aldehydes or cycloketones, promoted by Sm(OiꢀPr)3
or in absence of catalyst,12b required multistep and stepwise protocol with imine formation and
isolation,12a as well as showed limited applicability.12b Moreover, the use of silica gel13a or
alumina13b under microwave conditions or the molten ammonium salt13c promote the pyrrole
formation, however only a limited variation of 2ꢀmethyl or 2ꢀethyl substituted pyrroles can be
produced starting with the corresponding βꢀmethyl or ethyl substituted nitroalkenes.
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Scheme 1. Procedures for Pyrroles Synthesis Starting from Nitroalkenes.
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RESULTS AND DISCUSSIONS
The present catalytic protocol involves the reaction of 2ꢀphenyl propionaldehyde (1), butyl
amine (BuNH2), and (E)ꢀ1ꢀmethylꢀ4ꢀ(2ꢀnitrovinyl)benzene (2), catalyzed by various copper
[Cu(II) and Cu(I)] salts (see Table 1) and the recently reported CPs formulated
[M(II)(L)2(Z)2]·2(ClO4)·2MeCN (M=Cu, Z=MeCN, Cu-1), [Cu(II)(L)2(NO3)2] (Cu-2),
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[Cu(II)(L)2(MeCN)2]·2BF4
(Cu-3),
[Cu(II)(L)2(OTf)2]
(Cu-4),
L
is
1ꢀ{2ꢀ
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[(1Hbenzo[d][1,2,3]triazolꢀ1ꢀyl)methyl]benzyl}1Hbenzoꢀ[d][1,2,3]triazole.11 The reaction is
carried out into a sealed tube with equimolar amounts of 1, BuNH2 and 2 in 1 mL of MeOH at 80
oC for 1h. The alcoholic media promotes this transformation and MeOH gives the optimum
results (screening tests in Tables S1). Under these conditions, Cu salts consume 2 in full, but
show low or medium activity towards the synthesis of pyrrole 3 (Table 1, entries 1ꢀ10), as
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1
observed by H NMR of the crude mixtures (Table 1). In all cases, two byꢀproducts were
observed; acetophenone (1a) that is formed via an oxidative transformation from 1 (Figure S1),14
and pꢀtolualdehyde (2a) that is produced via a nitromethane elimination from the Michael
addition of the butylamine to nitroalkene 2 (Figure S2).15,16 In these Cuꢀcatalyzed reactions, the
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relative yields of pyrrole 3 and byꢀproducts (1a and 2a) were determined by the H NMR
spectrum after filtration of the crude mixture on a short pad of silica in order to remove the
catalyst (Figure S3). Only Cu(OAc)2, CuI and [Cu(CH3CN)4]BF4 promote the formation of 3 in
moderate yields 49%, 59% and 55%, respectively (Table 1, entries 2, 9 and 10); however, 20
mol% loading is required. Other Lewis acids, such as Sm(iOPr)3, AuCl3, AgNO3, Zn(ClO4)2 and
Zn(NO3)2 showed poor catalytic performance under the present conditions (Table S2). Also, the
reaction of 1, butyl amine and 2 in the presence of molten ammonium salt did not yield the
corresponding pyrrole 3.13c The use of Cu-1 ꢀ Cu-4, in only 1 mol% loadings, give 3 in
significantly increased yields (Table 1, entries 13 – 16) when compared to metal salts (Table 1,
entries 1 – 10). Cu-4 showcases superior behavior, with 89% yield (Table 1, entry 16). The use
of 20 mol% of Cu(OTf)2 and 20 mol% ligand L yields 3 in 45% yield (Table 1, entry 12),
slightly higher when compared with Cu(OTf)2 (38% yield, Table 1, entry 4). In the later two
1
cases, a significant amount of the two byꢀproducts 1a and 2a was identified by the crude H
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NMR after filtration over a small pad of silica. In addition, control experiments in which 20
mol% of Cu-4 and 1 mol% of CuI were performed. In the first case, the corresponding pyrrole 3
was formed in a faster manner (ca. 20min) with 80% relative yield, although a significant
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amount (13%) of unidentified products was observed by H NMR of the crude reaction mixture
(Table 1, entry 17). In contrary, in the latter case, 3 was formed in only 31%, accompanying with
26% and 13% relative yields of the byꢀproducts 1a and 2a, respectively (result not shown).
These results support the efficiency of the Cu-4 as catalyst with one order of magnitude less
loading compared to the corresponding salt (1 mol%), as well as highlights the need of a wellꢀ
defined and characterized catalyst for this process. Notably, in the absence of catalyst, 3 is
formed in only 25% yield along with significant amounts of the byꢀproducts 1a and 2a (Table 1,
entry 11). Further, the use of aniline and 4ꢀmethoxyaniline result in a mixture of unidentified
products; whereas no reaction was observed in the presence of benzaldehyde or pꢀtolualdehyde
(Figures S4 and S5).
Table 1. Catalyst Evaluations of Pyrrole 3 from 2-Phenyl Propionaldehyde 1, BuNH2 and
Nitrostyrene 2
Entry
Catalysta
Conversion (%)b
Relative yields (%)c
3
1a
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2a
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Cu(NO3)2 3H2O
Cu(OAc)2 H2O
Cu(ClO4)2 6H2O
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100
80
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Cu(OTf)2
Cu(BF4)2
CuSO4 5H2O
CuBr2
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CuI
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11d
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Cu-1
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Cu-2
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Cu-3
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Cu-4
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Cu-4
aConditions: 1 (0.2 mmol), BuNH2 (0.2 mmol), 2 (0.2 mmol), MeOH (1 mL), at
refluxfor 1h. The Cu salts were used in 20% mol, however Cu-1 – Cu-4 were
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used in 1mol%, based on 2 amount. Based on the consumption of 2 determined
1
c
from the crude H NMR mixture of the reaction. Relative yields determined by
1H NMR of the crude mixture. In the case of Cuꢀsalts catalyzed reactions,
significant amounts of unidentified products were observed by 1H NMR (see also
Figure S3). dA significant amount of the corresponding imine 2b formed from the
reaction between 1 and BuNH2 remain intact and observed by 1H NMR spectrum
e
of the crude mixture. 20 mol% ligand L (benzotriazole) was added into the
f
reaction mixture. The Cu-4 was used in 20% mol and significant amount of
1
unidentified products (13%) was observed by H NMR within 20 min (not
shown).
