The Paal-Knorr reaction revisited. A catalyst and solvent-free synthesis of underivatized and N-substituted pyrroles

Article abstract of DOI:10.1039/c4gc01523a

A new, modified synthesis of pyrroles is described. The reaction of 2,5-hexandione with a variety of amines yielded the expected pyrrole analogues in excellent yields. The reactions were carried out under the ultimate green conditions excluding both catalyst and solvent applying simple stirring at room temperature. The variety of amines include aqueous ammonium hydroxide for the synthesis of pyrroles with a free NH group, and benzylamines, anilines and phenylene-diamines for the synthesis of several N-derivatized pyrroles. The reaction also occurs efficiently with a variety of 1,4-diketones, although the reaction rates and yields are lower for the diketones that do not possess terminal methyl group(s). This journal is

Full text of DOI:10.1039/c4gc01523a

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Cho, R.
Madden, B. Nianci and B. Torok, Green Chem., 2014, DOI: 10.1039/C4GC01523A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Page 1 of 13
Green Chemistry
View Article Online
DOI: 10.1039/C4GC01523A
Table of Contents graphics for The Paal-Knorr reaction revisited. A catalyst and solvent-free
synthesis of underivatized and N-substituted pyrroles by Hyejin Cho, Richard Madden, Bilal
Nisanci and Béla Török
A catalyst and solvent-free room temperature synthesis of pyrroles is described.

CREATED USING THE RSC ARTICLE TEMPGLArTeEe(VnERC. 3h.1)e-mSEiEsWtrWyW.RSC.ORG/ELECTRONICFILES FOR DETAILS
View ArticlPe Oanglinee 2 of 13
DOI: 10.1039/C4GC01523A
ARTICLE TYPE
www.rsc.org/xxxxxx | XXXXXXXX
The Paal-Knorr reaction revisited. A catalyst and solvent-free synthesis
of underivatized and N-substituted pyrroles
Hyejin Cho,a Richard Madden, a Bilal Nisanci a,b and Béla Török a,*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
A new, modified synthesis of pyrroles is described. The reaction of 2,5-
hexandione with a variety of amines yielded the expected pyrrole analogues in
excellent yields. The reactions were carried out under the ultimate green
10 conditions excluding both catalyst and solvent applying simple stirring at room
temperature. The variety of amines include aqueous ammonium hydroxide for
the synthesis of pyrroles with free a NH group, and benzylamines, anilines and
phenylene-diamines for the synthesis of several N-derivatized pyrroles. The
reaction also occurs efficiently with a variety of 1,4-diketones, although the
15 reaction rates and yields are lower for the diketones that do not possess terminal
methyl group(s).
well-founded. The emergence of green chemistry, coupled
with the continuous need for new pyrroles, resulted in
extended development in the modernization of time-honored
synthetic techniques, such as the Paal-Knorr reaction
Introduction
Heterocyclic compounds possess a wide range of biological
20 properties such as antibacterial, antiviral, anti-inflammatory,
antitumor and antioxidant activities.1,2Among heterocycles,
the pyrrole core has always been one of the most prominent,
as it is a useful intermediate in the synthesis of natural
products, as well as in medicinal chemistry. Polymerized
25 derivatives of pyrroles 3 are also widely used in materials
science indicating the widespread application possibilities.
Due to the broad interest in pyrroles, the synthesis of these
compounds has always been among the most important
research areas in synthetic chemistry, resulting in the
30 development of several classic named reactions. The classic
methods for the synthesis of pyrroles are as follows: (i) the
Hantzsch reaction,4 which provides pyrroles from a reaction
of α-halo ketones with β-ketoesters and ammonia (or primary
amines); (ii) the Knorr reaction,5 which assembles pyrroles by
35 the reaction between α-aminoketones derived from -
haloketones and ammonia, and β-ketoesters; (iii) the Paal-
Knorr reaction, 6 one of the most common approaches in
which γ-diketones are converted to pyrroles from the reaction
with primary amines (or ammonia) in the presence of various
40 promoting agents.7 Several methods, partially related to the
previously mentioned general processes, were also reported
for the synthesis of specific pyrroles, often as a part of a
larger ring system.8
60
Several catalysts, including green alternatives, such as
solid acids, water soluble acids etc., have been applied for the
synthesis of a variety of pyrroles. These catalysts include
glutathione bearing nanoferrites,11 copper iodide on activated
carbon (CuI/C),12 polystyrenesulfonate,13 and many others as
65 reviewed earlier.14
Independent of the catalysts, the presence of harmful
solvents or harsh reaction conditions, the waste of energy and
long and high temperature heating also presented problems.
To overcome these issues, the development of more time,
70 solvent and energy efficient procedures initiated the use of
rapid and environmentally acceptable alternatives, such as
microwave-assisted organic synthesis (MAOS), in favour of
the classic methods that have been emphasized for the
15
synthesis of pyrroles. The use of microwave heating,
75 environmentally benign solvents or solvent-free conditions
have been introduced to avoid harmful or difficult to recycle
organic solvents or severe reaction conditions (high
temperatures, strong liquid acid catalysts etc.). 16 , 17 , 18 Gas
phase reactions of ammonia with diketones were also
80 investigated.19
Our earlier investigations resulted in the development
of several green methods for the synthesis of pyrroles,
indoles, and carbazoles among other heterocycles using
solvent-free reaction conditions. These processes were
85 catalyzed by an environmentally benign, microwave-active
The Paal-Knorr synthesis has been frequently applied in
45 the synthesis of pyrroles. In their original method, Paal9 and
Knorr10 independently, used a weak mineral acid catalyst.
Since the reaction occurs via the elimination of two moles of
water the application of an acid catalyst appears
mechanistically
20 , 21
, 22
solid-acid (K-10 montmorillonite).
While our
syntheses provided the product pyrrole derivatives in high
yield, our recent data obtained in the reaction of a 1,4-
diketone and amines casted doubt on the necessity of a
90 catalyst in the Paal-Knorr reaction. In order to substantiate
this observation and develop the ultimate green Paal-Knorr
reaction, a detailed investigation was carried out on the
subject. Herein, we report the first catalyst and solvent-
50
a
University of Massachusetts Boston, 100 Morrissey Blvd. Boston, MA,
USA. Fax: (+1)-617-287-6030; Tel: (+1)-617-287-6159; E-mail:
bela.torok@umb.edu
b Current address: Atatürk University, Erzurum, Turkey
55
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

View Article Online
DOI: 10.1039/C4GC01523A
Page 3 of 13
Green Chemistry
As depicted in Table 1, the reaction proceeded efficiently
under a broad range of conditions. First, two activation
methods, microwave irradiation and ultrasounds, known to
35 generate high yields in reduced times, were investigated. A 1
hour ultrasonic irradiation yielded only 68% product (Table 1,
entry 2). The microwave-assisted processes performed much
better, yielding up to 88% product, although requiring
elevated temperatures for fast completion (Table 1, entries 1,
40 3-5). As the greenest possible alternative, the reaction was
carried out at ambient temperature as well, without the use of
any activation. The data show that while the reaction proceeds
comparatively slowly (30% yield in 6 h, Table 1, entry 6) it
can reach quantitative conversion without significant
45 byproduct formation after 120 h (Table 1, entry 7). It was also
observed that the molar ratio of the reactants was an
important variable. By increasing the amount of NH4OH, the
reaction yielded more products regardless of whether
microwave activation or ambient temperature stirring was
50 applied. Thus, to achieve practical reaction times, it was
decided that a 10 fold molar excess of the reagent would be
used to improve the rate of the ambient temperature reaction.
At such excess the reaction was completed in 3 h requiring
only stirring. While the green chemistry principles are against
55 the use of excess chemicals, in the current example the
product is easily separated from the aqueous phase, thus the
remaining NH4OH can be readily recycled. Most importantly,
however, the data unambiguously indicate that the formation
of pyrrole does not require the application of a catalyst.
free synthesis of pyrroles at room temperature, a truly
environmentally benign version of the classic Paal-Knorr
pyrrole synthesis (Scheme 1).
5
Scheme 1 Paal-Knorr cyclization of 1,4-diones with aqueous
ammonium hydroxide and primary amines
10 Results and discussion
During our recent investigations, it was observed that a 1,4-
diketone formed pyrrole while reacted with aqueous NH4OH.
This phenomenon prompted us to investigate the reaction in
detail. Hexan-2,5-dione was selected as the diketone for these
15 investigations due to our previous success with this
reactant.19-21 As a source of active NH2 group, a commercially
available, inexpensive aqueous ammonium hydroxide, with
28-30% NH3 content, was selected. If successful, this reaction
would provide pyrrole underivatized on its N-atom. While in
20 the first attempts the reaction appeared to occur readily, a
series of optimization tests were carried out to establish the
conditions that result in the best performance (Table 1).
60
While the data in Table 1 were obtained in small scale
experiments, an effort was made to scale up the process.
