Nickel-Catalyzed Synthesis of N-Substituted Pyrroles Using Diols with Aryl- and Alkylamines

Article abstract of DOI:10.1021/acs.joc.8b02666

Herein, nickel-catalyzed sustainable strategy for the synthesis of N-substituted pyrroles using butene-1,4-diols and butyne-1,4-diols with a series of aryl-, alkyl-, and heteroarylamines is reported. The catalytic protocol is tolerant of free alcohol, halide, alkyl, alkoxy, oxygen heterocycles, activated benzyl, and the pyridine moiety and resulted in up to 90% yield. Initial mechanistic studies involving defined nickel catalyst, determination of rate, and order of reaction including deuterium-labeling experiments were performed for pyrrole synthesis.

Full text of DOI:10.1021/acs.joc.8b02666

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Article
Nickel-Catalyzed Synthesis of N-substituted
Pyrroles using Diols with Aryl and Alkyl Amines
Khushboo Singh, Lalit Mohan Kabadwal, Sourajit Bera, Anitha Alanthadka, and Debasis Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02666 • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 26, 2018
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The Journal of Organic Chemistry
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Nickel-Catalyzed Synthesis of N-substituted Pyrroles using Diols
with Aryl and Alkyl Amines
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Khushboo Singh, Lalit Mohan Kabadwal, Sourajit Bera, Anitha Alanthadka, and Debasis Banerjee*
Department of Chemistry, Laboratory of Catalysis and Organic Synthesis, Indian Institute of Technology Roorkee, Roorkee
247667 (India)
ABSTRACT: Herein, nickel-catalyzed sustainable strategy for the synthesis of N-substituted pyrroles using butene-1,4-diols and
butyne-1,4-diols with a series of aryl, alkyl and hetero-aryl amines is reported. The catalytic protocol is tolerant to free alcohol,
halides, alkyl, alkoxy, oxygen heterocycles, activated benzyl and the pyridine moiety and resulted in up to 90% yield. Initial
mechanistic studies involving defined nickel-catalyst, determination of rate and order of reaction including deuterium-labeling
experiments were performed for pyrrole synthesis.
KEYWORDS: 1,4-Diols • Nickel • Earth-abundant metal • Amines • N-substituted pyrroles
INTRODUCTION
diols and used of acids in presence of phosphine ligands
resulted other heterocycles.
8
f,i
The use of renewable resources to establish sustainable, atom-
economic and environmentally benign technology for the
production of bulk and speciality chemicals is a challenging
Scheme 1: (i) Metal-catalyzed pyrrole synthesis (ii) Nickel-
catalyzed sustainable synthesis of pyrroles
1
goal in chemical research. In this direction, application of
(
i) Prior art:
lignocellulose derived inexpensive alcohols, are potential and
attractive green alternative to the existing metal-catalyzed
H
N
R2
OH
R2
R1
(a)
NH2
Ir, Ru, Mn
2
transformations. Notably, such catalytic de-hydrogenative
OH
R1
Kempe, Milstein
R3
R3
transformations relieved only water as sole by product and are
in high demand in organic synthesis. Therefore, such processes
could be more attractive if selectively used for pyrrole
synthesis in a tandem fashion in one pot operation.
Pyrroles are omnipresent in natural products, drugs, functional
materials and are used as intermediate in the synthesis of
bioactive molecules and as ligands in catalysis. Poly-pyrroles
R3
3
R2
OH
R1
R2
R3 NH2
Co
N
R1
(b)
(c)
4
OH
Milstein
R3
OH
OH
O
Ru
R4
N
R3 NH2
R1
R1
R4
Beller
4
R2
(ii) Our previous work:
NH2
R5
R5
R2
have extensively used in material chemistry, batteries, and solar
5
cells. Classical methodologies, such as, Hantzsch, Knorr and
1H-pyrroles
Paal-Knorr synthesis as well as others multi-step
transformations are known for pyrroles, unfortunately, harsh
reaction conditions, special substrate designing including
H
N
O
Ni
R2
R1
(d)
(e)
OH
R2
R1
-H2
-
2 H2O
6
generation of stoichiometric waste are key limitations. As a
Present strategy:
R'
result, the recent surge is to develop more vibrant and potential
sustainable technologies, that utilize abundantly available
renewable resources and significantly extend the scope of
Ni
R
NH2
R'
N
R
R = Alkyl, benzyl
aryl, heteroaryl
1-2,7
OH
OH
existing
methodologies.
Though,
acceptorless
-2 H2O
R' = H, Ar
dehydrogenation of alcohols were widely used for pyrrole
synthesis, often limited with noble metal-catalysts, such as, Ru-,
Nevertheless, in terms of sustainability, application of
renewable resources in combination with non-precious earth-
8
-9
and Ir-complexes (Scheme 1, a). For instance, Kempe and
Milstein independently reported the intermolecular cyclization
to pyrroles using secondary alcohol and amino alcohol with Ir-
and Ru-catalysts. Similarly, interesting, contribution by Beller
using Ru-catalyzed multi-component transformations to
substituted pyrroles involving ketones and vicinal diols in
abundant and rare noble metal catalysts are equally important
10-11
for such key catalytic conversions.
Therefore, development
of new catalytic protocols using base metal-catalysts, such as,
Fe, Mn, Ni, Co-etc. are in demand. Though, in this direction,
several approaches were established for pyrrole synthesis using
8
b,c
combination with amines is noteworthy (Scheme 1, c).
Further, un-saturated diols, such as, cis-buten-1,4-diol or butyn-
,4-diols were also used for construction of substituted pyrroles
12
13
14-15
Co, Mn, and Fe-catalysts (Scheme 1, a,b).
Notably, often
these Mn-, and Co-based metal complexes used diethylamine-
1
3
core PNP ligands, pyridinyl-core PNP ligands, PN P ligands as
8f
8g,i
with suitable amines using Pd-, and Ru-catalysts. However,
most of these reported precious-metal catalyzed protocols are
often limited with poor selectivity of pyrroles using butyn-1,4-
5
well as triazinyl-core PN P ligands for selective catalytic
12-13
transformations.
