Nickel-Catalyzed Double Dehydrogenative Coupling of Secondary Alcohols and β-Amino Alcohols to Access Substituted Pyrroles

Article abstract of DOI:10.1021/acs.joc.9b01819

Herein, we demonstrate the first nickel-catalyzed double dehydrogenative condensation of secondary alcohols and β-amino alcohols in one pot to the pyrrole derivatives. A series of 2,5- and 2,3,5-substituted pyrroles were obtained in ≤83% yield, releasing

Full text of DOI:10.1021/acs.joc.9b01819

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Article
Nickel-Catalyzed Double Dehydrogenative Coupling of Secondary
Alcohols and #-Amino Alcohols to Access Substituted Pyrroles
Anitha Alanthadka, Sourajit Bera, MARI VELLAKKARAN, and Debasis Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01819 • Publication Date (Web): 18 Sep 2019
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The Journal of Organic Chemistry
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Nickel-Catalyzed Double Dehydrogenative Coupling of Secondary
Alcohols and β-Amino Alcohols to Access Substituted Pyrroles
Anitha Alanthadka,ǂ Sourajit Bera,ǂ Mari Vellakkaran and Debasis Banerjee*
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Department of Chemistry, Laboratory of Catalysis and Organic Synthesis, Indian Institute of Technology Roorkee, Roorkee-
247667, Uttarakhand, India. Email: dbane.fcy@iitr.ac.in
OH
OH
-amino alcohols
H
H
N
R2
R2
N
Ar
NH2
R1
R1
Ar
OH
R1
Ni
Ni
2,5-disubstituted pyrroles
Mechanistic studies Phosphine free catalysis
31 examples and up to 83% yield
2,3,5-trisubstituted pyrroles
Inexpensive Ni-catalyst
Deuterium labeling experiments
ABSTRACT: Herein, we demonstrated the first nickel-catalyzed double dehydrogenative condensation of secondary alcohols and
β-amino alcohols in one-pot operation to the pyrrole derivatives. A series of 2,5 and 2,3,5-substituted pyrroles were obtained in up to
83% yield, releasing water and hydrogen gas as by-products. Initial mechanistic studies including defined Ni-catalysts, deuterium
labeling experiments, quantitative determination of hydrogen gas evaluation and detection of water generation in the reaction mixture
were performed.
KEYWORDS. β-Amino Alcohols • Nickel • Substituted Pyrrole • Secondary Alcohols • Dehydrogenative Coupling
often limited with precious metal-catalysts, Ru, and Ir-based
complexes.7-8 In this direction, intermolecular cyclization to
pyrroles was independently developed by Kempe and Milstein
involving coupling of secondary alcohols with amino alcohols
using Ir- and Ru-based catalysts (Scheme 1a). Interesting Ru-
catalyzed multi-component transformations to pyrroles
involving activated ketones and diols with amines was
developed by Beller.7b-c Again, catalytic transformations using
unsaturated-diols with suitable amines were also reported for
pyrroles synthesis using Pd-,7f Ru-,7g and Pt,7h based catalysts.
INTRODUCTION
Nitrogen containing N-heterocycles are highly important and
common structural motifs present in various pharmaceuticals,
agrochemicals and in functional materials.1 Among these,
pyrroles are significantly utilized in a large no of drug
molecules, and play an important role in bio-active compounds,
such as, porphyrins, corrins as well as in chlorins. Further,
substituted pyrroles derivatives also found in, haemoglobin,
vitamin B12 and in chlorophyll including various natural
products.2 Apart from these, a large number of bioactive non-
natural pyrroles are widely used for multi-targeted receptor,
tyrosine kinase inhibitors and as anti-inflammatory drug
zomepirac.3 Therefore, synthesis of multi-substituted pyrroles
remains an attractive target in chemical research.
Unfortunately, despite their significant biological importance,
straightforward procedures for the synthesis of pyrroles are
much less known.