Based on the data presented above, considering the benefits
and disadvantages of different systems, ambient temperature
reaction conditions have been selected. In this reaction 0.114
65 g of hexane-2,5-dione was added to 1.29 mL 28-30% aqueous
NH4OH. The reaction appeared to proceed efficiently yielding
75% isolated product suggesting that the process can be
scaled up to practical levels.
Table 1. Reaction of hexan-2,5-dione with aqueous NH4OH
After the successful completion of the Paal-Knorr reaction
70 with aqueous NH4OH to underivatized pyrrole, our attention
turned toward extending the scope of the reaction. Three
groups of amines were considered: aliphatic amines
(including cyclic and benzylic amines), aromatic amines (e.g.
anilines) and diamines. Similarly to Table 1, an extensive
75 optimization was carried out for all three groups of amines
with similar results. While microwave irradiation appeared to
be more effective with primary amines than with NH4OH,
yielding quantitative reactions, it required elevated
temperatures (e.g. 120 ˚C). It was also observed, that the
80 room temperature reactions provided equally high yields in
relatively short times. Thus, further reactions were carried out
with simple stirring at RT. Due to the higher reactivity of
amines, the reactions can be carried out at a 1:1 molar ratio. It
is particularly advantageous; since the reaction is selective
85 and quantitative, the products form exclusively, thus no
purification is required. Using excess amine, the separation of
the remaining amine from the pyrrole would add an
unnecessary purification step. In addition, it was observed
that the presence of the solvent was not mandatory. Since
90 both the ketone and the amines are liquids at room
temperature and perfectly miscible with each other, the
25
Entry 1/2 ratioa activationb
T
(˚C)
80
RT
40
Time
(h)
Yieldc
(%)
84
68
9
30
88
30
100
60
1
2
1
1
MW
US
0.25
1
0.25
0.25
0.25
6
120
0.5
1
2
3
3
4
5
6
7
8
9
10
11
2.5
2.5
2.5
2.5
2.5
MW
MW
MW
-
-
-
-
-
-
60
80
RT
RT
RT
RT
RT
RT
10
10
10
10
82
89
100
a 28-30% NH4OH, active NH3 content was taken into account in
calculating reactant ratios
b MW-microwave activation, US-ultrasonic activation
30 c GC yields
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
View ArticlPe Oanglinee 4 of 13
DOI: 10.1039/C4GC01523A
reaction could be carried out in a solvent-free environment
using the neat reactants. Therefore, based on the second
optimization carried out with amines, the neat reaction at
room temperature was selected as the most effective and
environmentally benign reaction condition for further pyrrole
synthesis.
anilines with electron-donating and electron-withdrawing
groups were used (Table 3). These reactions were also carried
out at room temperature without any solvent or catalyst
resulting in very good to excellent yields. As expected the
40 reaction of anilines required significantly longer time to
complete than that of the alkylamines (with the exception of
cycloalkyl amines, Table 2 entries 5, 6). It can also be
observed, that despite the longer reaction times, the yields are
mostly not as high as in Table 2. This is due to the decreased
45 basicity and nucleophilicity of the aniline amino group, which
is caused by multiple factors. First, the electron withdrawing
nature of the phenyl ring decreases the electron density on the
N. The direct attachment of the ring to the NH2 group
sterically hinders the attack on the N and also decreases
50 reactivity. Based on the analysis of the yields, the substituents
of the phenyl ring did not appear to have a noteworthy effect
on the reactions, except OCH3, in which case the reaction
time was noticeably shorter (4 h vs. 24h).
5
First, the Paal-Knorr type pyrrole synthesis using
alkylamines was carried out. The reactions resulted in
excellent yields, with quantitative conversions in 5-10 min, as
10 tabulated in Table 2. As the carbon number of the amino-
bearing carbon chain increases, the reaction time is shortened
(Table 2, entries 1-3). As the longer chain farther removes the
electron withdrawing effect of the phenyl groups from the
NH2, these data are in line with the increased reactivity of
15 primary phenyl-alkylamines. The reactions of the acyclic
alkyl or benzylamines (Table 2 entries 1-4, 7,8) are much
faster than those of the cycloalkyl amines (entries 5, 6), due to
steric hindrance caused by the rings immediately attached to
the amino group that significantly decrease its nucleophilicity
20 as compared to linear analogues.
55 Table 3. Reaction of hexan-2,5-dione with substituted
anilinesa
Table 2. Reaction of hexan-2,5-dione with alkyl-, cycloalkyl-
and benzylaminesa
Entry
amine
Time
(min)
GC Yield Isolated Yield
Entry
aniline
Time
(h)
GC Yield Isolated Yield
(%)
100
100
(%)
(%)
(%)
1
2
5
7
97
1
2
3
4
24
24
24
24
83
80
98
76
92
92
70
87
90
3
10
88
81
4
5
10
100
100
96
96
24b
5
24
71
65
6
7
24b
5
100
100
97
97
6
7
24
21
88
91
80
87
8
7
100
98
8
4
100
94
25
a
1mmol amine, 1 mmol diketone, both neat, mixed and
stirred at room temperature
reaction time is given in h
a
b
1mmol aniline, 1 mmol diketone, both neat, mixed and
stirred at room temperature
60
30
The conversion of the starting materials was nearly
quantitative providing the products in high isolated yields
indicating the versatility of the reaction.
To further extend the scope of the reaction, the Paal-Knorr
type pyrrole synthesis was investigated with diamines (Table
4). Based on the above data, it is expected that the diamines
After the successful experiments with alkylamines, the
scope was extended to aromatic amines, for example anilines.
65 will react with 2,5-hexanedione. The major question to be
answered was how these reactions occur. Using a diamino
35 In order to observe the effect of substituents, a variety of
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
DOI: 10.1039/C4GC01523A
Page 5 of 13
Green Chemistry
While the above reactions were carried out using 1 mmol
of the reactants each, a possible scale-up of the process was
35 also attempted. The amounts of the reactants were increased
to 10 mmol, about 1.2-2 g of the amine and the diketone,
respectively (Table 5). It was observed that the selected larger
scale reactions occurred with similar efficiency as their
previous counterparts. In fact, all three reactions gave nearly
40 quantitative yields. The exclusive selectivity, obtained under
mild conditions, made the usual extra isolation step
unnecessary, resulting in only negligible loss of product.
While usually scaling up a procedure requires longer reaction
time, the data showed that no significant increase in reaction
45 time was necessary in order to scale up the reaction by a
factor of 10. These results indicate that the further scale up of
the reaction is most likely possible.
compound as the reactant with 2,5-hexandione may result in
the formation of multiple products. The potential possibilities
were the formation of a single pyrrole (only one NH2 reacts
with 1 mol of diketone) a double pyrrole (both NH2 groups
react with 2 mol diketone) or the two amino groups would
react with the two carbonyl groups in a 1:1 molar ratio,
respectively and form a C8 ring.
5
During the optimization of the diamine-dione reaction it
was observed that the reaction selectively resulted in the
10 formation of the mono-pyrrole product. The mono-pyrrole
was the exclusive product even when an excess amount of
2,5-hexanedione was used. 1,6-Diaminohexane was the only
exception to this rule; it gave bis-pyrrole product when an
excess amount of 2,5-hexanedione was applied. However, at
15 1:1 reactant ratios both mono-pyrrole and di-pyrrole were
produced. The previously described difference in reactivity
was observed here as well; the aliphatic diamine (Table 4,
entry 6) reacted at a higher rate than that of the aromatic
diamines (Table 4, entries 1-5, 7) and provided the expected
20 products in a shorter time, as well as in higher yield. The
selective mono-pyrrole formation of phenylene-diamine
regioisomers results in potentially useful building blocks, that
possess an underivatized primary amino group that can be
used to attach the products to other structures as needed.
Table 5. Scale-up of the reaction of hexan-2,5-dione with
50 primary aminesa
Entry
amine
Time
(min)
GC Yield Isolated Yield
(%)
(%)
25
1
2
5
100
99
Table 4. Reaction of hexan-2,5-dione with aliphatic and
aromatic diaminesa
240
5
100
100
99
3
99b
a
10 mmol amine (1.2-2 g), 10 mmol diketone, both neat,
mixed and stirred at room temperature
10 mmol amine, 20 mmol diketone, the isolated yield is
that of the bis-pyrrole product formed
Entry
1
Time GC Yield Isolated Yield
b
(h)
(%)
(%)
55
24
80
77
2
24
68
61
After studying pyrrole synthesis using 2,5-hexanedione
3
4
5
60 and a broad variety of amines of different types our attention
turned toward the applicability of other appropriate (1,4
dicarbonyl) diketones. Several commercially available
diketones have been applied with a smaller but representative
group of amines. The results are tabulated in Table 6.