The major concerns associated with these
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phosphine based pincer ligands as well as Knölker type Fe- intermediate C from intermediate B. Thereafter, nickel-
1
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3
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5
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
complexes are their highly expensive nature, required multi-
step synthesis as well as storing and handling under standard
laboratory environments. Overall, in terms of cost-efficiency,
these ligand systems are quite expensive in comparison to the
base-metal catalysts.
catalyzed second isomerisation of alcohol C to intermediate D,
followed by intermolecular cyclization and dehydration lead to
the construction of N-substituted pyrroles 3-6 in one pot
operation (Scheme 2). Additionally, another possibility is that,
intermediate B could undergoes metal-catalyzed isomerization
to intermediate D followed by intermolecular cyclization
facilitate to N-substituted pyrroles 3-6. To the best of our
knowledge, this represents the first report for Ni-catalyzed
phosphine free intermolecular cyclization of various cis-buten-
1,4-diol and butyn-1,4-diol with a range of primary amines to
substituted pyrroles in a tandem fashion.
1
4
On the other hand, in our continuous efforts recently we
established the applications of commercially available bench
1
7
stable ligands with nickel using renewable resources. Overall,
phosphine free catalytic system, use of inexpensive alcohols
and metal-catalysts rendering these transformations sustainable.
Herein, we demonstrated a general, operationally simple and
improved Ni-catalyzed protocol for construction of N-
substituted pyrroles using unsaturated-1,4-diol with aryl, alkyl
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
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2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1. Catalytic screening for Ni-catalyzed synthesis of
8
f-i
a
and heteroaryl amines in up to 90% yield (Scheme 1, e).
pyrrole from 1a with 2a.
Preliminary catalytic and mechanistic studies using deuterium
labelling experiments were performed to establish the
Ni-cat./ligand
Ph
N
Ph
NH2 +
HO
OH
base/solvent
30 °C, 36 h
1a
2a
3a
1
8
f-i
elementary steps for pyrrole synthesis.
3a Conv. (%)b,c
Entry catalyst
Ligand Base
RESULTS AND DISCUSSION
1
2
3
4
5
6
NiBr
NiCl
Ni(acac)2
2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
-
t-BuOK
t-BuOK
22
32
In general, free hydroxyl group in unprotected alcohol has very
strong binding affinity with Ni-catalyst and resist its further
2
t-BuOK
t-BuOK
t-BuOK
5
1
6
transformations. We envisioned that, application of suitable
Ni-catalyst with specific nitrogen ligand, could facilitate to
overcome these long standing problems. To our delight,
recently we established an efficient and general Ni-catalyzed
system for selective mono-alkylation of amines and amides.
Further, we realized the application of 2-(2-aminophenyl)
ethanol as well as β-amino alcohols, having free amines and
hydroxyl groups, for intramolecular cyclization to indole,
pyrroles, pyridine and quinolines using Ni-catalysts (Scheme 1,
NiCl
NiCl
NiCl
2
2
2
.DME
18
75(55)
92(66)
62
Na
2
CO
3
3
3
7d
8e
NiCl2
Na CO
2
NiCl
NiCl
-
2
Na
-
2
CO
55
9
2
9
1
0
Na
Na
Na
2
2
2
CO
CO
CO
3
3
3
13
1
7
d). Having witnessed these impressive results, we envisioned
that cis-butene 1,4-diol could be used with primary amines for
Ni-catalyzed pyrrole synthesis (Scheme 2).
11
NiCl
2
35
1
2
-
-
7
aUnless specified otherwise (entries 1-4), the reaction was carried
out with benzylamine 1a (0.5 mmol), cis-2-butene-1,4-diol 2a (1.0
mmol), Ni-cat. (0.05 mmol), L1 (0.06 mmol), and t-BuOK (0.5
mmol) under an N atmosphere at 130 °C (oil bath) in toluene (2.0
2
mL) for 36 h in a Schlenk tube. Conversion was determined by
GC-MS (isolated yield in parentheses, average yield of two runs).
Scheme 2: Postulated Ni-catalyzed intermolecular
cyclization to pyrroles based on Ref. 14
b
oligomerization (side reaction)
c
d
e
Entries 5-12, 2a (2.0 mmol) was used. 120 °C was used. 110 °C
was used.
isomerization
O
OH
H2O
HO
OH
A
2
a
Ni-H
Ni
Optimization of the catalytic protocol for Ni-catalyzed
synthesis of N-substituted pyrroles. To extend the
possibilities for optimization of the efficient catalytic system
initially we investigated the efficacy of four different nickel pre-
catalysts with bipyridine L1 as ligand of our choice using
benzylamine 1a and cis-butene-1,4-diol 2a (Table 1, entries 1-
-
R-NH2
1
imine formation
R
HN
C
OH
R
N
Allylic amine
B
OH
Ni
Ni
is
o
m
e
ri
z
2
4 and SI Table S1). Using a combination of NiCl /L1 system
Ni-H
Ni-H
a
ti
o
only 32% selectivity to pyrrole was obtained (Table 1, entry 2).
Further, an increment of butene-1,4-diol 2a significantly
increase the product conversion to 75%, with 55% isolated yield
of 3a (Table 1, entry 5 and SI Table S2). Next, application of a
series of nitrogen and phosphorus ligands L2-L11 with variable
electronic and steric nature did not influence much on the
product selectivity and resulted only 29-54% conversion to
product (Table 2 and SI Table S3). However, when the reaction
n
cyclization
H2O
R
HN
N
R
O
D
3-6
Previously we observed that, using a combination of β-amino
alcohols with acetophenones resulted to base catalysed
condensation to imine. Thereafter, in situ Ni-catalyzed
dehydrogenation of alcohol followed by condensation resulted
2 3
was performed using milder base, such as, Na CO almost
17c
quantitative conversion to product 3a was obtained (Table 1,
entry 6 and SI Table S4). Thereafter, when toluene get replaced
by different non-polar
substituted pyrroles in one pot operation (Scheme 1d). On the
14
other hand, based on earlier report, presently we hypothesized
that, initially metal catalysed dehydrogenation or isomerization
of cis-butene-1,4-diol 2a followed by condensation with
primary amine 1 resulted the formation of allylic amine
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The Journal of Organic Chemistry
Table 2. Ligand screening for Ni-catalyzed pyrrole
desired pyrroles in 60-70% yields (3b and 3c). However, when
2,4-dimethoxy benzyl amine was used as coupling partner,
excellent yield of pyrrole was obtained (3d). To our delight, α-
methyl benzyl amine efficiently transformed into the desired
pyrrole in 60% yield (Table 3, 3e).
a,b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
synthesis.