Herein the formation of 3 proceeds via a 1,2ꢀphenyl migration,17 a process that is not
previously observed;12,13 thus the scope and limitations of this reaction were explored with
respect to the aldehyde moiety. Ιn this context, 2ꢀphenyl propionaldehyde (1) was initially used
with a variety of amines (alkyl or benzyl) and nitroalkenes (aryl or alkyl) and the results are
shown in Figure 1. Interestingly, the corresponding 1,2,3,4ꢀtetrasubstituted pyrroles (3 ꢀ 15) were
isolated in high yields. The pyrroles were characterized by HRMS and NMR spectroscopy,
although their structures were determined by 1D NOEꢀNMR experiments, indicating that the
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phenyl group is located at the Cꢀ2 position of the pyrrole ring. The pyrrole derivatives 6 and 7
were characterized by single Xꢀray diffraction (Figures S6 and S7). It is worth noting that the use
of aliphatic nitroalkenes (isopropyl and cyclohexyl derivatives) leads to the corresponding
pyrroles 14 and 15 in good isolated yields, 78% and 83% respectively (Figure 1), results that
support the general applicability of the present methodology.
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Figure 1. Cu-Catalyzed Synthesis of 1,2,3,4-Tetrasubstituted Pyrroles from 2-Phenyl
Propionaldehyde (1), Amines and Nitroalkenes.
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To expand the scope of this methodology, αꢀalkyl substituted aliphatic aldehydes, such as 2ꢀ
methyl butyraldehyde (R1 = Et) and 2ꢀmethyl propionaldehyde (R1 = Me), were employed with a
variety of amines and nitroalkenes. As shown in Figure 2, the corresponding pyrroles (16 ꢀ 27)
were formed as major products in good to high isolated yields (75% ꢀ 90%), regardless of the
nature of amine and nitroalkene. The values in parentheses show the isolated yields of the
corresponding pyrroles, as well as the appropriate time for reaction completion based on TLC
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analysis. In all cases, an analogous 1,2ꢀmethyl and 1,2ꢀethyl migration was observed to further
support the potential of this protocol for the selective synthesis of polysubstituted pyrroles.
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Figure 2. Cu-Catalyzed Synthesis of Various 1,2,3,4-Tetrasubstituted Pyrroles from α-
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Methyl Substituted Aliphatic Aldehydes, Amines and Nitroalkenes
It is interesting that under the present methodology even the use of βꢀmethyl substituted
nitrostyrenes, such as (E)ꢀ(2ꢀnitropropꢀ1ꢀenꢀ1ꢀyl)benzene and (E)ꢀ1ꢀmethylꢀ4ꢀ(2ꢀnitropropꢀ1ꢀenꢀ
1ꢀyl)benzene, yields the corresponding pentasubstituted pyrroles (28 ꢀ 32) in high isolated yields
in the range of 80% ꢀ 87% (Figure 3). On the contrary, αꢀmethyl substituted nitrostyrene, (1ꢀ
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nitropropꢀ1ꢀenꢀ2ꢀyl)benzene, degrades to the byꢀproduct acetophenone 1a, as shown in Figure
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S8.
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Figure 3. Cu-Catalyzed Synthesis of Pentasubstituted Pyrroles Starting with β-Methyl
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Substituted Nitrostyrenes
The general applicability of the present Cuꢀcatalytic system (Cu-4) was verified by
performing reaction between non αꢀalkyl substituted aldehydes, such as 3ꢀmethylbutanal (R3 = iꢀ
Pr), pentanal (R3 = Pr), 3ꢀphenyl propionaldehyde (R3 = PhCH2) or phenylacetaldehyde (R3 =
Ph), with BuNH2 or benzyl amine and a series of βꢀnitrostyrenes. As shown in Figure 4, in all
cases the corresponding 1,3,4ꢀtrisubstituted pyrroles 33 ꢀ 41 were formed in good to high isolated
yield 67% – 90%. Based on these promising results, the Cu-4 catalyst was further used for
possible largerꢀscale production of pyrrole. Thus, a reaction with 3 mmol of nitrostyrene 2, 3
mmol of aldehyde 1, 3 mmol of BuNH2 and Cu-4 (0.3 mol %) in 10 mL MeOH, was performed.
After reaction completion (~3 h based on TLC analysis), the corresponding pyrrole 3 was
isolated in 71% yield. This result corresponds to a high turnover number (TON) of 237 as
measured from the ratio of product 3 (mmol) / Cu-4 (mmol), and turnover frequency (TOF)
value of 79 hꢀ1.
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Figure 4. Synthesis of 1,3,4-Trisubstituted Pyrroles under Cu-Catalyzed Conditions
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Regarding the reaction mechanism, we observed the following:
a) The reaction, under N2 saturated solution, proceeds with similar conversion and relative
product yield of 3 (87%). However, under O2 saturated solution, a significant decrease in the
yield of the pyrrole 3 (35%) and increase in the yield of the corresponding degradation product
acetophenone 1a, in ca. 30% relative yield, were observed (Table S1, entries 2 and 3). Also, the
use of 50 mol% of TEMPO decreases the reaction conversion to 90% and the relative yield of 3
to 37% (Table S1, entry 4). These results support the predominance of a radical pathway,
although a plausible Lewis acid mediated reaction pathway cannot be excluded (Scheme 3).18
b) The use of 3ꢀpropiophenone (1’) in place of 2ꢀphenyl propionaldehyde 1, did not yield the
expected pyrrole 3 (Scheme 2). In addition, the use of 3ꢀpentanone, propiophenone or
acetophenone, in place of 1, did not promote the transformation (Scheme 2). These observations
may exclude the use of ketones as starting carbonyl compounds and support the necessity of αꢀ
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substituted aldehydes towards the convenient synthesis of polysubstituted pyrroles. Probably, a
transient slowly formation of the corresponding enamine can be an explanation of the observed
incompatibility of using ketones as starting materials.
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c) The use of other conjugated compounds, such as transꢀmethyl cinnamate, in place of βꢀ
nitrostyrene 2, showed no reactivity under the present conditions (Scheme 2). However, the use
of methyl propiolate or dimethyl acetylene dicarboxylate (DMAD),19 instead of βꢀnitrostyrene 2,
yield a mixture of unidentified products (Scheme 2). These results indicate the necessity of the
conjugated nitroalkenes for the pyrrole synthesis.
d) The inꢀsitu mixture of equivalent amounts of ligand L (20% mol) and Cu(OTf)2 (20% mol)
in the given reaction slightly increases the relative yield of pyrrole 3 to 45% (from 38% in
absence of L), whereas the formation of other byꢀproducts is observed. In addition, This result
indicates that the use of the wellꢀcharacterized catalyst, i.e. Cu-4 in such low loading 1%, in
which the Cu center has a preꢀdetermined octahedral (N4O2) geometry, provides, in high yields,
the catalytically active specie (we envisage this to be the CuIIL(TfO)2, see text below and Figure
S9 and precludes the, inꢀsitu, formation of other nonꢀcatalytically active CuxLy species (not
shown).
e) Finally, the nature of the protic solvent has a significant role to the reaction process. MeOH
promotes the catalytic reaction in a faster and selective manner when compared to EtOH or
tBuOH (Table S1). Interestingly, a significant increase of pyrrole 3 relative yield (51%) was
observed when the reaction was carried out in CF3CH2OH as solvent, compared to EtOH, in
which a 22% of 3 was measured. These results support the reaction promotion by the alcoholic
media, as well as dependence on the pyrrole 3 relative yield and the different pKa values of the
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alcoholic solvents was observed.20 In addition, experiment in CF3CH2OH and in the absence of
catalyst (Cu-4) gave a lower relative yield of 3 (35%) with significant amounts of the byꢀ
products 1a (21%) and 2a (14%) and the remain imine 2b (25%) (Table S1). This result confirms
the catalytic enhancement of the present synthetic methodology. However, the use of CF3CH2OH
as solvent is not recommended for environmental and costing reasons.