24
24
78
81
57
72
24
87
79
65
6
7
0.083
100
96b
24
83
80
a
70
1mmol diamine, 1 mmol diketone, both neat, mixed
and stirred at room temperature
bis-pyrrole product with excess of the diketone
30
b
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
View ArticlPe Oanglinee 6 of 13
DOI: 10.1039/C4GC01523A
a significant effect on its reactivity. Replacing one terminal
methyl group (R1 = Phe, 1-phenylpentane-1,4-dione, Table 6,
entries 1-4) to phenyl does not appear to significantly affect
25 the reactivity of the diketone, thus the reaction times and
temperature are similar to those observed in the reaction of
2,5-hexanedione with the same amines (Tables 1-4). It is
worth mentioning, that the reaction readily occurred with aq.
NH4OH as well. Despite the mild conditions, all reactions
30 provided the products in high to excellent yields. Replacing
Table 6. Reaction of various diones with amines and
diaminesa
both terminal methyl groups (R1, R2
=
Phe, 1,4-
diphenylbutane-1,4-dione, Table 6, entries 5-7), however,
resulted in reasonable decrease in the activity of the diketone.
While the pyrrole synthesis readily progressed with alkyl or
35 aryl-amines as well as, 4,5-dimethyl-o-phenylene diamine, the
reaction required elevated temperature and long reaction time.
The reaction, however, did not proceed with NH4OH, even at
elevated temperatures most likely due to the rapid release of
NH3 gas from the solution. Nonetheless, despite the
40 decreasing activity the N-substituted products were obtained
in good yields. Adding a third phenyl group to the substrate
(R1, R2, R3=Phe, 1,2,4-triphenylbutane-1,4-dione, Table 6
entries 8-10) further decreased the reactivity. The product
formation required long reaction times at elevated
45 temperature and the observed yields are moderate to good.
Replacing the terminal groups to an electron rich thiophen-2-
yl (R1, R2=thiophen-2-yl, 1,4-di(thiophen-2-yl)butane-1,4-
dione, Table 6 entries 11-13) resulted in similar performance
to the diphenyl analog (Table 6, entries 5-7). The reaction
50 proceeded at 100 ˚C, required considerable time and yielded
the expected pyrroles in moderate to high yields.
Time
T
GC Isolated
diketone
amine
(h) (˚C) Yield Yield
(%)
90
(%)
72
1
5 min RT
2
3
24
24
RT
RT
97
99
88
92
NH4OH
4
5
5
RT 100
98
72
48
100
89
6
7
80
80
100
100
80
71
70
64
8
50
100
88
72
The experiments with the various diketones suggest a
generic pattern; terminal methyl and potentially alkyl groups
perform well in the reaction even at room temperature.
55 Increasing the complexity of the compounds by replacing the
terminal methyl groups with larger and electron withdrawing
phenyl groups appears to gradually decrease the reactivity of
the diketone and the reaction requires elevated temperature
and extended reaction times.
9
72
72
100
100
55
74
42
56
10
11
48
100
91
79
12
13
80
80
100
100
37
71
32
65
60
Based on the above presented data the synthetic utility of
the method appears broadly applicable. Several amines of
different types as well as ammonia (in the form of the
conveniently available NH4OH) were proven to be useful
substrates for the reaction with a variety of 1,4-diketones.
a
5
1mmol diamine, 1 mmol diketone, both neat, mixed
and stirred at the desired temperature
65 However, none of the compounds in the above Tables
contained acid labile functional groups. As often times
reactions are carried out in the presence of acid labile
protecting groups23 it is important to investigate whether the
above reaction conditions are applicable for compounds with
In selecting the diketones, a simple approach was
followed: 2,5-hexanedione possesses methyl groups as end
10 groups R1 and R2. Thus, the emphasis was placed on 70 such acid sensitive functional groups.
substituting the alkyl groups with phenyl and observing the
Therefore a study has been carried out on the stability of
effect of structure on the performance of the reaction. First,
one methyl group was substituted as R1 (1-phenylpentane-1,4-
dione), then another (both R1 and R2 are Phe, 1,4-
15 diphenylbutane-1,4-dione) and then three (R1, R2, R3=Phe,
such substituents under the current catalyst and solvent free
conditions. We have selected four amines and two 1,4-
dicarbonyl compounds to observe whether the protecting
75 groups would be removed. The data are tabulated in Table 7.
1,2,4-triphenylbutane-1,4-dione).
Finally, another di-
heteroaryl diketone (R1, R2=thiophen-2-yl, 1,4-di(thiophen-2-
yl)butane-1,4-dione) was selected to observe the effect of a
heteroaryl ring. The data indicate that the catalyst and solvent
20 free system is mostly effective for carrying out the Paal-Knorr
reaction. It is also apparent that the structure of the dione has
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
DOI: 10.1039/C4GC01523A
Page 7 of 13
Green Chemistry
Table 7. Reaction of various diones with amines and
diamines possessing protecting groupsa
Time
T
GC Isolated
diketone
amine
(h) (˚C) Yield Yield
(%)
98
(%)
91
1
2
24
24
RT
RT
89
99
84
30 Figure 7 The proposed mechanism of the non-catalytic Paal-
Knorr cyclization of 1,4-diones with aqueous ammonium
hydroxide (R3=H) and primary amines
3
4
5
15 min RT
97
96
15 min RT 100
35
Accordingly, it is suggested that the carbonyl group reacts
with the amino group to form the hemiaminal (Fig. 7, III).
Amarath et al. described24 that meso- and dl-3,4-diethyl-2,5-
hexanediones cyclize at different rates, and that the
stereochemistry of the unchanged dione is preserved during
24
24
100
100
82
95
73
91
6
40 the reaction. These observations led to the conclusion that
under non-acidic conditions the formation of an enamine
intermediate can be ruled out. In contrast, under typical acidic
conditions the hemiaminal could undergo a loss of water and
the subsequent formation of an imine that could isomerize to
45 an enamine, which could initiate the cyclization. Thus we
propose that as a next step, the hemiaminal attacks the other
carbonyl to cyclize to 2,5-dihydroxy-2,5-dialkyl-N-alkyl-
hydropyrrole (Fig. 7, V), which, step-by–step, undergoes a
double water elimination to give the corresponding N-
50 substituted pyrrole. Use of ammonium hydroxide instead of
amines gives the underivatized NH containing pyrrole. In the
above mentioned studies24 it was reported that the substituents
on the aryl end-groups (Fig. 7, I, R1, R2) had a reasonable
effect on the reaction. A similar phenomenon was observed in
55 the current work as well. When at least one terminal group
(Fig. 7, I, R1or R2) was methyl (dimethyl- and methyl/phenyl)
the reaction readily progressed at room temperature, while
when both terminal groups were phenyl, the reaction required
heating and provided lower yields. If R2 in the hemiaminal is
60 Me (Fig. 7, III) its electron donating effect would enhance the
electron density on the N, thus facilitating the cyclization. R1
of III appears unimportant as indicated by the similar reaction
rates of the two diketones (Tables 1-4 and Table 6 entries1-4).
However, when both R1 and R2 are Phe, the electron
65 withdrawing nature of the phenyl group would decrease the
electron density of the N and the availability of the lone pair
of the nitrogen. Thus, in such cases, the cyclization requires
higher activation energy than that provided by RT to occur.
7
8
3
3
100
100
92
94
88
93
a
5
1mmol diamine, 1 mmol diketone, both neat, mixed
and stirred at the desired temperature, the protecting
groups remained in the products and no deprotected
product was observed.
10
Table 7 indicates that the protected amines and hydroxyl
compound underwent the cyclization reaction without any
difficulty and the expected products were isolated in good to
excellent yields. In all cases the acid labile protecting groups
remained in the product indicating that the methods tolerates
15 these functional groups. Therefore, it appears that the method
can be expanded to such compounds, which only adds to the
advantages of our catalyst and solvent-free reaction process.
Analyzing the mechanism of the reaction provides an
explanation for this phenomenon. Being classical and well-
20 studied, the mechanism of the Paal-Knorr reaction has been
thoroughly studied. 24 It is reasonable to propose that the
transformations in the current work follow a different
mechanism than that described in our earlier catalytic pyrrole
synthesis under strongly acidic conditions.19-21 The proposed
25 current mechanism is summarized in Fig. 7.
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
View ArticlPe Oanglinee 8 of 13
DOI: 10.1039/C4GC01523A
The procedure presented above allows the use of a wide
variety of amines with diketones in the Paal-Knorr reaction,
including aqueous NH4OH, alkyl- or cycloalkyl amines,
anilines and various diamines. It was observed that the
pyrrole synthesis occurred in high yields without a catalyst or
a solvent. The reaction represents the ultimate green synthesis
of a large number of 2,5-substituted-pyrroles and possessing
the following major advantages: (i) other than the starting
materials, the reaction occurs without the use of any
10 additional reagent or catalyst, thus the catalyst recycling or
the reagent disposal do not need to be considered; (ii) the
starting materials react under “neat” conditions, without the
presence of a solvent, thus any hazard related to solvents or
the cost of solvent recycling are eliminated; (iii) the reaction,
15 in most cases, occurs with nearly quantitative conversions and
provides high isolated yields; (iv) the starting materials react
in 1:1 ratio, no excess of either one is required for good
yields; (iv) the atom economy of the process is around 90%
(the exact value is dependent on the molecular mass of the
20 amines) and the only byproduct that forms is H2O; (v) in most
cases the process is truly “solvent-free”, namely no solvent is
needed to isolate the products; (vi) in several cases no further
purification step is necessary to obtain pure products, a simple
drying will eliminate the byproduct water; (vii) the reactions
25 all occur at room temperature, which is convenient, safe and
energy efficient finally (viii) the process appeared to tolerate
acid labile protecting groups as well.
electron impact ionization) using a 30m long DB-5 type
column (J&W Scientific).