Classical approaches, such as Knorr, Paal–Knorr, and
Hantzsch synthesis utilized activated substrates (ketones or
esters) and suffer from pre-functionalization of starting
materials, harsh reaction conditions, low chemical economy
and generation of stoichiometric waste.4 Therefore,
development of an efficient synthetic protocol for substituted
pyrroles in an atom and step economic fashion is a challenging
goal. In this context, in terms of sustainability, potential and
exciting approaches which efficiently utilizes available
renewable resources and minimize the waste generation are in
high demand.5 Nevertheless, metal-catalyzed hydrogen-
borrowing strategy for alcohols are widely utilised for C-C and
C-N bond formations, which releases water and dihydrogen as
side products. However, applications of such processes for the
tandem one-pot operation involving synthesis of N-
heterocycles are much less developed.6 Notably, such an
acceptorless dehydrogenation of alcohol for pyrrole synthesis is
a) Previous strategy:
NH2
OH
H
Pincer-catalysts
[M]
N
R2
R1
Air-sensetive ligands
Multi-step ligand synthesis
Expensive PNP ligands
+
OH
[M] = Ir, Ru, Mn, Co
R1
R2
OH
H
b) Present work:
N
Ar
R1
Ar
Bench-stable Nitrogen ligands
2,5-disubstituted pyrroles Inexpensive Ni-catalyst
Deuterium labelling experiments
NH2
Ni
OH
R1
H
-H
-2
-2
H2O
2
Mechanistic studies
Phosphine free catalysis
N
R2
R1
-amino alcohols
OH
2,3,5-trisubstituted pyrroles
R2
Scheme 1: (a) Metal-catalyzed hydrogen borrowing processes
for pyrrole synthesis. (b) Nickel-catalyzed sustainable synthesis
of pyrroles.
However, applications of biomass derived alcohols along with
earth-abundant base-metals (Fe, Mn, Ni, Co) have attract
significant attention for hetero-aryl synthesis.9 For instance,
Mn, Co, and Fe-based pincer complexes have been well studied
for the synthesis of N-heterocycles.10 However, such pincer-
complexes required expensive multi-dentate NNS, PNN-, or
NNN-ligands as well as sensitive phosphine-based ligands.7-8,10
Therefore, still there is a need to establish a simple, more
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general and inexpensive catalytic protocol for substituted
Page 2 of 8
Unfortunately, only 17% conversion to the desired pyrrole 3a
was obtained when using 10 mol% NiCl2, 12 mol% bipyridine
L3, 1 equiv. of t-BuOK at 130 °C in toluene (Table 1, entry 3).
At this point we realized that, dehydrogenation of 1-
phenylethanol, 2a to the desired carbonyl is crucial to obtain
higher product yield. Therefore, to establish an efficient
catalytic protocol, we examined different nickel pre-catalysts
having oxidation states of Ni(0) or Ni(II) using bipyridine, L3
as ligand. However, an increment of product conversion, up to
28%, to pyrrole 3a was observed (Table 1, entries 2-4 and ESI
Table S1). Thereafter, when using different nitrogen ligands
L1-L2 and L4-L5; 1,10-phenanthroline L1 resulted moderate
product conversion (Table 1, entries 5-8). At this point, we
choose ligand L1 of our choice and studied the influence and
scope of different bases, such as, t-BuONa, NaOH, KOH,
K3PO4, and Cs2CO3 did not improve the product yield further
(Table 1, entries 9-10 and ESI Table S2), whereas, an increment
of base equivalency resulted 42% conversion to product 3a
(Table 1, entry 11). Notably, Ni-catalysts strongly bind with
free alcohols to form Ni-alkoxy species and -hydride
elimination resulted the corresponding carbonyl derivatives.
Again, base also plays a key role for the cyclisation to pyrrole
synthesis following C-C bond formation.
1
2
3
4
5
6
7
8
pyrrole derivatives.
To the best of our knowledge, herein we established the first
nickel-catalyzed double de-hydrogenation of secondary
alcohols and amino alcohols following one-pot condensation
and C-C/C-N bond formations to the pyrrole derivatives. A
simple Ni-catalyst enables selective activation of a number of
bonds in one-pot operation releasing water and hydrogen gas as
by-products. Preliminary mechanistic investigations and
deuterium labeling experiments establish the reaction pathways
for pyrroles synthesis (Scheme 1b).10
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Table 1. Optimization of the Reaction Conditionsa,b
NiBr2 (10 mol%)
L1
H
OH
NH2
N
(12 mol%)
OH
+
t-BuOK (2.0 equiv.)
toluene, 150 oC, 36 h
1a
2a
3a
entry
deviations from standard conditions
Conv.