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Scheme 2. Substrate Evaluation for the Cu(II)-Catalyzed Synthesis of Pyrroles
Regarding the active catalytic species, taking into account: i) the ESIꢀMS spectra of Cu-4 (see
Figure S10 for its structure) in methanolic solution shows the presence of various speciation, ii)
the partial dissociation of the ligand (L) from the coordination sphere of the Cu center; observed
1
in the crude HꢀNMR spectra when higher loadings of Cu-4 were involved, iii) the
crystallographic characterization of the “deꢀactivated” catalyst, formulated as Cu(I)LCl2 in
previous studies,11a iv) the significant decrease in the yield of the pyrrole formation (Table 1
entry 13) when Cu-3 is used in which the coordination geometry of the Cu(II) center and the
anion are different when compared with Cu-4, v) the reversible Cu(II)L2(OTf)2↔ Cu(I)L2(OTf)
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behavior as observed in cyclic voltammetry studies,11b and vi) other reports in which organic
transformations are promoted from the suggested tetrasubstituted CuN2X2 species,21 we envisage
that [Cu(II)L(TfO)2] (Figure S9) might be the catalytically active specie.11,22 Efforts to isolate as
well crystallographically and spectroscopically characterize other derivatives of the catalyst Cu-
4 are in progress.
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Based on these observations, we propose that the first step involves the formation of the imine
from the aldehyde and amine. Then, the imine probably tautomerizes to the corresponding
enamine, which in turn reacts with the active species of the catalyst (Scheme 3). Ligand
exchange with enamine yields the amino–Cu(II) intermediate A, which is in equilibrium with the
nitrogen radical B and the Cu(I) complex C.21,23 In the presence of the βꢀnitrostyrene (excellent
radical acceptor), the nitrogen radical B couples with the double bond, generating the
intermediate D, which in turn is transformed into the desired cycloꢀintermediate E through a
proton elimination/1,2ꢀphenyl migration cyclization process. The reactions under the O2
saturated solution and in the presence of TEMPO probably prevent the formation of this radical
intermediate leading to the degradation product acetophenone 1a in significant amount, as
described above. Finally, after the HNO and H2O elimination and the Cuꢀcatalyst regeneration,
intermediate E converts to the desired pyrrole (Scheme 3). A similar Nꢀradical intermediate
mechanism was proposed in the Cu(II) promoted coupling reactions between vinyl arenes and
anilines, as well as intramolecular alkene oxidative amination for the synthesis of indoles.23
Further mechanistic studies to support the present proposed catalytic mechanism are in progress
using different mono nuclear Cu(II) and Cu(I) complexes as well as deuterium labeled organic
starting materials.
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Scheme 3. Proposed Mechanism for the Cu(II)-Catalyzed Reaction of α-Methyl Substituted
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Aldehydes, Amines and Nitrostyrenes Towards Pyrrole Synthesis.
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NO2
NO2
BuNH2
BuNH2
Ph
Ph
Ph
Me
Me
Ph
Me
Cu-4 (1%mol)
Cu-4 (1%mol)
O
Ph
Ph
N
O
MeOH, reflux
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MeOH, reflux
1
1'
Bu
pyrrole
Me
O
Ph
1
Cu(II)L2(TfO)2
-L MeOH
-H2O
Me
BuNH2
N
Cu(II)L(TfO)2
Me
Me Cu(II)L(TfO)
H
N
N
Ph
Bu
Ph
Bu
Ph
Bu
-TfO-
A
O
N
OH
Ar
H
Ar
Me
Ph
Me
N
Cu(I)L(TfO)
Bu
Cu(II)L(TfO)
O
Ph
N
N
C
B
OH
Bu
D
proton elimination
1,2-Ph migration
aromatization
-HNO, -H2O
Ar
Ar
Me
Ph
Me
O
Cu(II)L(TfO)
-TfO-
N
OH
Ph
N
N
Bu
Bu
pyrrole
Cu(II)L(TfO)2
E
CONCLUSIONS
In conclusion, the oneꢀpot Copper(II) catalyzed regioselective protocol of polysubstituted
pyrroles from commercial available βꢀnitroalkenes, αꢀalkyl substituted aldehydes and amines is
been presented. The reaction proceeds under mild catalytic conditions with low catalyst loading
(0.3 ꢀ 1mol %), a broad scope, very good functionalꢀgroup tolerance and can be easily scaled up.
The access to a wide range of triꢀ, tetraꢀ or pentasubstituted pyrroles, via an overwhelming 1,2ꢀ
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phenyl/alkyl migration, dependent on the aldehyde moiety, represents, the exceptional prospect
of this synthetic protocol and to the best of our knowledge this opportunity was not feasible
before. The use of ketones, in place of αꢀalkyl substituted aldehydes, does not promote the
transformation showcasing the necessity of the use of αꢀsubstituted aldehydes in the present
catalytic conditions. From the mechanistic point of view, a possible radical pathway is proposed
including the formation of a nitrogen radical intermediate, which in turn reacts with the
nitroalkene to yield the desired pyrrole.
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EXPERIMENTAL SECTION
General: Chemicals (reagent grade) were purchased from SigmaꢀAldrich, Acros Organics,
and Alfa Aesar. Materials and solvents were used with no further purification. Safety note:
perchlorate salts are potentially explosive; such compounds should be used in small quantities
and handled with caution and utmost care at all times.
Preparation of catalysts: Ligand L and compounds Cu-1 – Cu-4 were synthesized according
to the reported procedure.11
Catalytic procedure for the synthesis of pyrroles: To a sealed tube containing equimolar
amounts of the aldehyde (0.2 mmol) and the tube containing equimolar amounts of the aldehyde
(0.2 mmol) and the amine (0.2 mmol) in methanol (1 mL), 0.2 mmol of the nitroalkene and 1
mol% of the catalyst were added and the mixture was stirred at reflux for the appropriate time.