60 General Procedure: Amine (10 mmol) and 2,5-hexanedione
(10 mmol) were mixed and stirred in a 25ml round-bottom
flask at room temperature. After the reaction was complete,
the product was placed under vacuum to remove the
byproduct water. The products were isolated as low melting
65 crystals or oils. NMR and GC-MS confirmed the identity of
the products and indicated the sufficient purity (> 95% and no
water according to the 1H NMR)
5
2,5-dimethyl-1-(3-phenylpropyl)-1H-pyrrole (Table 2 entry
70 1)
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.20-
7.06 (m, 5H), 5.67 (s, 2H), 3.62 (t, J = 7.5 Hz, 2H), 2.54 (t, J =
7.5 Hz, 2H), 2.06 (s, 6H), 1.83 (quintet, J = 7.5 Hz, 2H); 13C
NMR (75.474 MHz, CDCl3), δ (ppm) 140.9, 128.3, 128.1, 127.0,
75 125.9, 104.9, 42.8, 32.9, 32.1, 12.3; MS-C15H19N (213) m/z (%):
213 (M+, 100), 108 (100), 109 (72), 94 (34), 92 (23).
2,5-dimethyl-1-(2-phenylethyl)-1H-pyrrole (Table 2 entry
2)
80 Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.49-
7.43 (m, 3H), 7.29 (d, J = 9.0 Hz, 2H), 6.01 (s, 2H), 4.13 (t, J =
7.5 Hz, 2H), 3.07 (t, J = 7.5 Hz, 2H), 2.34 (s, 6H); 13C NMR
(75.474 MHz, CDCl3), δ (ppm) 138.3, 128.6, 128.3, 127.0, 126.4,
105.0, 45.0, 37.3, 12.1; MS-C14H17N (199) m/z (%): 199 (M+,
85 100), 108 (92), 200 (16), 104 (10), 77 (8).
Conclusions
30 A simple, selective and environmentally benign synthesis
of dimethyl-pyrroles is described. The reaction of 1,4-
diones with aqueous ammonium hydroxide and a broad
variety of amines provides high yields under mild
conditions. The major advantages of this approach are:
35 high atom economy, catalyst and solvent-free reaction,
limited energy consumption (short reaction time and
generally no heating needed) and its waste-free nature as
H2O is the only byproduct.
1-benzyl-2,5-dimethyl-1H-pyrrole (Table 2 entry 3)
Dark brown crystal, MP = 45°C; 1H NMR (300.128 MHz,
CDCl3), δ (ppm) 7.42-7.32 (m, 3H), 7.00 (d, J = 9.0 Hz, 2H),
90 5.99 (s, 2H), 5.11 (s, 2H), 2.25 (s, 6H); 13C NMR (75.474 MHz,
CDCl3), δ (ppm) 138.4, 128.5, 127.7, 126.8, 125.4, 105.3, 46.5,
12.3; MS-C13H15N (185) m/z (%): 185 (M+, 72), 91 (100), 65
(15), 92 (15).
95 2,5-dimethyl-1-(4-methylbenzyl)-1H-pyrrole (Table 2 entry
4)
Brown crystal, MP = 44-47°C; 1H NMR (300.128 MHz,
CDCl3), δ (ppm) 7.13 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 9.0 Hz,
2H), 5.89 (s, 2H), 5.00 (s, 2H), 2.34 (s, 3H), 2.17 (s, 6H); 13C
100 NMR (75.474 MHz, CDCl3), δ (ppm) 136.4, 135.4, 129.3,
127.8, 125.5, 105.2, 46.4, 20.9, 12.4; MS-C14H17N (199) m/z
(%): 119 (M+, 81), 105 (100), 200 (12), 77 (9), 106 (9).
40 Experimental Section
Materials: All amines and 2,5-hexanedione were purchased
from Aldrich and used without any purification. CDCl3 used
as a solvent (99.8%) for NMR studies was an Aldrich
product. Ethyl acetate used for product isolation in the
45 NH4OH reactions (minimum purity of 99.5%) was a Fisher
product.
1-cyclohexyl-2,5-dimethyl-1H-pyrrole (Table 2 entry 5)
105 Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 5.65
(s, 2H), 3.85-3.76 (m, 1H), 2.21 (s, 6H), 1.88-1.63 (m, 8H), 1.27-
1.09 (m, 2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 127.7,
105.9, 56.3, 32.3, 26.6, 25.6, 14.3; MS-C12H19N (177) m/z (%):
177 (M+, 100), 94 (90), 95 (70), 96 (18), 55 (12).
1
NMR Analysis: The H and 13C spectra were obtained on a
300 MHz Varian NMR spectrometer, in CDCl3 with either
50 using the signal of tetramethylsilane or the residual solvent
signal as standards. The temperature was 25 °C (accuracy ±1
°C) and controlled by the Varian control unit.
110
1-cyclopentyl-2,5-dimethyl-1H-pyrrole (Table 2 entry 6)
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 5.77
(s, 2H), 4.54 (quintet, J = 9.0 Hz, 1H), 2.30 (s, 6H), 2.04-1.88 (m,
6H), 1.71-1.66 (m, 2H); 13C NMR (75.474 MHz, CDCl3), δ
GC-MS Analysis: The mass spectrometric identification of
55 the products have been carried out by an Agilent 6850 gas
chromatograph- 5973 mass spectrometer system (70 eV
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

View Article Online
DOI: 10.1039/C4GC01523A
Page 9 of 13
Green Chemistry
(ppm) 127.8, 105.8, 56.1, 31.1, 24.9, 14.0; MS-C11H17N (163)
138.0, 132.3, 129.8, 128.6, 121.5, 106.0, 13.0; MS-C12H12BrN
60 (250) m/z (%): 250 (M+, 97), 249 (100), 251 (95), 248 (92), 154
(50).
m/z (%): 163 (M+, 46), 94 (100), 95 (58), 96 (17), 80 (16).
3-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)-1H-indole (Table
5
2 entry 7)
2,5-dimethyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrrole
(Table 3 entry 6)
1
Brown crystal, mp = 85°C; H NMR (300.128 MHz, CDCl3), δ
(ppm) 7.88 (s, br, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.35-7.20 (m, 65 Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.61-
3H), 6.85 (s, 1H), 5.92 (s, 2H), 4.08 (t, J = 7.5 Hz, 2H), 3.10 (t, J
= 7.5 Hz, 2H), 2.29 (s, 6H); 13C NMR (75.474 MHz, CDCl3), δ
10 (ppm) 136.0, 127.4, 127.0, 122.0, 121.9, 119.3, 118.3, 112.3,
111.2, 105.0, 44.2, 26.7, 12.4; MS-C16H18N2 (238) m/z (%): 238
(M+, 91), 130 (100), 108 (25), 143 (19), 239 (17).
7.33 (m, 4H), 5.85 (s, 2H), 1.96 (s, 6H); 13C NMR (75.474 MHz,
CDCl3), δ (ppm) 131.6, 129.7, 129.2, 128.7, 128.3, 125.2, 124.4,
118.2, 106.4, 13.0; MS-C13H12F3N (239) m/z (%): 239 (M+, 69),
238 (100), 145 (11), 224 (10), 240 (9).
70
2-(2,5-dimethyl-1H-pyrrol-1-yl)benzenethiol (Table 3 entry
7)
1-hexyl-2,5-dimethyl-1H-pyrrole (Table 2 entry 8)
15 Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 5.85
(s, 2H), 3.79 (t, J = 9.0 Hz, 2H), 2.30 (s, 6H), 1.72-1.64 (m, 2H),
Yellow powder, MP = 111-116°C; 1H NMR (300.128 MHz,
CDCl3), δ (ppm) 7.50 (d, J = 9.0 Hz, 1H), 7.32-7.22 (m, 2H),
1.42 (m, 6H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR (75.474 MHz, 75 7.13 (d, J = 6.0 Hz, 1H), 5.93 (s, 2H), 4.2 (broad, 1H), 1.93 (s,
CDCl3), δ (ppm) 127.0, 104.8, 43.5, 31.4, 30.9, 26.5, 22.5, 13.9,
12.3; MS-C12H21N (179) m/z (%): 179 (M+, 86), 108 (100), 109
20 (66), 94 (35), 122 (31).