3a (%)
53 (48)b
28
17
18
1
2
3
none
NiBr2, L3, t-BuOK (1 equiv.), 130 oC
NiCl2, L3, t-BuOK (1 equiv.), 130 oC
4
5
Ni(acac)2, L3, t-BuOK (1 equiv.), 130 oC
L1, t-BuOK (1 equiv.), 130 oC
L2, t-BuOK (1 equiv.), 130 oC
L4, t-BuOK (1 equiv.), 130 oC
L5, t-BuOK (1 equiv.), 130 oC
t-BuONa (1 equiv.), 130 oC
NaOH (1 equiv.), 130 oC
130 oC
32
Next, applications of solvents with variable polarities, such as,
t-amyl alcohol, p-xylene, 1,4-dioxane, tetrahydrofuran and
2-methyltetrahydrofuran proof inefficient (Table 1, entry 12
and ESI Table S3). However, when the reaction was performed
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13
14
22
9
11
25
25
42
20
45
o
at 150 C, 53% conversion to pyrrole 3a was obtained along
with 48% isolated yield (Table 1, entries 1 and 13, and ESI,
Table S7). As expected, control experiments in absence of base,
ligand as well as catalyst revealed their independent role and we
did not observe any desired product (Table 1, entry 14 and ESI
Table S4-S6). Further, reactions in presence of hydrogen
acceptor (styrene) or molecular sieves, did not improve the
yield or selectivity of 3a. Notably, during optimization studies
(Table 1), we observed unreacted alcohols, acetophenone and
unidentified mixtures of products in the GC-MS analysis of the
crude reactions mixtures.
p-xylene, 130 oC
toluene, 140 oC
no base, no catalystc
0
R
R
N
N
N
N
N
L3
L4
N
R = H;
R = Me;
R
R
L5
L1
R = H;
L2
R = Me;
aReaction conditions: 2-aminobutan-1-ol 1a (0.25 mmol),
1-phenylethanol 2a (0.5 mmol), NiBr2 (0.025 mmol), L1 (0.03
mmol), t-BuOK (0.5 mmol), toluene (2.0 mL), High pressure
reactor under N2 atmosphere in a heating magnetic stirrer, 150
°C, 36 h reaction time. Conversion was determined by GC-
MS (isolated yield in parentheses, average yield of two runs).
ct-BuOK (0.5 mmol) was used.
Table 2. Ni-Catalyzed Synthesis of 2,5-di-Substituted Pyrrolesa
OH
H
NH2
NiBr2 / Phen
R
R
N
+
b
OH
t-BuOK
toluene, 150 °C, 36 h
R
R
1a-1g
2a-2h
3
2-amino-1-butanol
Cl
H
N
H
H
N
H
N
N
OMe
RESULTS AND DISCUSSION
3a
, 48%
3c
3b
, 45%
, 40%
3d
3h
, 61%
Recently, we demonstrated Ni-catalyzed a couple of novel
protocols involving (de)hydrogenative transformations of
renewable alcohols, diols or amino alcohols for the synthesis of
indoles, pyrroles, pyridines, quinolines, benzimidazoles and
quinoxalines.11 However, cross-couplings of two different
alcohols; secondary alcohols and β-amino alcohols to
substituted pyrroles remains challenging involving two key
issues; i) self-condensation of secondary alcohols and ii) self-
condensation of β-amino alcohol to pyrazine. Notably,
couplings of secondary alcohols and β-amino alcohols involves
one-pot multi-steps transformations; dehydrogenation of
secondary alcohols to carbonyls, condensations to imine
followed by β-amino aldehyde, thereby, base-catalyzed
condensation to the desired pyrroles (Scheme 4). Initially, we
studied the model reaction between 2-aminobutane-1-ol 1a with
1-phenylethanol 2a following our recently established
intermolecular cyclisation of β-amino alcohols with ketones.11b
L-leucinol
Cl
Br
H
H
N
H
H
N
N
N
, 66%
3e
, 32%
3f
3g
, 36%
, 39%
L-valinol
MeO
OMe
H
H
H
N
H
N
N
N
3j
, 34%
3k
, 44%
3l
, 49%
3i
, 33%
phenylglycinol
isoleucinol
OMe
H
N
H
H
N
H
N
N
Ph
OMe
3o
, 52%
3n
, 35%
3p
, 43%
3m
, 39%
alaninol
phenylalaninol
OMe
H
N
H
N
H
N
H
N
Ph
Ph
3s
, 31%
3t
, 54%
3q
, 46%
3r
, 68%
a
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), NiBr2 (0.025
mol %), L1 (0.03 mol %), t-BuOK (0.5 mmol), toluene (1.0 mL),
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The Journal of Organic Chemistry
HO
Ph
Ph
high pressure reactor under N2 atmosphere at 150 °C in a heating
magnetic stirrer for 36 h. Isolated yields reported.