After reaction completion (monitored by TLC), the slurry was filtered through a short pad of
Celite and silica gel to withhold the catalyst using MeOH (~5 mL) as an eluent. The solvent was
then evaporated under vacuum and the residue was separated by column chromatography using
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silica gel and the mixture solvent hexane/EtOAc = from 50/1 to 20/1 as eluent, to give the
corresponding pyrrole in pure form. It is worth noting that, electron rich polysubstituted pyrroles
are unstable molecules during the chromatographic purification procedure. For this reason,
neutralized silica (with the addition of a few drops of triethylamine in the eluent solvent mixture)
was used for the column chromatography, as well as pretreated CDCl3 with K2CO3 was used for
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accomplished the NMR spectra. Product analysis was conducted by H NMR and C NMR
spectroscopy (Agilent AM 500). Mass spectra were determined on an electrospray ionization
mass spectrometry (ESIꢀMS), by using a ThermoFisher Scientific (Bremen, Germany) model
LTQ Orbitrap Discovery MS, at a flow rate of 10 ꢁL/min using syringe pump. The infusion
experiments were run using a standard ESI source operating in a positive ionization mode.
o
Source operating conditions were a 3.7 kV spray voltage and a 300 C heated capillary
temperature. LCMSꢀ2010 EV Instrument (Shimadzu) under Electrospray Ionization (ESI)
conditions and on a MS EV AutospecFissins instrument (EI at 70eV) were also used for the mass
determination.
Synthesis of aromatic β-nitrostyrenes: Aromatic βꢀnitrostyrenes were synthesized according
to the literature procedure.24 To a solution of ammonium acetate (12.5 mmol) in acetic acid (10
mL), pꢀsubstituted benzaldehyde (5 mmol) and nitromethane (15.5 mmol) were added in one
portion. The mixture was heated at reflux for 4 hours. The reaction mixture was cooled at room
temperature and then poured into iceꢀwater to precipitate the corresponding nitrostyrene. After
extraction with organic solvent (EtOAc) the organic layer was evaporated under vacuum and the
residue was purified by column chromatography using silica gel, to give final the corresponding
products in 55ꢀ72% yields.
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Synthesis of (E)-1-methyl-4-(2-nitroprop-1-en-1-yl)benzene: (E)ꢀ1ꢀmethylꢀ4ꢀ(2ꢀnitropropꢀ
1ꢀenꢀ1ꢀyl)benzene was synthesized according to the literature procedure.24 To a solution of
ammonium acetate (12.5 mmol) in acetic acid (10 mL), pꢀtolualdehyde (5 mmol) and nitroethane
(15.5 mmol) were added. The mixture was heated at reflux for 4 hours. The reaction mixture was
cooled at room temperature and then poured into iceꢀwater to form the solid mixture of product
that was isolated by filtration through a short path of silica. The organic solvent was then
evaporated under vacuum and the residue was separated by column chromatography using silica
gel to give the corresponding product in 59% yield.
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Synthesis of (E)-(1-nitroprop-1-en-2-yl)benzene: (E)ꢀ(1ꢀnitropropꢀ1ꢀenꢀ2ꢀyl)benzene was
synthesized according to the literature procedure.25 To a sealed tube charged with molecular
sieves, DCE (5 mL), αꢀmethyl styrene (2 mmol), silver nitrite (3 mmol) and TEMPO (1 mmol)
were added in one portion. The mixture was heated at 70 °C for 12 hours. The reaction mixture
was cooled at room temperature and filtered through a short pad of Celite with ethyl acetate as
eluent. The organic solvent was then evaporated under vacuum and the residue was separated by
column chromatography using silica gel to give the corresponding product in 80% yield.
Synthesis of aliphatic nitroalkenes: Aliphatic nitroalkenes were synthesized according to
the literature procedure.26 Το a solution of aliphatic aldehyde (5 mmol) and nitromethane (5
mmol) in methanol (4 mL), a solution of sodium hydroxide (6 mmol) in iceꢀwater (2 mL) was
added dropwise at 0 °C. External 2 mL of methanol were added into the above reaction mixture
and stirred at 0 °C for 1 hour. Then water was added and the mixture was acidified with
concentrated hydrochloric acid. The aqueous mixture was extracted with DCM (10 mL x3) and
the combined organic layers were dried over sodium sulfate. The organic solvent was then
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evaporated under vacuum and the residue was separated by column chromatography using silica
gel to give the corresponding products in pure form in 35ꢀ65% yields.
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1ꢀbutylꢀ3ꢀmethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (3): colorless oil (54 mg, 89% yield). H
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NMR (500 MHz, CDCl3): 7.46 – 7.43 (m, 2H), 7.40 – 7.35 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H),
6.83 (s, 1H), 3.81 (t, J = 7.4 Hz, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.63 – 1.57 (m, 2H), 1.25 – 1.18
13
(m, 2H), 0.82 (t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3): 134.7, 133.7, 132.9, 131.9,
130.6, 129.0, 128.2, 127.6, 127.0, 123.9, 118.4, 114.4, 46.9, 33.5, 21.1, 19.8, 13.6, 11.3. HRMS
(ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C22H26N 304.2060; found 304.2047.
1
1ꢀbutylꢀ3ꢀmethylꢀ2,4ꢀdiphenylꢀ1Hꢀpyrrole (4): colorless oil (51 mg, 88% yield). H NMR
(500 MHz, CDCl3): 7.49 (d, J = 7.3 Hz, 2H), 7.46 – 7.43 (m, 2H), 7.39 – 7.35 (m, 5H), 7.22 (t, J
= 7.3 Hz, 1H), 6.86 (s, 1H), 3.82 (t, J = 7.4 Hz, 2H), 2.14 (s, 3H), 1.63 – 1.57 (m, 2H), 1.26 –
1.18 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): 136.7, 132.9, 132.1, 130.6,
128.3, 128.2, 127.7, 127.1, 125.2, 124.0, 118.6, 114.4, 46.9, 33.5, 19.8, 13.6, 11.3. HRMS
(ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C21H24N 290.1903; found 290.1891.
1ꢀbutylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrrole (5): colorless oil (58 mg, 90%
1
yield). H NMR (500 MHz, CDCl3): 7.46 – 7.32 (m, 9H), 6.83 (s, 1H), 3.80 (t, J = 7.3 Hz, 2H),
13
2.10 (s, 3H), 1.61 – 1.57 (m, 2H), 1.24 – 1.17 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H). C NMR (125
MHz, CDCl3): 135.2, 132.7, 132.3, 130.9, 130.6, 128.8, 128.4, 128.3, 127.2, 122.9, 118.6, 114.3,
46.9, 33.5, 19.8, 13.6, 11.3. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C21H23ClN
324.1514/326.1484; found 324.1509/326.1482.