Ni-cat./ligand
Ph
N
Ph
NH2 + HO
OH
t-BuOK
toluene, 130 °C, 36 h
1a
2a
3a
Table 4: Scope of anilines and alcoholsa
NiCl2 (5 mol%)
L1 (6 mol%)
R1
N
N
NH2
+
HO
OH
N
N
N
N
R
L1 (75%); 55%c
2a-b
R'
N
Na2CO3 (0.5 mmol)
toluene, 140 °C, 36 h
L2 (45%)
L3 (44%)
R
1f-p
R' = H, Ar
-
4a l
OMe
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
N
N
N
N
L5 (43%)
L4 (40%)
Ph
P
Ph
P
Ph
Ph
Ph
P
4a, 75%
4b, 75%
4c, 30%
4d, 55%
P
P
Ph
Ph
Ph
P
Ph
Ph
Ph
L8 (54%)
F3C
N
Ph
L7 (54%)
N
N
N
L6 (29%)
Br
Cl
4g, 36%
Ph
Ph
MeO
4h, 30%
P
P
Ph
O
4e, 70%
4f, 90%
O
Ph
PPh2
PPh2
OMe
PPh2
PPh2
L9 (50%)
MeO
MeO
N
L10 (48%)
L11 (49%)
O
N
aUnless specified, the reaction was carried out with benzylamine
N
N
1
a (0.5 mmol), cis-2-butene-1,4-diol 2a (1.0 mmol), NiCl
2
(5
O
N
mol%), Ligand (6 mol%), Base (1.0 equiv.) under N atmosphere
2
4i, 52%
4j, 85%
b
at 130 °C in toluene (2.0 mL) for 36 h. Conversion of 3a was
MeO
4k, 45%
4l, 45%b
c
determined by GC-MS. Isolated yield.
aReaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), NiCl
mmol), L1 (0.03 mmol), Na CO (0.5 mmol), toluene (2.0 mL),
Schlenk tube under N atmosphere, 140 °C oil bath, 36 h reaction
time. 2a (4.0 mmol), NiCl (0.05 mmol), L1 (0.06 mmol), Na CO
(1.0 mmol) was used. Isolated yield was reported.
(0.025
2
and polar solvents, such as, xylene, 1-4-dioxane, N,N-dimethyl
formamide, N-N-dimethyl acetamide, tetrahydrofuran as well
as t-amyl-alcohol, resulted moderate to poor product yields (SI
Table S5). Moreover, pyrrole synthesis could also be performed
using lower reaction temperature albeit with moderate product
conversions (Table 1, entries 7-8 and SI Table S8).
Further, control experiments revealed their potential role as
individual catalytic component to achieve higher product
conversions. For instance, in absence of base, ligand and
catalyst only poor product conversions were observe. (Table 1,
entries 9-12 and SI Table S1-S7). Notably, a combination of 5
2
3
2
b
2
2
3
Further, we studied the pyrrole synthesis using a series of
electronically different anilines with cis-butene-1,4-diols. For
instance, anilines substituted with methyl or methoxy groups
afford a series of interesting pyrroles in up to 75% yields (Table
4
, 4a-4b, and 4d-4e). Sterically hindered o-ethyl aniline as well
as p-bromo and m-trifluoromethyl anilines resulted only poor
product yield (Table 4, 4c, 4g-4h). Excellent yield of pyrrole
was obtained with p-chloro (4f) and 1,4-dioxolone anilines (4j).
Pleasingly, 1-naphthyl aniline resulted corresponding pyrrole in
moderate yield (4i). To our delight, C-2 substituted pyrrole was
obtained when 3,4,5-trimethoxy phenyl substituted cis-butene-
1,4-diols was used as coupling partner (4k).
2 2 3
mol% NiCl , 6 mol% bipyridine L1, 0.5 mmol of Na CO and
toluene, as the best solvent, 66% isolated yield of 3a was
obtained (Table 1, entry 6).
Table 3: Scope of benzyl aminesa
NiCl2 (5 mol%)
L1 (6 mol%)
Ar
NH2 +
N
Ar
N
Table 5: Synthesis of N-alkyl pyrrolesa
HO
OH
Na2CO3 (0.5 mmol)
toluene, 130 °C, 36 h 3a-e
1a-e
2a
NiCl2 (5 mol%),
L1 (6 mol%)
R
NH2
1q-x
+
R
N
MeO
N
HO
OH
Na2CO3, toluene
30 °C, 36 h
N
2a
5a-g
1
MeO
3a, (66%)
3b, (70%)
3c, (60%)
N
N
N
N
5a, 45%
5b, 44%
5c, 53%
N
MeO
OMe
3d, (80%)
3e, (60%)
O
N
N
aReaction conditions: 1 (0.5 mmol), cis-2-butene 1,4-diol 2a (2.0
mmol), NiCl (0.025 mmol), L1 (0.03 mmol), Na CO (0.5 mmol),
toluene (2.0 mL), Schlenk tube under N atmosphere, 130 °C oil
N
N
5f, 62%
5g, 54%
2
2
3
2
5d, 54%
5e, 51%
bath, 36 h reaction time. Isolated yield in parenthesis.
aReaction conditions: 1 (0.5 mmol), cis-2-butene-1,4-diol 2a (2.0
mmol), NiCl (0.025 mmol), L1 (0.03 mmo), Na CO (0.5 mmol),
toluene (2.0 mL), Schlenk tube under N atmosphere, 130 °C oil
bath, 36 h reaction time. Isolated yield was reported.
After having optimized conditions in hand, we explored the
scope and limitations of the catalytic protocol using
electronically different various benzyl amines with cis-butene-
1,4-diol (Table 3). p- and m-Methoxy benzyl amines resulted
2
2
3
2
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Next, we studied the reactivity profile of more challenging We are pleased to witness an alternative synthesis of pyrroles
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
acyclic and cyclic alkylamines with cis-butene-1,4-diol as
coupling partner for pyrrole synthesis (Table 5). Gratifyingly,
alkylamines, such as, n-butyl, n-pentyl, n-octyl and 3-
methylheptyl amines as well as cyclohexyl and cyclooctyl
amines resulted in up to 62% yield of N-alkylated pyrroles (5a-
using nickel-catalysts via intermolecular cyclization. Notably,
the catalytic protocol is tolerant to primary alcohol, halides,
alkyl alkoxy, trifluoromethyl and oxygen heterocycles,
including benzyl and the pyridine derivatives. Gratifyingly,
remarkable transformations in the presence of alkyl amines and
2-amino pyridines evident the synthetic potential of the
catalytic system.