L1
/
NiBr2
MeO
H
H
1
2
3
4
5
6
7
8
HN
t-BuOK, toluene
150 °C, 36 h
H
NH2
MeO
H
H
OH
H
2l
1f
5
, 41%
Next we explored the synthesis of 2,5-disubstituted pyrroles
using the optimized conditions of Table 1 (entry 1). Initially, we
studied the scope of seven different amino alcohols, bearing
alkyl, aryl and benzyl groups, with 1-phenylethanol 2a (Table
2). Interestingly, a series of less reactive amino alcohols having
ethyl, iso-butyl, iso-propyl, secondary-butyl as well as methyl
groups resulted the desired 2,5-disubstituted pyrroles in up to
61% yields (Table 2, 3a-3o and 3s-3t). To our delight,
phenylglycinol 1e, and phenylalaninol 1f, efficiently
transformed into 2,5-diaryl substituted pyrroles 3p-3r in up to
68% isolated yield (Table 2). The general applicability of the
Scheme 2. synthetic utility: pyrrole synthesis using steroid
derivative.
Again, to establish the synthetic utility, intermolecular
cyclization using secondary alcohol derivative of steroid
hormone 2l, with phenylalaninol 1f, was performed and the
desired 2,5-disubstitutedpyrrole 5 was obtained in 41% yield
without much affecting the steroid framework (Scheme 2). For
a practical utility, a higher scale synthesis of tri-substituted
pyrrole 4a resulted 52% isolated yield (Scheme 3). Importantly,
the established protocol is tolerant to amino alcohols including
a variety of aryl, alkyl, methoxy, halides (Cl and Br) and
unsaturated steroid framework.
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protocol was further demonstrated using
a series of
electronically different secondary alcohols bearing functional
groups such as, o-OMe m-OMe, p-OMe, p-Cl, p-Br including
p-ethyl and naphthyl substituents and resulted moderate to good
isolated yields of 2,5-disubstituted pyrroles (3b-3d, 3f-3h, 3i-
3l, and 3m-3n) with different β-amino alcohols (Table 2).
OH
NH2
HN
NiBr2 / Phen
t-BuOK
toluene, 150 °C, 36 h
OH
+
1a
52%
2i,
1 g
Table 3. Synthesis of 2,3,5-tri-Substituted Pyrrolesa
4a
H
Scheme 3: Higher-Scale Synthesis of 4aa. Reaction conditions:
a2-aminobutan-1-ol 1a (3.37 mmol, 300 mg), 1,2,3,4-
tetrahydronaphthalen-1-ol 2i (6.74 mmol, 1 g), NiBr2 (10
mol%, 74 mg), 1,10-phenanthroline L1 (12 mol%, 121 mg), t-
BuOK (6.74 mmol, 756 mg), toluene (4.0 mL), High pressure
reactor under N2 atmosphere at 150 °C in a heating magnetic
stirrer for 36 h.
OH
R2
2i-2k
R1
N
NH2
NiBr2 / Phen
R2
+
OH
t-BuOK
toluene, 150 °C, 36 h
R1
4
1
Ph
HN
HN
HN
HN
4d
, 51%
4a
, 48%
4c
, 64%
4b
, 55%
Next, to interrogate the reaction mechanism for
dehydrogenative couplings of alcohols and to understand the
participation of the key Ni-intermediate species, Cat. A was
independently prepared,11 and employed using standard
conditions of Table 1, 3a was obtained in 83% yield (Scheme
4a). Nevertheless, reaction of acetophenone 2a’ with 2-
aminobutan-1-ol 1a, resulted 74% yield to pyrrole 3a, support
the dehydrogenation of secondary alcohol to ketone derivative
(Scheme 4bi). Again, deuterium labeling experiment using 1a
with 2a-d3 (96% D), resulted 3a-d2 in 52% isolated yield and
exhibited almost 40% deuterium incorporation in pyrrole core
(Scheme 4b, ii and SI Scheme S3). Further, when 1a was
reacted with 2a-d1 (96% D), 3a-d2 was obtained in 58% yield
along with 32% deuterium incorporation in pyrrole ring
(Scheme 4b, iii and SI Scheme S4). These deuterium labeling
experiments are in agreement for the participation of the alkyl
C-H bond of secondary alcohol. Interestingly, under standard
conditions, we did not observe any intermolecular cyclization
or dimerization of β-amino alcohol 1a to corresponding 2,5-
diethylpyrazine (Scheme 4b, iv).10
Additionally, we independently performed a series of control
experiments in absence of base and catalyst involving β-amino
alcohol 1a with 2a, which established the potential role of the
individual component (Scheme 4c). Next, imine A was
independently prepared and resulted 41% yield to pyrrole 3a
under standard catalytic conditions, whereas, intramolecular
cyclization of imine A in absence of base and catalyst resulted
albeit with poor product yields (Scheme 4c). Thereafter, to
determine the actual reaction pathway a control experiment
using N,N-dimethyl-ethanol with 2a was performed using
standard catalytic conditions, which exclude the possibility of
the reaction pathway II (Scheme 5a and SI Scheme S2).