1ꢀbenzylꢀ3ꢀmethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (6): white crystals (60 mg, 89% yield),
mp. 142ꢀ144. 1H NMR (500 MHz, CDCl3): 7.40 – 7.38 (m, 4H), 7.34 – 7.22 (m, 6H), 7.19 (d, J
= 7.9 Hz, 2H), 7.03 (d, J = 7.0 Hz, 2H), 6.82 (s, 1H), 5.02 (s, 2H), 2.38 (s, 3H), 2.18 (s, 3H). 13C
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NMR (125 MHz, CDCl3): 138.6, 134.9, 133.5, 132.6, 132.5, 130.7, 129.0, 128.5, 128.2, 127.6,
127.23, 127.16, 126.8, 124.7, 119.2, 114.8, 50.8, 21.1, 11.4. HRMS (ESI/LTQ Orbitrap) m/z: [M
+ H]+ calcd for C25H24N 338.1903; found 338.1889.
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1ꢀbenzylꢀ4ꢀ(4ꢀbromophenyl)ꢀ3ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrrole (7): white crystals (70 mg, 87%
1
yield). H NMR (500 MHz, CDCl3): 7.47 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.36 –
7.32 (m, 3H), 7.30 – 7.26 (m, 5H), 7.01 (d, J = 7.5 Hz, 2H), 6.82 (s, 1H), 5.00 (s, 2H), 2.14 (s,
3H). 13C NMR (125 MHz, CDCl3): 138.5, 135.5, 132.9, 132.4, 131.4, 130.7, 129.3, 128.6, 128.4,
127.5, 127.4, 126.9, 123.7, 119.3, 119.2, 110.1, 50.9, 11.4. HRMS (ESI/LTQ Orbitrap) m/z: [M
+ H]+ calcd for C24H21BrN 402.0857/404.0837; found 401.0841/403.0823.
1ꢀisopropylꢀ3ꢀmethylꢀ2,4ꢀdiphenylꢀ1Hꢀpyrrole (8): colorless oil (48 mg, 87% yield). 1H NMR
(500 MHz, CDCl3): 7.51 (d, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.40 – 7.35 (m, 5H), 7.22
(t, J = 7.3 Hz, 1H), 6.95 (s, 1H), 4.30 (sept, J = 6.7 Hz, 1H), 2.13 (s, 3H), 1.38 (d, J = 6.7 Hz,
13
6H). C NMR (125 MHz, CDCl3): 136.8, 133.0, 131.8, 130.8, 128.3 (2C), 127.6, 127.1, 125.2,
124.4, 114.2, 114.0, 47.3, 24.0, 11.2. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for
C20H22N 276.1747; found 276.1736.
3ꢀmethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1ꢀ(4,4,4ꢀtrifluorobutyl)ꢀ1Hꢀpyrrole (9): colorless oil (32 mg,
89% yield). 1H NMR (500 MHz, CDCl3): 7.47 (t, J = 7.6 Hz, 2H), 7.42 ꢀ7.37 (m, 3H), 7.37 ꢀ7.34
(m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.81 (s, 1H), 3.93 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H), 2.14 (s,
13
3H), 1.96ꢀ1.85 (m, 2H), 1.86ꢀ1.78 (m, 2H). C NMR (125 MHz, CDCl3): 135.1, 133.5, 132.0,
130.6, 129.4, 129.1, 128.7 (q, J = 288.2 Hz), 128.5, 128.2, 127.7, 127.4, 118.4, 115.4, 45.9, 30.9
(q, J = 29.3 Hz), 23.8 (q, J = 3.0 Hz), 21.1, 11.3. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+
calcd for C22H23F3N 358.1742; found 358.1728.
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1ꢀcyclopentylꢀ3ꢀmethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (10): colorless oil (53 mg, 84%
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yield). H NMR (500 MHz, CDCl3): 7.46 (t, J = 7.6 Hz, 2H), 7.40 – 7.35 (m, 5H), 7.20 (d, J =
7
8
7.8 Hz, 2H), 6.91 (s, 1H), 4.40 (p, J = 7.6 Hz, 1H), 2.38 (s, 3H), 2.12 (s, 3H), 2.06 – 2.02 (m,
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2H), 1.87 – 1.84 (m, 4H), 1.59 (brs, 2H). C NMR (125 MHz, CDCl3): 134.7, 133.8, 133.2,
132.4, 130.8, 129.0, 128.2, 127.6, 127.1, 124.4, 114.5, 114.0, 57.2, 34.3, 24.4, 21.1, 11.2. HRMS
(ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C23H26N 316.2060; found 316.2045.
1
3ꢀmethylꢀ2ꢀphenylꢀ1ꢀpropylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (11): colorless oil (26 mg, 89% yield). H
NMR (500 MHz, CDCl3): 7.46 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.40ꢀ7.35 (m, 3H),
7.22 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 3.79 (t, J = 7.4 Hz, 2H), 2.40 (s, 3H), 2.16 (s, 3H), 1.69ꢀ
1.61 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): 134.7, 133.1, 132.0, 130.7,
129.3, 129.0, 128.2, 127.7, 127.0, 124.0, 118.5, 114.5, 48.9, 24.6, 21.1, 11.3, 11.2. HRMS
(ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C21H24N 290.1864; found 290.1856.
4ꢀ(4ꢀfluorophenyl)ꢀ3ꢀmethylꢀ2ꢀphenylꢀ1ꢀpropylꢀ1Hꢀpyrrole (12): colorless oil (25 mg, 86%
1
yield). H NMR (500 MHz, CDCl3): 7.48ꢀ7.41 (m, 4H), 7.36ꢀ7.32 (m, 3H), 7.06 (t, J = 8.7 Hz,
2H), 6.81 (s, 1H), 3.77 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.68ꢀ1.60 (m, 2H), 0.81 (t, J = 7.5 Hz,
13
3H). C NMR (125 MHz, CDCl3): 161.2 (d, J = 243.2 Hz), 133.0, 132.8 (d,J = 3.2 Hz), 130.7,
129.1 (d, J = 7.7 Hz), 128.3, 127.2, 123.2, 118.5, 115.1 (d, J = 21.0 Hz), 115.0, 114.4, 110.0,
48.9, 24.7, 11.2 (2). HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C20H21FN: 294.1613;
found 293.1608.
4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ2ꢀphenylꢀ1ꢀpropylꢀ1Hꢀpyrrole (13): colorless oil (24 mg, 79%
yield). 1H NMR (500 MHz, CDCl3): 7.43 (t, J = 7.1 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.36ꢀ7.32
(m, 3H), 6.93 (d, J = 8.5 Hz, 2H), 6.79 (s, 1H), 3.84 (s, 3H), 3.77 (t, J = 7.0 Hz, 2H), 2.11 (s,
13
3H), 1.68ꢀ1.59 (m, 2H), 0.81 (t, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl3): 161.5, 133.2,
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130.7, 129.4, 129.1, 128.9, 128.3, 128.2, 127.1, 118.2, 113.9, 110.1, 55.3, 48.9, 24.7, 11.3 (2).