6H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 173.5, 136.8,
136.1, 129.3, 128.5, 127.1, 126.0, 117.0, 106.2, 12.6; MS-
C12H13NS (203) m/z (%): 203 (M+, 53), 188 (100), 186 (42), 200
(25), 173 (17).
80
2,5-dimethyl-1-phenyl-1H-pyrrole (Table 3 entry 1)
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.45-
25 7.33 (m, 3H), 7.18 (d, J = 6.0 Hz, 1H), 5.88 (s, 2H), 2.00 (s, 6H);
13C NMR (75.474 MHz, CDCl3), δ (ppm) 138.9, 130.0, 129.0,
128.7, 128.2, 127.6, 105.6, 12.7; MS-C12H13N (171) m/z (%):
171 (M+, 80), 170 (100), 77 (14), 154 (11), 156 (10).
1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole (Table
3
entry 8)
1
Brown needle, MP = 58°C; H NMR (300.128 MHz, CDCl3), δ
85 (ppm) 7.12 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H) 5.87 (s,
2H), 3.83 (s, 3H), 2.01 (s, 6H); 13C NMR (75.474 MHz, CDCl3),
δ (ppm) 158.7, 131.5, 129.0, 128.8, 114.0, 105.1, 55.2, 12.8; MS-
C13H15NO (201) m/z (%): 201 (M+, 100), 200 (67), 186 (24), 125
(18), 202 (13).
30 2,5-dimethyl-1-(m-tolyl)-1H-pyrrole (Table 3 entry 2)
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.32-
7.00 (m, 4H), 5.89 (s, 2H), 2.39 (s, 3H), 2.03 (s, 6H); 13C NMR
(75.474 MHz, CDCl3), δ (ppm) 138.9, 138.8, 128.8, 128.7, 128.3,
125.1, 105.4, 21.2, 13.0; MS-C13H15N (184) m/z (%): 184 (M+,
35 100), 185 (77), 170 (11), 168 (10), 186 (10).
90
4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylaniline (Table
entry 1)
4
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.09
(d, J = 6.0 Hz, 1H), 6.54-6.47 (m, 2H), 5.87 (s, 2H), 3.66 (s, br,
95 2H), 2.19 (s, 3H), 2.04 (s, 6H); 13C NMR (75.474 MHz, CDCl3),
δ (ppm) 144.9, 137.6, 130.6, 128.6, 121.5, 118.0, 114.2, 105.0,
17.0, 12.8; MS-C13H16N2 (200) m/z (%): 200 (M+, 100), 199 (88),
144 (17), 201 (16), 185 (16).
1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (Table 3 entry
3)
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.15-
40 7.07 (m, 4H), 5.86 (s, 2H), 1.98 (s, 6H); 13C NMR (75.474 MHz,
CDCl3), δ (ppm) 163.4, 160.1, 129.8, 128.8, 116.1, 115.8, 105.7,
12.9; MS-C12H12FN (189) m/z (%): 189 (M+, 83), 188 (100), 95 100 2-(2,5-dimethyl-1H-pyrrol-1-yl)aniline (Table 4 entry 2)
1
(13), 174 (12), 172 (10).
Black needle, MP = 70-73°C; H NMR (300.128 MHz, CDCl3),
δ (ppm) 7.17-7.10 (m, 1H), 7.00 (d, J = 9.0 Hz, 1H), 6.74-6.69
(m, 2H), 5.85 (s, 2H), 3.37 (s, br, 2H), 1.90 (s, 6H); 13C NMR
(75.474 MHz, CDCl3), δ (ppm) 144.1, 129.3, 129.3, 128.4, 124.4,
45 1-(4-ethylphenyl)-2,5-dimethyl-1H-pyrrole (Table 3 entry
4)
1
Dark brown oil; H NMR (300.128 MHz, CDCl3), δ (ppm) 7.30 105 118.2, 115.5, 105.8, 12.3; MS-C12H14N2 (186) m/z (%): 186 (M+,
(d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 5.93 (s, 2H), 2.74
(q, J = 7.5 Hz, 2H), 2.07 (s, 6H), 1.32 (t, J = 7.5 Hz, 3H); 13C
50 NMR (75.474 MHz, CDCl3), δ (ppm) 143.5, 136.4, 128.3, 127.9,
115.1, 105.3, 28.4, 15.4, 12.9; MS-C14H17N (199) m/z (%): 199
(M+, 93), 198 (100), 143 (17), 154 (15), 200 (13).
66), 171 (100), 132 (37), 131 (28), 185 (20).
5-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)aniline (Table
110 entry 3)
4
Tan powder, MP = 87-90°C; 1H NMR (300.128 MHz, CDCl3), δ
(ppm) 6.90 (d, J = 9.0 Hz, 1H), 6.71-6.66 (m, 2H), 5.85 (s, 2H),
3.45 (s, br, 2H), 1.89 (s, 6H); 13C NMR (75.474 MHz, CDCl3), δ
(ppm) 145.2, 134.7, 130.3, 128.4, 122.8, 118.1, 115.1, 106.2,
1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrole (Table 3 entry
55 5)
1
Brown needle, MP = 75°C; H NMR (300.128 MHz, CDCl3), δ
(ppm) 7.60 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 5.92 (s, 115 12.3; MS-C12H13ClN2 (220) m/z (%): 220 (M+, 67), 205 (100),
2H), 2.04 (s, 6H); 13C NMR (75.474 MHz, CDCl3), δ (ppm)
207 (32), 222 (17), 219 (16).
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
Green Chemistry
DOI: 10.1039/C4GPC0a1g52e3A10 of 13
(263) m/z (%): 263 (M+, 100), 207 (26), 262 (22), 248 (21),
8-(2,5-dimethyl-1H-pyrrol-1-yl)naphthalen-1-amine (Table
4 entry 4)
264 (20).
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.18-
7.05 (m, 6H), 6.25 (d, J = 9.0 Hz, 2H), 3.97 (s, br, 2H), 1.08 (s,
6H); 13C NMR(75.474 MHz, CDCl3), δ (ppm) 145.6, 137.2,
129.0, 128.0, 127.5, 125.2, 124.9, 121.9, 117.9, 115.4, 113.4,
103.3, 11.6; MS-C16H16N2 (236) m/z (%): 236 (M+, 58), 221
(100), 206 (41), 222 (17), 205 (15).
5
4,5-dimethyl-2-(2-methyl-5-phenyl-1H-pyrrol-1-yl)aniline
60 (Table 6 entry 3)
Dark yellow oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm)
7.21-7.02 (m, 5H), 6.77 (s, 1H), 6.49 (s, 1H), 6.40 (d, J = 3.0 Hz,
1H), 6.09 (d, J = 3.0 Hz, 1H), 3.28 (s, br, 2H), 2.16 (s, 3H), 2.08
(s, 3H), 2.02 (s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm)
65 141.33, 137.59, 133.39, 133.35, 131.93, 129.98, 128.00, 126.62,
126.45, 125.57, 122.69, 117.22, 108.41, 107.36, 19.61, 18.69,
12.49; MS-C19H20N2 (276) m/z (%): 276 (M+, 100), 261 (75),
275 (32), 277 (21), 199 (20).
10
2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,5-dimethylaniline (Table
4 entry 5)
1
Black crystal, MP = 80-83°C; H NMR (300.128 MHz, CDCl3),
δ (ppm) 6.71 (s, 1H), 6.51 (s, 1H), 5.82 (s, 2H), 3.16 (s, br, 2H),
15 2.13 (s, 3H), 2.07 (s, 3H), 1.89 (s, 6H); 13C NMR (75.474 MHz,
CDCl3), δ (ppm) 141.6, 137.6, 129.8, 128.4, 126.3, 122.0, 117.0,
105.5, 19.6, 18.7, 12.4; MS-C14H18N2 (214) m/z (%): 214 (M+,
51), 199 (100), 200 (15), 213 (14), 197 (11).
70 2-methyl-5-phenyl-1H-pyrrole (Table 6 entry 4)
Pink solid, MP = 81°C; 1H NMR (300.128 MHz, CDCl3), δ
(ppm) 8.11 (s, br, 1H), 7.37 (d, J = 6.0 Hz, 2H), 7.27 (t, J =
7.5Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H),
5.91 (d, J = 3.0 Hz, 1H), 2.26 (s, 3H); 13C NMR (75.474 MHz,
20 1,6-bis(2,5-dimethyl-1H-pyrrol-1-yl)hexane (Table 4 entry
6)
Ivory powder, MP = 104-105°C; 1H NMR (300.128 MHz,
CDCl3), δ (ppm) 5.86 (s, 4H), 3.81 (t, J = 7.5 Hz, 4H), 2.31 (s, 75 CDCl3), δ (ppm); 132.88, 131.09, 128.74, 127.95, 125.56, 123.27,
12H), 1.75-1.70 (m, 4H), 1.50-1.47 (m, 4H); 13C NMR (75.474
25 MHz, CDCl3), δ (ppm) 127.1, 104.9, 43.4, 30.9, 26.6, 12.4; MS-
C18H28N2 (272) m/z (%): 272 (M+, 100), 108 (39), 164 (33), 109
(31), 273 (20).