HN
HN
HN
MeO
MeO
MeO
4e
, 44%
4g
, 48%
4f
, 74%
HN
HN
HN
MeO
MeO
4j
, 32%
4h
, 62%
4i
, 61%
a
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), NiBr2
(0.025 mol %), L1 (0.03 mol %), t-BuOK (0.5 mmol), toluene
(1.0 mL), High pressure reactor under N2 atmosphere at 150 °C
in a heating magnetic stirrer for 36 h. Isolated yields
reported.
After having this potential catalytic activity for secondary
alcohols, we further explored the synthesis of 2,3,5-
trisubstituted bicyclic pyrroles (Table 3). Importantly, when α-
tetralol 2i, was employed with β-amino alcohols, 1a, 1b, 1e and
1f, tri-substituted bicyclic pyrroles 4a-4d were obtained in 48-
64% isolated yields (Table 3). Further, 7-methoxy-1-tetralol 2j,
with substituted β-amino alcohols also gave the tri-substituted
bicyclic pyrroles in up to 74% yield respectively (Table 3, 4e-
4i). Again, intermolecular cyclization of more challenging 1-
phenyl-1-propanol 2k, efficiently transformed into 2,3,5-
trisubstituted pyrroles in acceptable yield (Table 3, 4j).
Applications of these challenging alcohols established the
potential significance of the present protocol.
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a) Control experiments to determine reaction pathways:
Nevertheless, catalytic reaction of 1a with 2a was monitored
OH
2a
Path I
N
1
2
3
using GC-MS and intermediate imine A was detected, however,
we did not observe any β-amino aldehyde B. We anticipated
that, intra-molecular C-C coupling is reasonably fast to detect
in GC-MS analysis, which is in support with the literature
observations.8a These experiments are in agreement for the
involvement of the catalytic pathway I (Scheme 5a and SI
Schemes S1-S2)
-H2O
Ph
-H2
-H2O
n
NH2
Cat.
-H2
N
o
i
t
OH
A
a
OH
O
B
n
Ph
Ph
O
e
1a
g
o
3a
r
4
d
Path II
y
X
O
h
NH2
e
5
6
Cat.
d
-H2
Ph
O
-H2O
Ph
C
2a'
-H2O
1a'
NH2
b) Postulated reaction mechanism:
7
8
9
OH
NH2
H
N
R2
R2
2
t-BuOK
R2
R1
OH
a) Catalytic studies using Cat. A
R2
R1
Ni-cat.
H2
1
N
N
NH2
3
Ni-cat.
- H2
O
OH
Imine A
Detected using GC-MS
H2O
R1

R1
O
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H2O
OH
Detected using
in situ 1H-NMR
-amino
aldehyde B
H
1a
N
R2
Cat. A (10 mol%)
2'
+
N
N
Ph
Quantitative determination of H2 was performed
One pot C-N/C-C coupling/intermolecular cyclization
H2 gas was detected using GC
H2O was detected in 1H-NMR
Ni
standard conditions
83% yield
OH
Br
Cat. A
Br
3a
H3C
Ph
Scheme 5. Plausible mechanism for pyrrole synthesis
2a
b) Deuterium labeling experiments:
CONCLUSIONS
H
N
O
standard conditions
Ph
74% yield
NH2
In summary, the first Ni-catalyzed double dehydrogenative
couplings of two different alcohols to substituted pyrroles is
demonstrated. Inexpensive NiBr2/1,10-phenanthroline enables
a series of 2,5-di-substituted and 2,3,5-tri-substituted pyrroles
in up to 83% yield. Amino alcohols, alkyl, alkoxy, halides
including steroid derivative were efficiently transformed into
interesting pyrrole derivatives. Mechanistic studies including
defined Ni-catalyst and intermediate species, deuterium
labeling and control experiments as well as quantitative
determination of hydrogen gas and detection of water
generation in the reactions were performed.