HRMS (ESI/LTQ Orbitrap) m/z: [M + Η]+ calcd for C21H24NO 306.2850; found 305.2843.
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1ꢀbutylꢀ4ꢀisopropylꢀ3ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrrole (14): colorless oil (40 mg, 78% yield). H
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NMR (500 MHz, CDCl3): 7.40 (t, J = 7.4 Hz, 2H), 7.32 – 7.29 (m, 3H), 6.48 (s, 1H), 3.73 (t, J =
7.4 Hz, 2H), 2.86 (sept, J = 6.8 Hz, 1H), 1.99 (s, 3H), 1.60 – 1.54 (m, 2H), 1.24 (d, J = 6.8 Hz,
13
6H), 1.22 – 1.16 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3): 133.2, 130.8,
130.5, 129.6, 128.1, 126.6, 115.7, 114.5, 46.7, 33.6, 25.4, 23.6, 19.9, 13.7, 10.0. HRMS
(ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C18H26N 256.1823; found 256.1810.
1ꢀbutylꢀ4ꢀcyclohexylꢀ3ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrrole (15): colorless oil (49 mg, 83% yield). 1H
NMR (500 MHz, CDCl3): 7.41 (t, J = 7.5 Hz, 2H), 7.31 – 7.30 (m, 3H), 6.46 (s, 1H), 3.74 (t, J =
7.4 Hz, 2H), 2.48 – 2.44 (m, 1H), 2.02 (s, 2H), 1.99 (s, 3H), 1.82 (d, J = 12.6 Hz, 2H), 1.75 (d, J
= 12.6 Hz, 1H), 1.60 – 1.54 (m, 2H), 1.45 – 1.25 (m, 5H), 1.24 – 1.16 (m, 2H), 0.82 (t, J = 7.4
Hz, 3H).13C NMR (125 MHz, CDCl3): 133.3, 130.6, 130.5, 128.9, 128.0, 126.6, 116.0, 114.5,
46.7, 35.6, 34.3, 33.6, 27.1, 26.5, 19.9, 13.7, 10.0. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+
calcd for C21H30N 296.2373; found 296.2359.
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1ꢀbutylꢀ2ꢀethylꢀ3ꢀmethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (16): colorless oil (45 mg, 88% yield). H
NMR (500 MHz, CDCl3): 7.31 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 3.80 (t,
J = 7.5 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.15 (s, 3H), 1.78 – 1.72 (m, 2H), 1.44 –
13
1.36 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3):
134.6, 134.2, 131.7, 129.1, 127.8, 123.5, 116.7, 112.0, 46.5, 34.0, 21.2, 20.3, 17.7, 14.9, 14.0,
10.6. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C18H26N 256.2060; found 256.2054.
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1ꢀbutylꢀ2ꢀethylꢀ3ꢀmethylꢀ4ꢀphenylꢀ1Hꢀpyrrole (17): colorless oil (41 mg, 86% yield). H
NMR (500 MHz, CDCl3): 7.42 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.4 Hz,
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1H), 6.66 (s, 1H), 3.81 (t, J= 7.4 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 2.16 (s, 3H), 1.78 – 1.72 (m,
2H), 1.44 – 1.36 (m, 2H), 1.17 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz,
CDCl3): 137.0, 131.7, 128.2, 127.7, 125.0, 123.4, 116.8, 111.9, 46.3, 33.8, 20.2, 17.6, 14.8, 13.8,
10.5. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H24N 242.1903; found 242.1892.
1ꢀbutylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2ꢀethylꢀ3ꢀmethylꢀ1Hꢀpyrrole (18): colorless oil (45 mg, 81%
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yield). H NMR (500 MHz, CDCl3): 7.33 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.64 (s,
1H), 3.80 (t, J = 7.5 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1.77 – 1.71 (m, 2H), 1.43 –
13
1.35 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3):
135.5, 131.9, 130.6, 128.7, 128.3, 122.3, 116.9, 111.8, 46.4, 33.8, 20.1, 17.5, 14.7, 13.8, 10.5.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H23ClN 276.1514/278.1484; found
276.1519/278.1495.
4ꢀ(4ꢀbromophenyl)ꢀ1ꢀbutylꢀ2ꢀethylꢀ3ꢀmethylꢀ1Hꢀpyrrole (19): colorless oil (54 mg, 85%
1
yield). H NMR (500 MHz, CDCl3): 7.44 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.65 (s,
1H), 3.80 (t, J = 7.5 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.13 (s, 3H), 1.77 – 1.71 (m, 2H), 1.43 –
13
1.35 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), 0.97 (d, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3):
135.9, 132.0, 131.2, 129.1, 122.3, 118.7, 116.9, 111.8, 46.4, 33.8, 20.1, 17.5, 14.7, 13.8, 10.5.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H23BrN 320.1008/322.0988 found
320.1017/322.0995.
1ꢀbenzylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2ꢀethylꢀ3ꢀmethylꢀ1Hꢀpyrrole (20): colorless oil (46 mg, 75%
yield). 1H NMR (500 MHz, CDCl3): 7.37 – 7.27 (m, 7H), 7.08 (d, J = 7.5 Hz, 2H), 6.68 (s, 1H),
5.06 (s, 2H), 2.55 (q, J = 7.5 Hz, 2H), 2.16 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3): 138.4, 135.3, 132.4, 130.7, 128.8, 128.7, 128.3, 127.4, 126.5, 122.7, 117.9, 112.6, 50.4,
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17.6, 14.6, 10.5. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C20H21ClN
310.1357/312.1328; found 310.1346/312.1307.
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1ꢀbutylꢀ2,3ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (21): colorless oil (39 mg, 81% yield). H NMR
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(500 MHz, CDCl3): 7.31 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 6.65 (s, 1H), 3.80 (t, J =
7.3 Hz, 2H), 2.37 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H), 1.75 – 1.69 (m, 2H), 1.43 – 1.35 (m, 2H),
0.96 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3): 134.5, 134.0, 128.9, 127.7, 125.4, 123.3,
116.8, 112.5, 46.6, 33.5, 21.1, 20.0, 13.8, 10.6, 9.7. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+
calcd for C17H24N 242.1903; found 242.1894.