5
f). Additionally, methoxy substituted γ-amino alcohol could
efficiently used for pyrrole synthesis and resulted 54% yield of
g (Table 5).
5
Scheme 3: Mechanistic studies and control experiments for
pyrrole synthesis.
Table 6: Synthesis of pyrroles from 2-aminopyridinesa
3a. Stoichiometric and catalytic studies using Cat. A
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NiCl2 (8 mol%)
NH2
L1 (9.6 mol%)
N
R
1
+
a
Cat. A (10 mol%)
1a
+
2a
N
+
HO
OH
R
Cat. A
(100 mol%)
N
N
Na2CO3 (1.0 mmol)
toluene, 140 °C, 36 h
N
3a
Ni
2a
standard
conditions
standard
conditions
82%
Cl
Cl
1
y-ab
2a
6
a-d
Cat. A
58%
N
N
3
b. Detection of intermediate species
N
N
N
N
N
Ph
NH2
NiCl2 (5 mol%)
N
N
N
H
N
1a
Cl
Br
+
Na2CO3 (0.5 mmol)
toluene, 130 °C, 36 h
6d, 40%b
3a
m/z = 177
HO
Intermediate C
6
a, 50%
6b, 30%
6c, 51%
HO
OH
2
a
m/z = 157
aReaction conditions: 1 (0.5 mmol), cis-2-butene 1,4-diol 2a (2.0
mmol), NiCl (0.04 mmol), L1 (0.048 mmol), Na CO (1.0 mmol),
toluene (2.0 mL), Schlenk tube under N atmosphere, 140 °C oil
bath, 36 h reaction time. Isolated yield in parenthesis. 2a (4.0
mmol), NiCl (0.05 mmol), L1 (0.06 mmol), was used.
3
c. Competetive experiments
2
2
3
NH2
2
N
NiCl2 (5 mol%)
L1 (6 mol%)
N
O
1
j
b
O
+
0.25 mmol
+
HO
OH
2
Na CO (1.0 equiv.),
2
3
F3C
NH2
2.0 mmol
toluene, 140 °C, 36 h
CF3
2a
4
e
4h
Again, more exciting 2-aminopyridines were employed for
catalytic pyrrole synthesis using our optimized protocol (Table
1m
7
7% yield 23% yield
0.25 mmol
3d. Deuterium labeling experiment
6
). In general pyridines are often known to poison the catalysts,
1
2-14
NiCl2 (5 mol%)
hence diminished the reactivity.
Notably, we observed
N
Ph
NH2
+
DO
OD
t-BuOK (0.5 mmol)
toluene, 130 °C, 36 h
moderate to fair reactivity with chloro, bromo as well as methyl-
substituted 2-aminopyridines and resulted pharmaceutically
active N-heterocyclic pyrrole derivatives (Table 6, 6a-6c).
Additionally, we extended the catalytic protocol in the synthesis
of symmetrical bis-pyrroles. Importantly, cis-butene-1,4-diol
2a was utilized as coupling partner with 1,4-diamino benzene
and 2,6-di-amino pyridine. To our delight, respective bis-
pyrroles were obtained in reasonable yields (Table 4, 4l and
Table 6, 6d).
1a
3a
2
a-d2 (89% D)
m/z = 157
10% yield
3e. Control experiments
HO
Catalyst Base 3a Intermediate C
OH
2a
23
7
1
0
9
>5
Ph
NH2
0
0
1a
standard conditions
0 h
2
Further to establish the reaction pathways for pyrrole synthesis
and to understand the nature of the putative Ni-intermediate
species, Cat. A was radially prepared using literature
Table 7: Synthesis of pyrroles from butyne-1,4-diolsa
18
procedure. Next, Cat. A was independently employed in
catalytic (10 mol%) as well as in stoichiometric equiv. (100
mol%) for intermolecular pyrrole synthesis in the reaction of 1a
with 2a under standard conditions. To our delight, we observed
58% and 82% conversion of 3a (Scheme 3a and Table 1, entry
R'
NiCl2 (5 mol%)
L1 (6 mol%)
R'
NH2
+
R
R
N
HO
2c-e OH Na2CO3 (1.0 mmol)
toluene, 140 °C, 36 h
4a,f,h,l,m
1
a,f,h,l,m
R' = H, Ar
6
). Additionally, to confirm the participation of Ni-alkoxy
OMe
MeO
N
species, we attempted for in situ preparation of Ni-alkoxy
species of Cat. A (SI Scheme S1 C). Initially, 2a was allowed
to react with Cat. A under reflux condition for 24 h and the solid
residue was allowed to react with aniline 1j under standard
N
N
MeO
N
N
F3C
o
Me
Cl
conditions using toluene-d8 at 140 C. The reaction was
MeO
4m, 32%b
4
a, 32% 4f, 31%
4h, 33%
MeO
4k, 40%b
1
interrupted after twelve hours and H-NMR analysis of the
crude reaction mixture detected the formation of pyrrole 4e (SI
Scheme S1 C). These experiments support for the involvement
of the intermediate Ni-alkoxy species for pyrrole synthesis.
Next, to understand the involvement of the intermediate species
C (Scheme 2), we used model reaction of 1a with 2a under
standard conditions and was monitored using GC-MS analysis
aReaction conditions: 1 (0.5 mmol), cis-2-butene 1,4-diol 2 (2.0
mmol), NiCl (0.05 mmol), L1 (0.03 mmol), Na CO (1.0 mmol),
toluene (2.0 mL), Schlenk tube under N atmosphere, 140 °C oil
(1.0 mmol). Isolated yield was
2
2
3
2
b
bath, 36 h reaction time. Na
reported.