+
Ph
Ph
OH
OH
(i)
H3C
2a'
OH
Ph
1a
3a
H
N
standard conditions
52% yield
NH2
+
(ii)
D3C
1a
H/D
H/D
39%
2a-d3
(96% D)
H/D
40%
3a-d2
H
OH
Ph
standard conditions
N
NH2
+
Ph
(iii)
OH
H3C
58% yield
D
1a
32%
2a-d
(96% D)
H/D
32%
3a-d2
NH2
N
N
standard conditions
0% yield
Experimental section
OH
(iv)
1a
General Information:
1a''
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)
using a gradient of ethyl acetate and hexane as mobile phase. 1H
NMR spectral data were collected at, 400 (JEOL), 500 (Bruker)
MHz, while 13C NMR were recorded at 100, 125 MHz. 1H
NMR spectral data are given as chemical shifts in ppm followed
by multiplicity (s- singlet; d- doublet; t- triplet; q- quartet; m-
multiplet), number of protons and coupling constants. 13C{1H}
NMR chemical shifts are expressed in ppm. HRMS (ESI)
spectral data were collected using Bruker High Resolution Mass
Spectrometer. All nickel salts were purchased from Sigma
Aldrich. Nickel(II) bromide (Assay- 98%; CAS Number 13462-
88-9; EC Number 236-665-0; Pack Size- No 217891-10G). All
nitrogen ligands were purchased from Sigma Aldrich or Alfa
Aesar. Potassium tert-butoxide was purchased from Avra
Synthesis Pvt. Ltd., India. (Purity-98%, CAS No: 865-47-4,
Catalog No- ASP2012).
c) Control experiments:
Ph
OH
3a
53
0
Catalyst t-BuOK
+
+
-
2a
+
-
standard conditions, 36 h
+
0
3a
Catalyst t-BuOK
NH2
OH
N
+
41
10
7
+
-
A
OH
+
-
1a
Ph
+
standard conditions, 36 h
Scheme 4. preliminary mechanistic studies and control
experiments
On the basis of these control experiments, we postulated a
probable catalytic pathway for the Ni-catalyzed double
dehydrogenative condensation of two different alcohols
(Scheme 5b). Initially, acetophenone 2’ was formed from
secondary alcohol 2, following intermolecular condensation
with amino alcohol 1 resulted imine A. Thereafter, Ni-catalyzed
second dehydrogenation of intermediate A generates β-amino
aldehyde B, which subsequently undergoes base catalyzed C-C
coupling followed by cyclization to pyrrole 3 (Scheme 5b).
Notably, water and di-hydrogen are generated as side products
during these processes. Therefore, quantitative evaluation of
hydrogen gas was determined, and water generation was
confirmed through 1H-NMR studies in the reaction mixture (SI,
Schemes S5-S6).
General procedure for synthesis of pyrroles: For the
synthesis of 2-ethyl-5-phenyl-1H-pyrrole (3a): In a 5 mL oven
dried high pressure glass vials, 2-aminobutan-1-ol 1a (0.25
mmol, 23 mg), t-BuOK (0.5 mmol, 56 mg), NiBr2 (10 mol%,
10.9 mg), 1,10-phenanthroline L1 (12 mol%, 10.5 mg), 1-
phenylethanol 2a (0.5 mmol, 61 mg) in a toluene 1.0 mL were
taken under an atmosphere of N2 in a high pressure reactor and
°
heated in heating magnetic stirrer at 150 C for 36 h. The
reaction mixture was cooled to room temperature and 3.0 mL
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The Journal of Organic Chemistry
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 3a. This procedure was used as general
procedure for the synthesis of pyrroles
MHz, CDCl3) δ 8.08 (s, 1H), 7.36 (t, J = 2.7 Hz, 1H), 7.34 (d, J
= 1.8 Hz, 1H), 7.31-7.29 (m, 1H), 7.25 (s, 1H), 6.39 (t, J = 3.1
Hz, 1H), 6.05-5.94 (m, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.28 (t, J
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 136.2,
131.6, 131.2, 129.6, 129.0, 124.6, 106.6, 106.5, 21.1, 13.7.
2-Ethyl-5-(naphthalen-2-yl)-1H-pyrrole (3d):11b Following
the general procedure, the title product was obtained as a
colourless solid using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 33 mg, 61%;
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.83-7.76 (m, 4H),
7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.48-7.36 (m, 2H), 6.55 (t, J =
3.1 Hz, 1H), 6.04 (t, J = 3.0 Hz, 1H), 2.73 (q, J = 7.6 Hz, 2H),
1.33 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
136.2, 134.0, 132.0, 130.7, 130.5, 128.6, 127.8, 127.6, 126.5,
125.2, 123.2, 120.2, 106.9, 106.6, 21.2, 13.7.