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1ꢀbutylꢀ2,3ꢀdimethylꢀ4ꢀphenylꢀ1Hꢀpyrrole (22): colorless oil (36 mg, 80% yield). H NMR
(500 MHz, CDCl3): 7.42 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H),
6.69 (s, 1H), 3.81 (t, J = 7.4 Hz, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.76 – 1.70 (m, 2H), 1.44 – 1.36
13
(m, 2H), 0.97 (t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3): 137.0, 130.5, 128.2, 127.7,
125.0, 123.4, 117.0, 112.5, 46.6, 33.4, 20.0, 13.8, 10.6, 9.7. HRMS (ESI/LTQ Orbitrap) m/z: [M
+ H]+ calcd for C16H22N 228.1747; found 228.1738.
1ꢀbutylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2,3ꢀdimethylꢀ1Hꢀpyrrole (23): colorless oil (47 mg, 90% yield).
1H NMR (500 MHz, CDCl3): 7.33 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.66 (s, 1H),
3.80 (t, J = 7.4 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.74 – 1.68 (m, 2H), 1.42 – 1.35 (m, 2H), 0.96
13
(t, J = 7.4 Hz, 3H). C NMR (125 MHz, CDCl3): 135.5, 130.7, 128.8, 128.3, 125.8, 122.2,
117.0, 112.4, 46.7, 33.4, 20.0, 13.7, 10.6, 9.7. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd
for C16H21ClN 262.1357/264.1328; found 262.1352/264.1324.
1ꢀbutylꢀ2,3ꢀdimethylꢀ4ꢀ(naphthalenꢀ1ꢀyl)ꢀ1Hꢀpyrrole (24): colorless oil (47 mg, 85% yield).
1H NMR (500 MHz, CDCl3): 8.03 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.2
Hz, 1H), 7.49 – 7.39 (m, 4H), 6.65 (s, 1H), 3.87 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H), 1.89 (s, 3H),
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1.80 – 1.74 (m, 2H), 1.46 – 1.39 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3):
135.0, 133.8, 132.9, 128.0, 127.5, 127.1, 126.3, 125.4, 125.3 (2C), 124.6, 121.5, 118.5, 114.4,
46.6, 33.5, 20.0, 13.8, 10.3, 9.9. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C20H24N
278.1903; found 278.1894.
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1ꢀbenzylꢀ2,3ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (25): colorless oil (50 mg, 90% yield). H NMR
(500 MHz, CDCl3): 7.34 – 7.31 (m, 4H), 7.27 – 7.25 (m, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.08 (d, J
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= 7.6 Hz, 2H), 6.71 (s, 1H), 5.03 (s, 2H), 2.36 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H). C NMR (125
MHz, CDCl3): 138.3, 134.7, 133.9, 129.0, 128.7, 127.7, 127.3, 126.6, 125.9, 123.8, 117.7, 113.2,
50.6, 21.1, 10.7, 9.8. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C20H22N 276.1747;
found 276.1734.
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1ꢀbenzylꢀ2,3ꢀdimethylꢀ4ꢀphenylꢀ1Hꢀpyrrole (26): colorless oil (44 mg, 85% yield). H NMR
(500 MHz, CDCl3): 7.43 (d, J = 7.1 Hz, 2H), 7.36 – 7.31 (m, 4H), 7.27 – 7.25 (m, 1H), 7.20 (t, J
= 7.3 Hz, 1H), 7.08 (d, J = 7.7 Hz, 2H), 6.74 (s, 1H), 5.04 (s, 2H), 2.16 (s, 3H), 2.11 (s, 3H). 13C
NMR (125 MHz, CDCl3): 138.2, 136.8, 128.7, 128.2, 127.7, 127.3, 126.6, 126.1, 125.1, 123.9,
117.9, 113.2, 50.6, 10.7, 9.8. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C19H20N
262.1590; found 262.1581.
1ꢀbenzylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2,3ꢀdimethylꢀ1Hꢀpyrrole (27): colorless oil (49 mg, 83% yield).
1H NMR (500 MHz, CDCl3): 7.36 – 7.27 (m, 7H), 7.07 (d, J = 7.5 Hz, 2H), 6.72 (s, 1H), 5.03 (s,
13
2H), 2.14 (s, 3H), 2.11 (s, 3H). C NMR (125 MHz, CDCl3): 138.1, 135.3, 130.8, 128.8, 128.7,
128.4, 127.4, 126.5, 126.4, 122.7, 117.9, 113.2, 50.7, 10.7, 9.8. HRMS (ESI/LTQ Orbitrap) m/z:
[M + H]+ calcd for C19H19ClN 296.1201/298.1171; found 296.1189/298.1160.
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2,4ꢀdimethylꢀ3,5ꢀdiphenylꢀ1ꢀpropylꢀ1Hꢀpyrrole (28): colorless oil, (26 mg, 89% yield). H
NMR (500 MHz, CDCl3): 7.48ꢀ7.35 (m, 10H), 3.78 (t, J = 7.5 Hz, 2H), 2.33 (s, 3H), 2.01 (s,
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3H), 1.64ꢀ1.55 (m, 2H), 0.80 (t, J = 7.5 Hz, 2H). C NMR (125 MHz, CDCl3): 137.0, 133.7,
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130.8, 130.2, 128.6, 128.4, 128.2, 127.9, 126.8, 125.3, 125.1, 114.5, 46.0, 24.5, 11.2, 11.0, 10.8.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C21H24N: 290.1858; found 289.1852.
1ꢀbutylꢀ2,4ꢀdimethylꢀ5ꢀphenylꢀ3ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (29): colorless oil (53 mg, 84% yield).
1H NMR (500 MHz, CDCl3): 7.44 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.8
Hz, 1H), 7.27 – 7.25 (m, 2H), 7.22 (d, J = 7.8 Hz, 2H), 3.81 – 3.78 (m, 2H), 2.40 (s, 3H), 2.31 (s,
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3H), 1.99 (s, 3H), 1.58 – 1.52 (m, 2H), 1.23 – 1.16 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). C NMR
(125 MHz, CDCl3): 134.7, 133.8, 133.6, 130.7, 130.0, 129.9, 128.7, 128.1, 126.7, 125.0, 121.7,
114.4, 44.1, 33.3, 21.2, 19.9, 13.6, 11.0, 10.8. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd
for C23H28N 318.2216; found 318.2200.
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1ꢀbutylꢀ2ꢀethylꢀ3,5ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (30): colorless oil (43 mg, 80% yield). H
NMR (500 MHz, CDCl3):7.20 – 7.15 (m, 5H), 3.78 – 3.75 (m, 1H), 2.62 (q, J = 7.5 Hz, 2H),
2.38 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.70 – 1.64 (m, 2H), 1.46 – 1.38 (m, 2H), 1.18 (t, J = 7.5
13
Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). C NMR (125 MHz, CDCl3): 134.4, 134.1, 130.0, 129.2,
128.6, 122.8, 120.9, 111.6, 43.6, 33.9, 21.1, 20.3, 17.8, 15.2, 13.8, 10.7, 10.0. HRMS (ESI/LTQ
Orbitrap) m/z: [M + H]+ calcd for C19H28N 270.2216; found 270.2209.