2 3
CO
After having established the excellent catalytic activity with cis-
butene-1,4-diols, the generality of our nickel-catalyzed protocol
was further evaluated using butyne-1,4-diols as coupling
partner for pyrrole synthesis (Table 7). For instance, application
of electronically, different anilines with butyne-1,4-diols, 2c-
(Scheme 3b and SI Scheme S1 A). Gratifyingly, we detected
intermediate species C as well as pyrrole 3a using GC-MS
analysis. Further, a competitive experiment was performed
using a 1:1 mixture of anilines 1j and 1m with alcohol 2a under
standard catalytic conditions. We observed the formation of
pyrroles 4e and 4h at a ratio of 3:1 (Scheme 3c). These
2
e, resulted respective pyrroles in moderate yields (Table 7).
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The Journal of Organic Chemistry
experiments evident that, pyrrole formation occurred at higher
rates for electron-rich aniline (SI, Scheme S1 B).
NMR spectral data are given as chemical shifts in ppm followed
by multiplicity (s- singlet; d- doublet; t- triplet; q- quartet; m-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
However, using 1a with 2a-d2 (89% D) under optimized
conditions, we did not observe any deuterium incorporation in
multiplet), number of protons and coupling constants. C NMR
chemical shifts are expressed in ppm. HRMS (ESI) spectral data
were collected using Bruker High Resolution Mass
Spectrometer. GC-MS were recorded using Agilent GC Mass
Spectrometer.
1
pyrrole and detected 3a in 10% yield using H-NMR and GC-
1
7,19
MS analysis (Scheme 3d).
Additionally, control
experiments in absence of base and catalyst were performed and
interrupted after 20 hours. GC-MS analysis of the crude
reaction mixture revealed their potential role as individual
component to achieve higher catalytic selectivty to 3a (Scheme
General Procedure for Ni-catalyzed synthesis of pyrroles:
In a 15 mL oven dried Schlenk tube, amines (0.50 mmol),
Na
and diol (2.0 mmol) were added followed by toluene 2.0 mL
under an atmosphere of N and the reaction mixture was heated
2 3 2
CO (0.50 mmol), bipyridine L1 (6 mol%), NiCl (5 mol%)
3
e). Notably, we detected intermediate C and these reactions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
evident the potential role of base and catalyst in the
intermolecualr cyclization involving C-C and C-N bond
formation to pyrroles. Finally, we studied the rate and order of
the pyrrole formation. To determine the rate laws we performed
kinetic studies using two sets of experiments using our model
reaction of Table 1 (SI, Scheme S2). Considering a steady state
approximation for cis-butene-1,4-diol 2a, first order kinetics
with respect to 3a was observed for pyrrole formation.
2
at 130 °C for 36 h in a closed system. Next, the reaction mixture
was cooled to room temperature and 3.0 mL of ethyl acetate was
added and concentrated in vacuo. The residue was purified by
column chromatography using a gradient of hexane and ethyl
acetate (eluent system) to afford the pure product.
1
4a
1-Benzyl-1H-pyrrole (3a) : Following general procedure, the
title compound was isolated as a colorless oil using silica-gel
column chromatography eluting with 1% ethyl acetate in
It is noteowrthy to mention that, in general, using our standard
catalytic conditions we observed good to excellent substrate
conversions and selectivity using GC-MS analysis (Table 3-7).
However, in some cases isolated yields of the desired pyroles
were quite lower. Indeed, there might be unwanted side
reactions involving different active species not posible to detect
using GC-MS analysis of the crude reaction mixtures. For
instance, when cis-2-butene-1,4-diol 2a, and 2-butyne-1,4-diol
1
hexane. (Yield: 66%, 51 mg). H NMR (400 MHz, CDCl
3
) δ
7
6
.27-7.17 (m, 3H), 7.06-7.01 (m, 2H), 6.62 (t, J = 2.1 Hz, 2H),
13
.12 (t, J = 2.1 Hz, 2H), 4.99 (s, 2H). C{1H} NMR (100 MHz,
) δ 138.1, 128.7, 127.6, 126.9, 121.1, 108.4, 53.3.
CDCl
3
2
0
1-(4-methoxybenzyl)-1H-pyrrole (3b) : Following general
procedure, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 2% ethyl
1
acetate in hexane. (Yield: 70%, 65 mg). H NMR (400 MHz,
2
1
c, independently allowed using standard conditions of Table
, we did not detect any isomerized product using H-NMR.
CDCl
3
) δ 7.07 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.67
1
(
t, J = 2.1 Hz, 2H), 6.19-6.14 (m, 2H), 5.00 (s, 2H), 3.79 (s, 3H).
However, in case of 2a, the reaction mixture turned brown and
we observed unreacted diols, but, in case of 2c, the whole
reaction mixture turned into black precipitate as reported in
1
3
3
C{1H} NMR (100 MHz, CDCl ) δ 159.1, 130.1, 128.5, 120.9,
1
1
14.1, 108.3, 55.3, 52.8.
-(3-methoxybenzyl)-1H-pyrrole (3c) : Following general
2
0
1
4a
earlier studies (SI, Scheme S3).
procedure, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 2% ethyl
CONCLUSIONS
1
acetate in hexane. (Yield: 60%, 56 mg). H NMR (400 MHz,
In conclusion, for the first time we established a straightforward
and sustainable Ni-catalyzed dehydrogenative coupling for
pyrrole synthesis using butene-1,4-diols and butyne-1,4-diols
with a series of aryl, alkyl and heteroaryl amines. We
demonstrated the broad substrate scopes with high selectivity to
CDCl
3
) δ 7.29-7.22 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.72 (dd,
J = 6.2, 4.2 Hz, 4H), 6.25-6.17 (m, 2H), 5.05 (s, 2H), 3.78 (s,
13
3
1
1
3
H). C{1H} NMR (100 MHz, CDCl ) δ 159.9, 139.8, 129.7,
21.1, 119.2, 112.9, 112.7, 108.5, 55.1, 53.2.
-(2,4-dimethoxybenzyl)-1H-pyrrole
(3d)21:
Following
8f-i
pyrroles including catalytic and mechanistic studies. The
general procedure, the title compound was isolated as a
colorless oil using silica-gel column chromatography eluting
catalytic protocol is tolerant to amino alcohol derivatives,
halides, alkyl, alkoxy and oxygen heterocycles as well as
activated benzyl and the pyridine moiety. Initial mechanistic
studies using defined intermediate Ni-species, competitive
experiments between two electronically different anilines,
deuterium labeling experiments as well as rate and order of
reactions were crucial for elementary steps for nickel-catalyzed
pyrrole formations. Further studies regarding detailed
mechanistic investigation will be addressed in future
communications.