107.85, 106.09, 13.12 MS-C11H11N (157) m/z (%): 157 (M+, 71),
156 (100), 128 (11), 77 (8), 158 (7).
2,5-diphenyl-1-(3-phenylpropyl)-1H-pyrrole (Table 6 entry
2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methylaniline (Table
4
80 5)
30 entry 7)
Yellow oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.36-7.19
(m, 11H), 6.97 (m, 2H), 6.69-6.66 (m, 2H), 6.19 (s, 2H), 4.00 (t,
J = 7.5 Hz, 2H), 2.03 (t, J = 7.5 Hz, 2H), 1.44 (quin, J = 7.5 Hz,
2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 140.91, 136.47,
85 134.00, 128.87, 128.45, 128.15, 127.94, 126.86, 125.62, 109.50,
44.74, 32.33, 31.80; MS-C25H23N (337) m/z (%): 337 (M+, 52),
232 (100), 233 (27), 91 (16), 338 (14).
Dark brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 6.88
(d, J = 9.0 Hz, 1H), 6.58-6.55 (m, 2H), 5.88 (s, 2H), 3.33 (s, br,
2H), 2.28 (s, 3H), 1.94 (s, 6H); 13C NMR (75.474 MHz, CDCl3),
δ (ppm) 143.7, 139.2, 129.8, 129.5, 128.9, 119.1, 116.1, 105.6,
35 21.3, 12.3; MS-C12H20N2 (200) m/z (%): 200 (M+, 70), 185
(100), 199 (19), 183 (14), 186 (14).
2-methyl-5-phenyl-1-(3-phenylpropyl)-1H-pyrrole (Table 6
1-(4-methoxyphenyl)-2,5-diphenyl-1H-pyrrole (Table
6
entry 1)
90 entry 6)
40 Dark yellow oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm)
7.34-7.15 (m, 8H), 7.03 (d, J = 9.0 Hz, 2H), 6.10 (d, J = 3.0 Hz,
1H), 5.95 (d, J = 3.0 Hz, 1H), 3.88 (t, J = 7.5 Hz, 2H), 2.46 (t, J
= 7.5 Hz, 2H), 2.25 (s, 3H), 1.87 (quin, J = 7.5 Hz, 2H); 13C
NMR (75.474 MHz, CDCl3), δ (ppm) 140.88, 134.24, 133.78,
45 128.82, 128.32, 128.30, 128.11, 126.53, 125.90, 107.84, 106.76,
43.53, 32.73, 32.16, 12.63; MS-C20H21N (275) m/z (%): 275 (M+,
40), 170 (100), 171 (28), 91 (15), 156 (12).
1
Off white solid, MP = 223°C; H NMR (300.128 MHz, CDCl3),
δ (ppm) 7.18-7.00 (m, 10H), 6.89 (d, J = 9.0 Hz, 2H), 6.69 (d, J
= 9.0 Hz, 2H), 6.40 (s, 2H), 3.71 (s, 3H); 13C NMR (75.474
MHz, CDCl3), δ (ppm) 158.59, 136.05, 133.46, 132.02, 129.94,
95 128.81, 128.02, 126.26, 114.06, 109.78, 55.49; MS-C23H19NO
(325) m/z (%): 325(M+, 100), 326 (24), 207 (17), 310 (12), 178
(10).
1-(4-methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrole (Table
6 entry 2)
2-(2,5-diphenyl-1H-pyrrol-1-yl)-4,5-dimethylaniline (Table
100 4 entry 7)
1
50 Ivory solid, MP = 107°C; H NMR (300.128 MHz, CDCl3), δ
1
Pale yellow solid, MP = 189-190°C; H NMR (300.128 MHz,
(ppm) 7.13-7.00 (m, 7H), 6.84 (d, J = 9.0 Hz, 2H), 6.31 (d, J
= 6.0 Hz, 1H), 6.40 (d, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.08 (s,
3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 158.54,
134.14, 133.52, 132.13, 131.87, 129.34, 127.88, 127.64,
55 125.50, 114.05, 108.25, 107.11, 55.32, 13.21; MS-C18H17NO
CDCl3), δ (ppm) 7.15-7.10 (m, 10H), 6.69 (s, 1H), 6.49 (s, 1H),
6.37 (s, 2H), 3.24 (s, br, 2H), 2.09 (s, 3H), 1.96 (s, 3H); 13C
NMR (75.474 MHz, CDCl3), δ (ppm) 141.26, 137.68, 135.68,
105 133.07, 130.58, 127.94, 127.89, 126.59, 126.18, 122.68, 117.42,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

View Article Online
DOI: 10.1039/C4GC01523A
Page 11 of 13
Green Chemistry
109.83, 19.68, 18.71; MS-C24H22N2 (338) m/z (%): 338 (M+,
100), 234 (28), 337 (26), 339 (24), 261 (13).
9.0 Hz, 2H), 6.74 (t, J = 7.5 Hz, 2H), 6.50 (d, J = 3.0 Hz, 2H),
3.80 (s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 159.99,
135.05, 131.03, 130.99, 130.33, 126.86, 123.94, 123.81, 114.30,
109.37, 55.45; MS-C19H15NOS2 (337) m/z (%): 337 (M+, 100),
55 338 (24), 339 (12), 322 (10), 213 (8).
2,3,5-triphenyl-1-(3-phenylpropyl)-1H-pyrrole (Table
6
5
entry 8)
Yellow oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.52-7.34
(m, 9H), 7.26-7.09 (m, 9H), 6.79 (dd, J = 4.5 Hz, 2H), 6.51 (s,
1H), 3.97 (t, J = 7.5 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.59 (quin,
J = 7.5 Hz, 2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm)
2-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)-4,5-
dimethylaniline (Table 6 entry 13)
1
Yellow solid, MP = 127°C; H NMR (300.128 MHz, CDCl3), δ
10 140.77, 136.24, 135.14, 133.72, 133.30, 131.91, 131.14, 129.94,
129.60, 129.47, 129.17, 127.99, 127.89, 127.65, 127.56, 127.02,
125.64, 125.00, 122.96, 109.49, 44.45, 32.43, 31.72; MS-
C31H27N (413) m/z (%): 413 (M+, 60), 308 (100), 309 (35), 414
(19), 189 (85).
60 (ppm) 6.95(t, J = 3.0 Hz, 2H), 6.85 (s, 1H), 6.78-6.65 (m, 5H),
6.54 (s, 2H), 3.30 (s, br, 2H), 2.20 (s, 3H), 2.08 (s, 3H); 13C
NMR (75.474 MHz, CDCl3), δ (ppm) 142.65, 139.47, 134.62,
131.12, 129.58, 127.11, 126.99, 123.47, 122.90, 121.32, 117.61,
109.43, 19.93, 18.74; MS-C20H18N2S2 (350) m/z (%): 350 (M+,
65 100), 351 (31), 240 (27), 317 (20), 241 (10).
15
1-(4-methoxyphenyl)-2,3,5-triphenyl-1H-pyrrole (Table 6
entry 9)
tert-butyl (4-(2,5-dimethyl-1H-pyrrol-1-yl)benzyl)-carba-
mate (Table 7 entry 1)
Light yellow solid, MP = 139°C; 1H NMR (300.128 MHz,
CDCl3), δ (ppm) 7.94(d, J = 6.0 Hz, 1H), 7.45(m, 1H), 7.20-7.01
Dark orange oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.31
20 (m, 13H), 6.84 (t, J = 7.5 Hz, 2H), 6.65 (s, 2H), 6.62 (s, 1H), 70 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 5.84 (s, 2H), 5.01
3.69 (s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 159.25,
136.16, 134.86, 132.70, 132.44, 131.45, 129.96, 129.66, 129.49,
129.12, 129.09, 127.94, 127.82, 127.14, 126.84, 126.22, 125.38,
123.21, 113.60, 109.61, 55.23; MS-C23H29NO (401) m/z (%):
25 401(M+, 100), 402 (31), 403 (5), 386 (4), 400 (4).
(s, br, 1H), 4.32 (s, 2H), 1.96 (s, 6H), 1.43 (s, 9H); 13C NMR
(75.474 MHz, CDCl3), δ (ppm) 155.87, 138.41, 137.82, 128.64,
128.18, 127.84, 105.54, 79.54, 44.00, 28.30, 12.93; MS-
C18H24N2O2 (300) m/z (%): 300 (M+, 85), 244 (100), 200 (86),
75 199 (78), 184 (35).
tert-butyl (4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-carba-
mate (Table 7 entry 2)
4,5-dimethyl-2-(2,3,5-triphenyl-1H-pyrrol-1-yl)aniline
(Table 6 entry 10)
Off-white solid, MP = 175oC ; 1H NMR (300.128 MHz, CDCl3),
80 δ (ppm) 7.38 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 6.66
(s, br, 1H), 5.83 (s, 2H), 1.95 (s, 6H), 1.49 (s, 9H); 13C NMR
(75.474 MHz, CDCl3), δ (ppm) 152.94, 138.01, 133.86, 129.10,
128.90, 119.02, 105.61, 81.05, 28.51, 13.17; MS-C17H22N2O2
(286) m/z (%): 286 (M+, 28), 186 (100), 185 (63), 230 (53), 130
85 (34).