2ꢀethylꢀ1ꢀisopropylꢀ3,5ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (31): colorless oil (42 mg, 82%
yield). 1H NMR (500 MHz, CDCl3): 7.21ꢀ7.18 (m, 4H), 4.49 (sept, J = 7.1 Hz, 1H), 2.68 (q, J =
7.5 Hz, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 1.99 (s, 3H), 1.55 (d, J = 7.1 Hz, 6H), 1.18 (t, J = 7.5 Hz,
13
3H). C NMR (125 MHz, CDCl3): 134.4, 134.1, 130.3, 129.4, 128.5, 122.7, 122.1, 111.8, 46.9,
22.7, 21.1, 18.4, 15.4, 12.5, 10.0. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C18H26N
256.2060; found 256.2046.
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1ꢀcyclopentylꢀ2ꢀethylꢀ3,5ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (32): colorless oil (49 mg, 87%
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yield). H NMR (500 MHz, CDCl3): 7.22 – 7.17 (m, 4H), 4.61 (p, J = 9.3 Hz, 1H), 2.68 (q, J =
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7.4 Hz, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 2.10 (br, 2H), 2.05 – 2.02 (m, 2H), 1.99 (s, 3H), 1.96 –
1.92 (m, 2H), 1.73 – 1.71 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): 134.5,
134.0, 130.2, 130.0, 128.6, 122.8, 122.3, 111.8, 56.3, 31.8, 25.1, 21.1, 18.4, 15.4, 12.5, 10.0.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C20H28N 282.2216; found 282.2206.
1ꢀbutylꢀ3ꢀisopropylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (33): colorless oil (44 mg, 86% yield).1H NMR
(500 MHz, CDCl3): 7.30 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 6.62 (s, 1H), 6.48 (s, 1H),
3.83 (t, J = 7.4 Hz, 2H), 3.12 (sept, J = 6.8 Hz, 1H), 2.36 (s, 3H), 1.81 – 1.75 (m, 2H), 1.41 –
1.33 (m, 2H), 1.17 (d, J = 6.8 Hz, 6H), 0.96 (t, J = 7.4 Hz, 3H).13C NMR (125 MHz, CDCl3):
134.7, 134.2, 129.2, 128.9, 128.0, 123.2, 118.8, 116.8, 49.4, 33.5, 25.0, 24.4, 21.1, 20.1, 13.7.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C18H26N 256.2060, found 256.2055.
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1ꢀbutylꢀ3ꢀisopropylꢀ4ꢀphenylꢀ1Hꢀpyrrole (34):12 colorless oil (42 mg, 87% yield). H NMR
(500 MHz, CDCl3): 7.42 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H),
6.66 (d, J = 1.9 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 3.84 (t, J = 7.4 Hz, 2H), 3.15 (sept, J = 6.8Hz,
1H), 1.82 – 1.76 (m, 2H), 1.41 – 1.34 (m, 2H), 1.18 (d, J = 6.8 Hz, 6H), 0.96 (t, J = 7.4 Hz,
3H).13C NMR (125 MHz, CDCl3): 137.2, 129.3, 128.2, 128.1, 125.2, 123.2, 118.9, 116.9, 49.4,
33.5, 25.0, 24.4, 20.1, 13.7. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H24N
242.1903, found 242.1895.
1ꢀbutylꢀ3ꢀisopropylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀpyrrole (35): colorless oil (36 mg, 67% yield).
1H NMR (500 MHz, CDCl3): 7.32 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 2.3
Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.84 – 3.81 (m, 5H), 3.08 (sept, J = 6.8Hz, 1H), 1.80 – 1.74
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(m, 2H), 1.40 – 1.33 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.95 (t, J = 7.3 Hz, 3H). C NMR (125
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MHz, CDCl3): 157.6, 129.7, 129.20, 129.18, 122.9, 118.6, 116.7, 113.7, 55.2, 49.4, 33.5, 25.0,
24.3, 20.1, 13.7. HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C18H26NO 272.2009; found
272.2000.
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1ꢀbutylꢀ3ꢀ(4ꢀchlorophenyl)ꢀ4ꢀisopropylꢀ1Hꢀpyrrole (36): colorless oil (50 mg, 90% yield). H
NMR (500 MHz, CDCl3): 7.33 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 1.9 Hz,
1H), 6.48 (d, J = 1.9 Hz, 1H), 3.82 (t, J = 7.4 Hz, 2H), 3.08 (sept, J = 6.8Hz, 1H), 1.80 – 1.74 (m,
2H), 1.40 – 1.32 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz,
CDCl3): 135.7, 131.0, 129.2 (2C), 128.3, 122.0, 119.0, 117.2, 49.5, 33.5, 25.0, 24.3, 20.0, 13.7.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H23ClN 276.1514/278.1484; found
276.1515/278.1483.
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3ꢀ(4ꢀbromophenyl)ꢀ1ꢀbutylꢀ4ꢀisopropylꢀ1Hꢀpyrrole (37): colorless oil (52 mg, 81% yield). H
NMR (500 MHz, CDCl3): 7.45 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 2.0 Hz,
1H), 6.49 (d, J = 2.0 Hz, 1H), 3.83 (t, J = 7.4 Hz, 2H), 3.08 (sept, J = 6.8Hz, 1H), 1.80 – 1.74 (m,
2H), 1.40 – 1.33 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz,
CDCl3): 136.1, 131.3, 129.6, 129.2 (2C), 122.0, 119.0, 117.2, 49.5, 33.4, 25.0, 24.3, 20.0, 13.7.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C17H23BrN 320.1008/322.0988; found
320.0997/322.0976.
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1ꢀbenzylꢀ3ꢀisopropylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrrole (38): colorless oil (44 mg, 76% yield). H NMR
(500 MHz, CDCl3): 7.35 (t, J = 7.4 Hz, 2H), 7.32 – 7.29 (m, 3H), 7.19 (d, J = 7.4 Hz, 2H), 7.16
(d, J = 7.7 Hz, 2H), 6.67 (d, J = 1.8 Hz, 1H), 6.54 (d, J = 1.8 Hz, 1H), 5.04 (s, 2H), 3.14 (sept, J
= 6.8 Hz, 1H), 2.37 (s, 3H), 1.18 (d, J = 6.8 Hz, 6H). 13C NMR (125 MHz, CDCl3): 138.1, 134.9,
134.0, 130.0, 128.9, 128.7, 128.0, 127.6, 127.2, 123.8, 119.4, 117.5, 53.4, 25.0, 24.3, 21.1.
HRMS (ESI/LTQ Orbitrap) m/z: [M + H]+ calcd for C21H24N 290.1903; found 290.1892.
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