1
with 3% ethyl acetate in hexane. (Yield: 80%, 86 mg). H NMR
3
(400 MHz, CDCl ) δ 6.80 (d, J = 8.3 Hz, 1H), 6.70 (t, J = 2.1
Hz, 2H), 6.44 (d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.3, 2.4 Hz, 1H),
6.14 (t, J = 2.1 Hz, 2H), 4.99 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H).
13
3
C{1H} NMR (125 MHz, CDCl ) δ 160.6, 157.8, 129.4, 121.0,
1
1
19.2, 107.9, 104.2, 98.5, 55.4, 55.4, 47.8.
-(1-phenylethyl)-1H-pyrrole (3e) : Following general
22
procedure, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 1% ethyl
1
acetate in hexane. (Yield: 60%, 51 mg). H NMR (400 MHz,
CDCl
3
) δ 7.34-7.28 (m, 2H), 7.27-7.24 (m, 1H), 7.09 (dd, J =
EXPERIMENTAL SECTION
7
.8, 1.0 Hz, 2H), 6.76 (t, J = 2.1 Hz, 2H), 6.19 (t, J = 2.1 Hz,
13
General Experimental Details:
2H), 5.28 (q, J = 7.1 Hz, 1H), 1.83 (d, J = 7.1 Hz, 3H). C{1H}
All solvents and reagents were used, as received from the
suppliers. TLC was performed on Merck Kiesel gel 60, F254
plates with the layer thickness of 0.25 mm. Column
chromatography was performed on silica gel (100-200 mesh)
NMR (125 MHz, CDCl ) δ 143.6, 128.6, 127.4, 125.9, 119.5,
3
108.03, 58.1, 22.1.
1
9
1-(p-tolyl)-1H-pyrrole (4a) : Following general procedure,
the title compound was isolated as a white solid using silica-gel
column chromatography eluting with 1% ethyl acetate in
1
using a gradient of ethyl acetate and hexane as mobile phase. H
1
NMR spectral data were collected at, 400 MHz (JEOL), 500
hexane. (Yield: 75%, 58 mg). H NMR (500 MHz, CDCl ) δ
3
1
3
1
MHz (Bruker) and C NMR were recorded at 100, 125 MHz. H
7.32 (d, J = 7.4 Hz, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.09 (s, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
6
.37 (s, 2H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz, CDCl
138.5, 135.3, 130.0, 120.5, 119.4, 110.0, 20.8.
3
) δ
1H), 7.54-7.43 (m, 4H), 6.99 (t, J = 2.1 Hz, 2H), 6.41 (t, J = 2.1
1
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 2H). C{1H} NMR (125 MHz, CDCl
3
) δ 138.2, 134.2,
2
3
1-(2,4-dimethylphenyl)-1H-pyrrole (4b) : Following general
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 75%, 64 mg). H NMR (400 MHz,
CDCl
129.9, 128.1, 127.8, 126.9, 126.5, 125.3, 123.2, 123.2, 109.0.
2
8
1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrole (4j) :
Following general procedure, the title compound was isolated
as a white solid using silica-gel column chromatography eluting
1
1
3
) δ 7.16-7.08 (m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 6.76 (dd,
with 1% ethyl acetate in hexane. (Yield: 85%, 85 mg). H NMR
J = 2.5, 1.6 Hz, 2H), 6.30 (dd, J = 2.5, 1.6 Hz, 2H), 2.36 (s, 3H),
3
(400 MHz, CDCl ) δ 6.99 (t, J = 2.2 Hz, 2H), 6.92 (d, J = 2.6
1
3
2
1
1
3
.16 (s, 3H). C{1H} NMR (125 MHz, CDCl ) δ 138.2, 137.3,
Hz, 1H), 6.89-6.85 (m, 2H), 6.31 (t, J = 2.2 Hz, 2H), 4.31-4.26
1
3
33.6, 131.6, 127.1, 126.5, 122.1, 108.5, 20.9, 17.6.
3
(m, 4H). C{1H} NMR (125 MHz, CDCl ) δ 143.9, 141.7,
24
-(2-ethylphenyl)-1H-pyrrole (4c) : Following general
135.0, 119.6, 117.7, 113.8, 110.1, 109.9, 64.5, 64.2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 30%, 25 mg). H NMR (500 MHz,
1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-
2
9
pyrrole (4k) : Following general procedure, the title
1
compound was isolated as a white solid using silica-gel column
CDCl
3
) δ 7.36 (m, 2H), 7.28 (d, J = 5.1 Hz, 2H), 6.78 (s, 2H),
chromatography eluting with 3% ethyl acetate in hexane.
1
6
.31 (s, 2H), 2.51 (q, J = 7.4 Hz, 2H), 1.10 (t, J = 7.3 Hz, 3H).
(Yield: 45%, 76 mg). H NMR (400 MHz, CDCl
3
) δ 7.13-7.09
1
3
C{1H} NMR (125 MHz, CDCl
27.1, 126.4, 122.4, 108.6, 24.1, 15.1.
-(2-methoxyphenyl)-1H-pyrrole (4d) : Following general
3
) δ 140.2, 140.1, 129.3, 127.9,
(m, 2H), 6.88-6.83 (m, 3H), 6.40 (dd, J = 3.6, 1.8 Hz, 1H), 6.33-
1
3
1
1
6.31 (m, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.62 (s, 6H). C{1H}
NMR (125 MHz, CDCl ) δ 158.4, 152.8, 152.4, 136.6, 134.0,
2
5
3
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 2% ethyl
acetate in hexane. (Yield: 55%, 47 mg). H NMR (400 MHz,
CDCl
2
CDCl
55.7.
1
133.8, 132.2, 128.6, 114.1, 105.6, 105.6, 103.4, 63.6, 56.0, 55.9,
55.8.
1
30
1,4-di(1H-pyrrol-1-yl)benzene (4l) : Following general
3
) δ 7.22-7.16 (m, 2H), 6.96-6.87 (m, 4H), 6.23 (dd, J =
.5, 1.7 Hz, 2H), 3.74 (s, 3H). C{1H} NMR (125 MHz,
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
13
1
3
) δ 152.7, 130.2, 127.4, 125.7, 122.0, 120.9, 112.3, 108.7,
acetate in hexane. (Yield: 45%, 46 mg). H NMR (400 MHz,
CDCl
3
13
) δ 7.37-7.18 (m, 4H), 7.02-7.01 (m, 4H), 6.38-6.35 (m,
1
9
-(4-methoxyphenyl)-1H-pyrrole (4e) : Following general
4H). C{1H} NMR (125 MHz, CDCl
3
) δ 138.4, 121.5, 119.3,
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 2% ethyl
acetate in hexane. (Yield: 70%, 60 mg). H NMR (400 MHz,
115.0, 110.6.