1
Clear oil; H NMR (300.128 MHz, CDCl3), δ (ppm) 7.15-7.10
30 (m, 10H), 6.69 (s, 1H), 6.49 (s, 1H), 6.37 (s, 2H), 3.24 (s, br, 2H),
2.09 (s, 3H), 1.96 (s, 3H); 13C NMR (75.474 MHz, CDCl3), δ
(ppm) 141.26, 137.68, 135.68, 133.07, 130.58, 127.94, 127.89,
126.59, 126.18, 122.68, 117.42, 109.83, 19.68, 18.71; MS-
C30H26N2 (414) m/z (%): 414 (M+, 100), 310 (34), 415 (32), 337
35 (19), 413 (18).
tert-butyl (6-(2,5-dimethyl-1H-pyrrol-1-yl)hexyl)carbamate
(Table 7 entry 3)
1-(3-phenylpropyl)-2,5-di(thiophen-2-yl)-1H-pyrrole
(Table 6 entry 11)
1
Brown oil; H NMR (300.128 MHz, CDCl3), δ (ppm) 5.56 (s,
90 2H), 4.51 (s, br, 1H), 3.53 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz,
2H), 2.03 (s, 6H), 1.43-1.38 (m, 2H), 1.24 (s, 9H), 1.25-1.17(m,
6H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 155.66, 126.91,
104.54, 78.59, 45.57, 43.17, 30.58, 28.08, 26.28, 26.16, 12.17,
8.38; MS-C17H30N2O2 (294) m/z (%): 294 (M+, 72), 108 (100),
95 109 (85), 237 (67), 221 (45).
Brown oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.21-6.85
40 (m, 11H), 6.25 (s, 2H), 4.07 (t, J = 7.5 Hz, 2H), 2.35 (t, J = 7.5
Hz, 2H), 1.80 (quin, J = 7.5 Hz, 2H); 13C NMR (75.474 MHz,
CDCl3), δ (ppm) 140.81, 134.77, 128.35, 128.29, 128.19, 127.28,
125.88, 125.86, 125.20, 110.81, 44.62, 32.65, 32.36; MS-
C21H19NS2 (349) m/z (%): 349 (M+, 100), 245 (40), 230 (32), 244
45 (31), 91 (28).
5-(benzyloxy)-3-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)-
1H-indole (Table 7 entry 4)
1
Brown oil; H NMR (300.128 MHz, CDCl3), δ (ppm) 7.98 (s,
1-(4-methoxyphenyl)-2,5-di(thiophen-2-yl)-1H-pyrrole
(Table 6 entry 12)
100 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.43-7.31 (m, 3H), 7.21 (d, J = 9.0
Hz, 1H), 6.97 (d, J = 12.0 Hz, 2H), 6.82 (s, 1H), 5.83 (s, 2H),
5.13 (s, 2H), 3.98 (t, J = 7.5 Hz, 2H), 2.99 (t, J = 7.5 Hz, 2H),
2.18 (s, 6H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 153.34,
Pale green solid, MP = 183°C; 1H NMR (300.128 MHz, CDCl3),
50 δ (ppm) 7.18-7.13 (m, 2H), 6.98 (d, J = 3.0 Hz, 2H), 6.84 (d, J =
10 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
Green Chemistry
DOI: 10.1039/C4GPC0a1g52e3A12 of 13
137.89, 131.77, 128.82, 128.09, 127.87, 127.81, 127.76, 123.22,
113.21, 112.63, 112.24, 105.41, 102.21, 71.13, 44.60, 27.19,
12.76; MS-C23H24N2O (344) m/z (%): 344 (M+, 75), 236 (100),
253 (48), 91 (31), 108 (28).
Notes and References
1
P. A. Jacobi, L. D. Coults, J. S. Guo and S. I. Leung, J. Org. Chem.,
2000, 65, 205.
5
2
A. Fürstner, Angew. Chem., 2003, 115, 3706; Angew. Chem. Int. Ed.
2003, 42, 3528.
A. G. MacDiarmid, Synth. Met., 1997, 84, 27.
tert-butyl (4-(2-methyl-5-phenyl-1H-pyrrol-1-yl)benzyl)-
carbamate (Table 7 entry 5)
3
4
(a) A. Hantzsch, Ber. Dtsch. Chem. Ges. 1890, 23, 1474; (b) D. C.
Beelen van, J. Wolters and A. Gen van der, Recl. Trav. Chim. Pays-
Bas 1979, 98, 437; (c) A. W. Trautwein, R. D. Süßmuth and G. Jung,
Bioorg. Med. Chem. Lett. 1998, 8, 2381; (d) V. F. Ferreira, M. C. B.
V. De Souza, A. C. Cunha, L. O. R. Pereira and M. L. G. Ferreira,
Org. Prep. Proced. Int. 2002, 33, 411.
(a) L. Knorr, Ber. Dtsch. Chem. Ges. 1884, 17, 1635; (b) G. G.
Kleinspehn, J. Am. Chem. Soc. 1955, 77, 1546; (c) E. Fabiano and B.
T. Golding, J. Chem. Soc., Perkin Trans. 1 1991, 3371; (d) J. M.
Hamby and J. C. Hodges, Heterocycles 1993, 35, 843; (e) A.
Alberola, A. G. Ortega, M. L. Sadaba and C. Sanudo, Tetrahedron
1999, 55, 6555; (f) I. Elghamry, Synth. Commun. 2002, 32, 897.
(a) C. Paal, Ber. Dtsch. Chem. Ges. 1885, 18, 367; (b) R. A. Jones and
G. P. Been, The Chemistry of Pyrroles ; Academic Press: New York,
1977, Chapter 3; (c) P. K. Chiu, K. H. Lui, P. N. Maini and M. P.
Sammes, J. Chem. Soc., Chem. Commun. 1987, 109; (d) P. K. Chiu
and M. P. Sammes, Tetrahedron 1990, 46, 3439.
(a) S. X. Yu and P. W. L. Quesne, Tetrahedron Lett. 1995, 36, 6205;
(b) J. S. Yadav, B. V. S. Reddy, B. Eeshwaraiah and M. K. Gupta,
Tetrahedron Lett. 2004, 45, 5873; (c) R. U. Braun, K. Zeitler and T. J.
Mueller, J. Org. Lett. 2001, 3, 3297; (d) M. Curini, F. Montanari, O.
Rosati, E. Lioy and R. Margarita, Tetrahedron Lett. 2003, 44, 3923;
(e) B. K. Banik, S. Samajda and I. Banik, J. Org. Chem. 2004, 69,
213; (f) G. Balme, Angew. Chem., Int. Ed. 2004, 43, 6238; (g) A. R.
Bharadwaj and K. A. Scheidt, Org. Lett. 2004, 6, 2465; (h) R. Ballini,
L. Barboni, G. Bosica and M. Petrini, Synlett 2000, 391; (i) G.
Minetto, L. F. Raveglia and M. Taddei, Org. Lett. 2004, 6, 389; (j) G.
Minetto, L. F. Raveglia, A. Sega and M. Taddei, Eur. J. Org. Chem.
2005, 5277; (k) B. K. Banik, I. Banik, M. Renteria and S. K.
Dasgupta, Tetrahedron Lett. 2005, 46, 2643; (l) S. Raghavan and K.
Anuradha, Synlett 2003, 711; (m) B. Quiclet-Sire, L. Quintero, G.
Sanchez-Jimenez and Z. Zard, Synlett 2003, 75; (n) B. Wang, Y. R.
Kang, T. Yang and L. M. Yang, Synth. Commun. 2005, 35, 1051; (o)
B. Wang, Y. L. Gu, C. Luo, T. Yang, L. M. Yang and J. S. Suo,
Tetrahedron Lett. 2004, 45, 3417.
(a) A. W. Trautwein and G. Jung, Tetrahedron Lett. 1998, 39, 8263;
(b) M. S. South, T. L. Jakuboski, M. D. Westmeyer and D. R.
Dukesherer, Tetrahedron Lett. 1996, 37, 1351; (c) A. Padwa, D. C.
Deen, D. C. Hertzog, W. R. Wadler and L. Zhi, Tetrahedron 1992,
48, 7565; (d) T. N. Danks and D. Velo-Rego, Tetrahedron Lett. 1994,
35, 9443; (e) A. Furstner and B. Bogdanovic, Angew. Chem., Int. Ed.
1996, 35, 2442; (f) T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1
1998, 615; (g) B. Gabriele, G. Salerno and A. Fazio, J. Org. Chem.