1
2
3
4
5
6
7
8
Preparation of starting material (2l): In a 50 mL oven dried
RB flask, 3 methyl ether of 5-Pregnen-3β-ol-20-one 11b (88 mg,
°
0.26 mmol) in a MeOH 10 mL were taken and stirred at 0 C.
NaBH4 (2.0 equiv.) was added to the reaction mixture in portion
wise at 0 °C and continued reaction at RT for 15 h. The reaction
mixture was quenched with NH4Cl solution and the reaction
mixture was partitioned between ethyl acetate (25.0 mL) and
water (25.0 mL) in a separating funnel. The organic layer was
washed with water, and brine, dried over anhydrous Na2SO4 (s)
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 as colourless solid
(430 mg, 65% yield). NMR DATA:1H NMR (400 MHz, CDCl3
) δ 5.34 (dd, J = 3.4, 1.7 Hz, 1H), 3.73 (d, J = 4.0 Hz, 1H), 3.55-
3.47 (m, 1H), 3.34 (s, 3H), 3.09-3.01 (m, 1H), 2.40-2.3 (m, 1H),
2.27 (dd, J = 5.2, 1.9 Hz, 2H), 2.06 (dt, J = 12.5, 3.5 Hz, 2H),
2.01-1.92 (m, 3H), 1.91-1.79 (m, 5H), 1.67-1.61 (m, 3H), 1.50-
1.44 (m, 5H), 1.35-1.29 (m, 2H), 1.12 (s, 3H), 1.00 (s, 3H), 0.76
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3 ) δ 141.1, 121.5, 80.4,
71.9, 70.6, 58.6, 56.3, 55.7, 50.3, 42.4, 40.0, 38.8, 37.3, 36.6,
32.0, 31.8, 29.8, 28.1, 25.7, 24.6, 23.7, 21.0, 19.5, 12.5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Isobutyl-5-phenyl-1H-pyrrole (3e):11b Following the
general procedure, the title product was obtained as a colourless
solid using silica-gel column chromatography eluting with 1%
1
ethyl acetate in hexane. Yield = 15 mg, 32%; H NMR (400
MHz, CDCl3) δ 8.08 (s, 1H), 7.46-7.42 (m, 2H), 7.35 (dd, J =
10.6, 5.0 Hz, 2H), 7.20-7.13 (m, 1H), 6.44 (t, J = 3.0 Hz, 1H),
5.98 (t, J = 3.0 Hz, 1H), 2.51 (d, J = 7.1 Hz, 2H), 1.90 (dp, J =
13.5, 6.7 Hz, 1H), 0.98 (d, J = 6.6 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 133.4, 133.1, 130.5, 128.9, 125.7, 123.4, 108.1,
106.2, 37.5, 29.4, 22.6.
2-(4-Chlorophenyl)-5-isobutyl-1H-pyrrole (3f):11b Following
the general procedure, the title product was obtained as a
colourless oil using silica-gel column chromatography eluting
with 1% ethyl acetate in hexane. Yield = 22 mg, 39%; 1H NMR
(400 MHz, CDCl3) δ 8.02 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.28
(d, J = 8.7 Hz, 2H), 6.39 (t, J = 3.1 Hz, 1H), 5.95 (t, J = 3.0 Hz,
1H), 2.49 (d, J = 7.1 Hz, 2H), 1.94-1.82 (m, 1H), 0.95 (d, J =
6.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.8, 131.6,
131.1, 129.0, 128.3, 124.5, 108.3, 106.7, 37.4, 29.3, 22.5.
2-(4-Bromophenyl)-5-isobutyl-1H-pyrrole (3g):11b Following
the general procedure A, the title product was obtained as a
colourless oil using silica-gel column chromatography eluting
with 1% ethyl acetate in hexane. Yield = 24 mg, 36%; 1H NMR
(400 MHz, CDCl3) δ 8.04 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.28
(d, J = 8.6 Hz, 2H), 6.42-6.38 (m, 1H), 5.95 (t, J = 3.0 Hz, 1H),
2.48 (d, J = 7.1 Hz, 2H), 1.94-1.82 (m, 1H), 0.95 (d, J = 6.6 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.9, 131.9, 128.9,
124.8, 123.4, 119.0, 108.4, 106.7, 37.4, 29.3, 22.6.