2-(4-isopropylphenyl)-1-(4-methoxyphenyl)-1H-pyrrole
1
31
(4m) : Following general procedure, the title compound was
CDCl
3
) δ 7.34-7.30 (m, 2H), 7.02 (td, J = 2.3, 0.7 Hz, 2H), 6.98-
isolated as
a
white solid using silica-gel column
6
.93 (m, 2H), 6.34 (td, J = 2.2, 0.7 Hz, 2H), 3.84 (s, 3H).
chromatography eluting with 1% ethyl acetate in hexane.
13
1
C{1H} NMR (125 MHz, CDCl
14.6, 109.8, 55.5.
-(4-chlorophenyl)-1H-pyrrole (4f) : Following general
3
) δ 157.6, 134.5, 122.1, 119.6,
3
(Yield: 32%, 46 mg). H NMR (400 MHz, CDCl ) δ 7.14-7.08
1
1
(m, 2H), 7.06 (s, 4H), 6.88-6.81 (m, 3H), 6.39 (dd, J = 3.5, 1.8
Hz, 1H), 6.35-6.30 (m, 1H), 3.82 (s, 3H), 2.85 (hept, J = 6.9 Hz,
19
1
3
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 90%, 79 mg). H NMR (500 MHz,
CDCl
7
1H), 1.22 (d, J = 6.9 Hz, 6H). C{1H} NMR (100 MHz,
CDCl ) δ 158.1, 146.7, 134.0, 133.9, 130.4, 128.1, 127.0, 126.1,
124.2, 114.0, 109.7, 108.7, 55.4, 33.6, 23.9.
3
1
3
2
3
) δ 7.38 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H),
.08-7.04 (m, 2H), 6.35 (m, 2H). C{1H} NMR (125 MHz,
1-butyl-1H-pyrrole (5a) : Following general procedure, the
1
3
title compound was isolated as a colorless oil using silica-gel
CDCl
1
3
) δ 139.3, 131.1, 129.6, 121.6, 119.3, 110.8.
-(4-bromophenyl)-1H-pyrrole (4g) : Following general
column chromatography eluting with 1% ethyl acetate in
1
9
1
hexane. (Yield: 45%, 27 mg). H NMR (400 MHz, CDCl
3
) δ
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 36%, 39 mg). H NMR (500 MHz,
CDCl ) δ 7.56-7.52 (m, 2H), 7.28 (d, J = 2.1 Hz, 2H), 7.07-7.04
(m, 2H), 6.37-6.35 (m, 2H). C{1H} NMR (125 MHz, CDCl
δ 139.8, 132.6, 121.9, 119.2, 118.7, 110.9.
6.57 (t, J = 1.7 Hz, 2H), 6.06 (t, J = 1.7 Hz, 2H), 3.80 (t, J = 7.2
Hz, 2H), 1.67 (dt, J = 14.9, 7.4 Hz, 2H), 1.26-1.20 (m, 2H), 0.86
1
13
(dt, J = 7.4, 3.7 Hz, 3H). C{1H} NMR (100 MHz, CDCl
3
) δ
3
120.5, 107.7, 49.3, 33.6, 19.9, 13.6.
1
3
33
3
)
1-pentyl-1H-pyrrole (5b) : Following general procedure, the
title compound was isolated as a colorless oil using silica-gel
2
6
1
-(3-(trifluoromethyl)phenyl)-1H-pyrrole (4h) : Following
column chromatography eluting with 1% ethyl acetate in
1
general procedure, the title compound was isolated as a white
solid using silica-gel column chromatography eluting with 1%
ethyl acetate in hexane. (Yield: 30%, 31 mg). H NMR (500
hexane. (Yield: 44%, 30 mg). H NMR (400 MHz, CDCl
3
) δ
6.57 (s, 2H), 6.06 (s, 2H), 3.78 (t, J = 7.2 Hz, 2H), 1.69 (dt, J =
14.7, 7.3 Hz, 2H), 1.29-1.17 (m, 4H), 0.82 (dd, J = 8.2, 6.0 Hz,
1
1
3
MHz, CDCl
3
) δ 7.56 (s, 1H), 7.53-7.38 (m, 3H), 7.11 (t, J = 2.1
3
3H). C{1H} NMR (125 MHz, CDCl ) δ 120.4, 107.7, 49.6,
1
3
Hz, 2H), 6.38 (t, J = 2.2 Hz, 2H). C{1H} NMR (100 MHz,
CDCl
2
3
31.2, 28.9, 22.2, 13.9.
1-heptyl-1H-pyrrole (5c) : Following general procedure, the
34
3
) δ 141.1, 132.1 (d, JF-C = 30 Hz), 130.2, 123.7 (d, JF-C
70 Hz), 123.4, 122.1 (q, JF-C = 3.0 Hz), 119.2, 117.2 (q, JF-C
.9 Hz), 111.3.
=
=
title compound was isolated as a colorless oil using silica-gel
column chromatography eluting with 1% ethyl acetate in
1
hexane. (Yield: 53%, 43 mg). H NMR (400 MHz, CDCl
3
) δ
2
7
1-(naphthalene-1-yl)-1H-pyrrole (4i) : Following general
procedure, the title compound was isolated as a white solid
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 52%, 50 mg). H NMR (400 MHz,
3
CDCl ) δ 7.88 (dd, J = 18.2, 7.9 Hz, 2H), 7.75 (d, J = 8.3 Hz,
6.64 (t, J = 2.1 Hz, 2H), 6.12 (t, J = 2.1 Hz, 2H), 3.87-3.83 (m,
2H), 1.79-1.71 (m, 2H), 1.30-1.25 (m, 8H), 0.89-0.85 (m, 3H).
1
3
C{1H} NMR (125 MHz, CDCl ) δ 120.4, 107.7, 49.6, 31.7,
3
1
31.6, 28.9, 26.7, 22.6, 14.0.