2003, 68, 7853; (h) G. Bashiardes, I. Safir, F. Barbot and J.
Laduranty, Tetrahedron Lett. 2003, 44, 8417.
Off-white solid, MP = 125oC; 1H NMR (300.128 MHz, CDCl3),
δ (ppm) 7.17 (d, J = 9.0 Hz, 2H), 7.04-6.95 (m, 7H), 6.26 (d, J =
10 7.5 Hz, 1H), 6.01 (d, J = 7.5 Hz, 1H), 4.86 (s, br, 1H), 4.26 (s,
2H), 2.04 (s, 3H), 1.39 (s, 9H); 13C NMR (75.474 MHz, CDCl3),
δ (ppm) 155.86, 138.30, 138.08, 134.07, 133.37, 131.65, 128.41,
127.90, 127.75, 127.69, 125.61, 108.65, 107.48, 79.63, 44.03,
28.34, 13.30; MS-C23H26N2O2 (362) m/z (%): 362 (M+, 1), 262
15 (100), 207 (35), 261 (25), 263 (21).
5
tert-butyl (4-(2-methyl-5-phenyl-1H-pyrrol-1-yl)phenyl)-
carbamate (Table 7 entry 6)
6
7
1
Off-white solid, MP = 173oC; H NMR (300.128 MHz, CDCl3),
20 δ (ppm) 7.31 (d, J = 6.0 Hz, 2H), 7.09-7.00 (m, 7H), 6.63 (s, br,
1H), 6.31 (d, J = 3.0 Hz, 1H), 6.05 (d, J = 3.0 Hz, 1H), 2.07 (s,
3H), 1.49 (s, 9H); 13C NMR (75.474 MHz, CDCl3), δ (ppm)
152.85, 137.80, 134.26, 133.66, 132.04, 129.11, 128.18, 127.93,
125.84, 118.75, 108.67, 107.54, 81.02, 28.53, 13.51; MS-
25 C22H24N2O2 (348) m/z (%): 348 (M+, 1), 248 (100), 207 (27), 206
(24), 247 (20).
tert-butyl (6-(2-methyl-5-phenyl-1H-pyrrol-1-yl)hexyl)-
carbamate (Table 7 entry 7)
30 Yellow oil; 1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.34-7.22
(m, 5h), 6.02 (d, J = 4.5 Hz, 1H), 5.89 (d, J = 4.5 Hz, 1H), 4.40
(s, br, 1H), 3.79 (t, J = 6.0 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.24
(s, 3H), 1.46-1.33 (m, 2H), 1.29 (s, 9H), 1.27-1.20(m, 6H); 13C
NMR (75.474 MHz, CDCl3), δ (ppm) 134.33, 133.75, 129.61,
35 128.91, 128.25, 126.55, 118.68, 107.70, 106.64, 78.98, 43.81,
40.29, 30.79, 29.76, 28.36, 26.14, 26.11, 12.68; MS-C22H32N2O2
(356) m/z (%): 356 (M+, 55), 170 (100), 156 (31), 299 (30), 171
(27).
8
40 5-(benzyloxy)-3-(2-(2-methyl-5-phenyl-1H-pyrrol-1-
yl)ethyl)-1H-indole (Table 7 entry 8)
1
Greenish oil; H NMR (300.128 MHz, CDCl3), δ (ppm) 7.78 (s,
br, 1H), 7.46-7.13 (m, 10H), 6.86 (dd, J = 4.5 Hz, 1H), 6.71-6.68
(m, 3H), 6.09 (d, J = 3.0 Hz, 1H), 5.95 (d, J = 3.0 Hz, 1H), 4.96
45 (s, 2H), 4.10 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.25 (s,
3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 153.09, 137.54,
134.31, 133.71, 131.37, 129.68, 129.07, 128.54, 128.49, 128.28,
127.79, 127.59, 126.72, 122.67, 112.97, 112.23, 111.76, 107.96,
106.72, 101.76, 70.92, 44.80, 27.04, 12.70; MS-C28H26N2O (406)
50 m/z (%): 406 (M+, 100), 236 (96), 315 (53), 91 (40), 170 (36).
9
C. Paal, Chem. Ber. 1884, 17, 2756.
10 L. Knorr, Chem. Ber. 1884, 17, 1635.
11 R. B. N. Baig and R. S. Varma, Green Chem. 2013, 15, 398.
12 R. Srinivas, B. Thirupathi, J, K. P. Kumar, A. N. Prasad and B. M.
Reddy, Curr. Org. Chem. 2012, 16, 2482.
13 M. Banik, B. Ramirez, A. Reddy, D. Bandyopadhyay and B. K.
Banik, Org. Med. Chem. Lett. 2012, 2, 4.
14 Z. Wang, Paal-Knorr Pyrrole Synthesis. in Comprehensive Organic
Name Reactions and Reagents. 2010, Wiley, Hoboken, NJ, 2107–
2110.
15 L.Ackermann, L.Kaspar and C. J.Gschrei, Chem. Commun., 2004,
2824; A. R. Katritzky, S. Ledoux and S. Nair, J. Org. Chem., 2003,
68, 5728; J. Zhao and R. C. Larock, Org. Lett., 2005, 7, 701; R. B.
Bedford and C. S. Cazin, Chem. Commun., 2002, 2310–2311; Z. Liu
and R. C. Larock, Org. Lett., 2004, 6, 3739; X. Cai and V. Snieckus,
Org. Lett., 2004, 6, 2293; B. K. Banik, S. Samajdar and I. Banik, J.
Org. Chem., 2004, 69, 213.
Acknowledgement
Financial support provided by University of Massachusetts
Boston is gratefully acknowledged. B.N. is grateful for the
55 predoctoral fellowship received from the Turkish National
Science Foundation (TUBITAK BIDEB 2214).
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 11

View Article Online
DOI: 10.1039/C4GC01523A
Page 13 of 13
Green Chemistry
16 (a) Aqueous Microwave-Assisted Chemistry, ed. V. Polshettiwar and
R. S. Varma, RSC Publishing, Cambridge, 2010; (b) V. Polshettiwar
and R. S. Varma, Acc. Chem. Res., 2008, 41, 629; (c) V. Polshettiwar
and R. S. Varma, Chem. Soc. Rev., 2008, 37, 1546; (d) D. Dallinger
and C. O. Kappe, Chem. Rev., 2007, 107, 2563; (e) N. E. Leadbeater,
Chem. Commun., 2005, 2881.
17 (a) R. Martinez-Palou, Mol. Diversity, 2009, 13, 3; (b) E. Boros, K. R.
Seddon and C. R. Strauss, Chim. Oggi, 2008, 26(6), 28; (c) N. E.
Leadbeater and H. M. Torenius, in Microwaves in Organic Synthesis,
ed. A. Loupy, Wiley-VCH, Weinheim, 2nd ed., 2006, pp. 327; (d) J.
Habermann, S. Ponzi and S. V. Ley, Mini-Rev. Org. Chem., 2005, 2,
125; (e) N. E. Leadbeater, H. M. Torenius and H. Tye, Comb. Chem.
High Throughput Screen., 2004, 7, 511.
18 (a) R. S. Varma and Y. Ju, in Microwaves in Organic Synthesis, ed A.
Loupy,Wiley-VCH,Weinheim, 2nd ed., 2006, pp. 362–415; (b) R. S.
Varma, Green Chem., 1999, 1, 43; (c) A. Loupy, A. Petit, J. Hamelin,
F. Texier-Boullet, P. Jacquault and D. Mathe, Synthesis, 1998, 1213.
19
P. B. Cranwell, M. O'Brien, D. L. Browne, P. Koos, A. Polyzos, M.
Pena-Lopez and S. V. Ley, Org. Biomol. Chem, 2012, 10, 5774.
20 M. Abid, A. Spaeth and B. Török, Adv. Synth. Catal., 2006, 348,
2191; A. Solan, B. Nişanci, M. Belcher, J. Young, C. Schäfer, K. A.
Wheeler, B. Török and R. Dembinski, Green Chem. 2014, 16, 1120.
21 M. Abid, S.M. Landge and B. Török, Org. Prep. Proc. Int ., 2006,
38, 495; A. Kulkarni, A. Dastan and B. Török, Green Chem. 2012,
14, 17.
22 M. Abid, O. De. Paolis and B. Török, Synlett., 2008, 410; A.
Kulkarni and B. Török, Green Chem. 2010, 12, 875.
23 P. G. M. Wutts and T. Greene, Greene’s Protecting Groups in
Organic Synthesis, 4th ed., Wiley, Hoboken, 2007.
24 V. Amarnath, D. C. Anthony, K. Amarnath, W. M. Valentine, L. A.
Wetterau and D. G. Graham, J. Org. Chem. 1991, 56, 6924; V.
Amarnath, K. Amarnath, W. M. Valentine, M. A. Eng and D. G.
Graham Chem. Res. Toxicol. 1995, 8, 234.
12 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]