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1
9
1
-cyclohexyl-1H-pyrrole (5d) : Following general procedure,
using silica-gel column chromatography eluting with 3% ethyl
acetate in hexane. (Yield: 40%, 41 mg). H NMR (400 MHz,
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the title compound was isolated as a colorless oil using silica-
gel column chromatography eluting with 1% ethyl acetate in
CDCl
= 8.0 Hz, 2H), 6.31 (dd, J = 5.0, 2.8 Hz, 4H). C{1H} NMR
(125 MHz, CDCl ) δ 150.4, 140.8, 118.2, 115.0, 111.5, 106.7.
3
) δ 7.71 (t, J = 8.0 Hz, 1H), 7.51-7.48 (m, 4H), 7.03 (d, J
1
13
hexane. (Yield: 54%, 40 mg). H NMR (400 MHz, CDCl
3
) δ
6
1
1
.73 (t, J = 2.1 Hz, 2H), 6.13 (t, J = 2.1 Hz, 2H), 3.84-3.76 (m,
3
+
H), 2.10 (dd, J = 13.2, 1.9 Hz, 2H), 1.92-1.83 (m, 2H), 1.76-
.68 (m, 1H), 1.62 (ddd, J = 24.6, 12.4, 3.2 Hz, 2H), 1.45-1.33
HRMS (ESI-TOF) m/z: [M+H] Calcd for C13
Found 210.1021.
11 3
H N 210.0953;
1
3
(
m, 2H), 1.28-1.19 (m, 1H). C{1H} NMR (125 MHz, CDCl
δ 118.4, 107.3, 58.6, 34.7, 25.7, 25.5.
-cyclooctyl-1H-pyrrole (5e): Following general procedure,
3
)
AUTHOR INFORMATION
1
Corresponding Author
the title compound was isolated as a colorless oil using silica-
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* E-mail: dbane.fcy@iitr.ac.in
gel column chromatography eluting with 1% ethyl acetate in
1
hexane. (Yield: 51%, 45 mg). H NMR (400 MHz, CDCl
3
) δ
ASSOCIATED CONTENT
Supporting Information
6.75 (dd, J = 3.8, 1.9 Hz, 2H), 6.16 (dd, J = 3.9, 1.9 Hz, 2H),
4.12 (dq, J = 13.4, 4.4 Hz, 1H), 2.03 (dt, J = 12.0, 6.3 Hz, 4H),
1
3
1
.82 (dd, J = 6.0, 2.1 Hz, 2H), 1.72-1.53 (m, 8H). C{1H}
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxxx.
NMR (125 MHz, CDCl ) δ 118.6, 107.3, 59.9, 34.4, 26.9, 25.8,
3
+
2
1
1
4.5. HRMS (ESI-TOF) m/z: [M+H] Calcd for C12
78.1517; Found 178.1585.
-(5-methylheptyl)-1H-pyrrole (5f): Following general
19
H N
1
13
H, C NMR and HRMS spectra, screening of the reaction
conditions and mechanistic studies (PDF)
procedure, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 1% ethyl
Notes
1
acetate in hexane. (Yield: 62%, 55 mg). H NMR (400 MHz,
CDCl ) δ 6.62 (t, J = 2.1 Hz, 2H), 6.12 (t, J = 2.0 Hz, 2H), 3.76
(dd, J = 7.0, 3.7 Hz, 2H), 1.69 (dt, J = 12.4, 6.3 Hz, 1H), 1.31-
The authors declare no competing financial interest.
3
ACKNOWLEDGMENT
1
3
1.22 (m, 8H), 0.88 (td, J = 6.9, 3.7 Hz, 6H). C{1H} NMR (125
MHz, CDCl ) δ 121.0, 107.6, 53.2, 41.3, 30.6, 28.6, 23.8, 23.0,
The authors thank SERB, India (funding to D. B.,
ECR/2015/000600). K. S., L. M. K. and A. A. thank IIT-R for
financial support. S. B. Thank DST/2017/IF170766 for a
fellowship.
3
+
1
1
1
4.0, 10.6. HRMS (ESI-TOF) m/z: [M+H] Calcd for C12
80.1674; Found 180.1739.
-(3-methoxypropyl)-1H-pyrrole (5g) : Following general
21
H N
3
5
procedure, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 2% ethyl
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(
(
(
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5
49.6, 147.3, 138.2, 127.6, 118.1, 112.0, 111.7.
-bromo-2-(1H-pyrrol-1-yl)pyridine(6b) :
37
Following
general procedure, the title compound was isolated as a
colorless oil using silica-gel column chromatography eluting
1
with 3% ethyl acetate in hexane. (Yield: 30%, 26 mg). H NMR
(400 MHz, CDCl
3
) δ 8.45 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.8,
2
2
1
2
.4 Hz, 1H), 7.45 (t, J = 2.3 Hz, 2H), 7.20 (s, 1H), 6.37-6.34 (m,
1
3
3
H). C{1H} NMR (125 MHz, CDCl ) δ 149.6, 140.9, 118.1,
15.6, 115.0, 112.5, 111.8.
-methyl-6-(1H-pyrrol-1-yl)pyridine
3
8
(6c) :
Following
general procedure, the title compound was isolated as a
colorless solid using silica-gel column chromatography eluting
1
with 3% ethyl acetate in hexane. (Yield: 51%, 40 mg). H NMR
(400 MHz, CDCl ) δ 7.64-7.57 (m, 1H), 7.52-7.49 (m, 2H), 7.10
(d, J = 8.2 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.36-6.31 (m, 2H),
1
5135. (h) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J.
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1
3
3
2.53 (s, 3H). C{1H} NMR (125 MHz, CDCl ) δ 158.0, 150.8,
1
2
38.5, 119.5, 118.1, 111.0, 108.2, 24.3.
,6-di(1H-pyrrol-1-yl)pyridine (6d): Following general
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(
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ACS Paragon Plus Environment

The Journal of Organic Chemistry
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Graphical Abstract
R'
Ar/R
NH2
Ni
R'
Ar/R
N
N
R = Alkyl
Ar = Benzyl
OH
OH
R' = H, Ar
R'
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NH2
2
R
H2O
X
R
35 Examples
X
X = C, N
Synthesis of Pyrroles
Broad substrate scope
Mild Base
Up to 90% yield
1
0
ACS Paragon Plus Environment