Procedure for Gram-Scale Synthesis of 4a: The gram scale
reaction was performed using 2-aminobutan-1-ol 1a (3.37
mmol, 300 mg), t-BuOK (6.74 mmol, 756 mg), NiBr2 (10
mol%, 74 mg), 1,10-phenanthroline L1 (12 mol%, 121 mg),
1,2,3,4-tetrahydronaphthalen-1-ol 2i (6.74 mmol, 1 g) and
toluene (4.0 mL) in a 35 mL ace pressure tube under an
atmosphere of N2 at 150 °C in an oil bath for 36 h. The reaction
mixture was cooled to room temperature and 8.0 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 4a
(345 mg, 52% yield).
Characterization Data of the Synthesized Compounds:
2-Ethyl-5-phenyl-1H-pyrrole (3a):11b Following the general
procedure, the title product was obtained as a colourless oil
using silica-gel column chromatography eluting with 1% ethyl
2-Isobutyl-5-(naphthalen-2-yl)-1H-pyrrole
(3h):11b
1
acetate in hexane. Yield = 20 mg, 48%; H NMR (400 MHz,
Following the general procedure, the title product was obtained
as a colourless solid using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 41 mg, 66%;
1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.79 (dd, J = 10.7,
6.5 Hz, 4H), 7.67-7.60 (m, 1H), 7.49-7.35 (m, 2H), 6.58-6.53
(m, 1H), 6.05-6.00 (m, 1H), 2.55 (d, J = 7.5 Hz, 2H), 2.00-1.88
(m, 1H), 1.00 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 134.0, 133.8, 131.9, 130.6, 130.5, 128.6, 127.8, 127.6,
126.5, 125.2, 123.2, 120.1, 108.3, 107.0, 37.5, 29.4, 22.6.
CDCl3) δ 8.12 (s, 1H), 7.46-7.42 (m, 2H), 7.36-7.31 (m, 2H),
7.16 (t, J = 7.3 Hz, 1H), 6.42 (t, J = 3.0 Hz, 1H), 5.99 (t, J = 3.0
Hz, 1H), 2.69 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 135.7, 133.1, 130.7, 128.9,
125.8, 123.5, 106.3, 106.1, 21.1, 13.7.
2-Ethyl-5-(3-methoxyphenyl)-1H-pyrrole (3b):11b Following
the general procedure, the title product was obtained as a pale
brown oil using silica-gel column chromatography eluting with
2% ethyl acetate in hexane. Yield = 22 mg, 45%; 1H NMR (400
MHz, CDCl3) δ 8.12 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.02 (d, J
= 7.7 Hz, 1H), 6.99-6.95 (m, 1H), 6.72 (dd, J = 8.2, 2.5 Hz, 1H),
6.41 (t, J = 3.0 Hz, 1H), 5.98 (t, J = 2.9 Hz, 1H), 3.83 (s, 3H),
2.68 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 160.1, 135.8, 134.5, 130.5, 129.9, 116.1,
111.1, 109.4, 106.4, 106.3, 55.3, 21.1, 13.7.
2-Isopropyl-5-(2-methoxyphenyl)-1H-pyrrole
(3i):11b
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 17 mg, 33%;
1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.61 (dd, J = 7.7,
1.6 Hz, 1H), 7.14-7.07 (m, 1H), 6.95 (ddd, J = 10.7, 5.9, 2.1 Hz,
2H), 6.52-6.48 (m, 1H), 5.97 (t, J = 3.5 Hz, 1H), 3.95 (s, 3H),
3.03-2.93 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (125
MHz, CDCl3) δ 154.4, 139.1, 128.0, 126.2, 126.1, 121.5, 111.8,
106.1, 103.8, 55.8, 27.2, 22.6.
2-Ethyl-5-(4-chlorophenyl)-1H-pyrrole (3c):10a Following the
general procedure, the title product was obtained as a colourless
solid using silica-gel column chromatography eluting with 1%
1
ethyl acetate in hexane. Yield = 20 mg, 40%; H NMR (400
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2-Isopropyl-5-(4-methoxyphenyl)-1H-pyrrole
(3j):11b
Page 6 of 8
using silica-gel column chromatography eluting with 1% ethyl
1
1
2
3
4
5
6
7
8
Following the general procedure, the title product was obtained
as a white solid using silica-gel column chromatography eluting
with 1% ethyl acetate in hexane. Yield = 18 mg, 34%; 1H NMR
(400 MHz, CDCl3) δ 8.04 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 6.89
(d, J = 8.7 Hz, 2H), 6.29 (t, J = 3.0 Hz, 1H), 5.96 (t, J = 2.8 Hz,
1H), 3.81 (s, 3H), 3.01-2.88 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 158.0, 139.7, 130.6, 126.3,
125.0, 125.0, 114.3, 104.8, 55.4, 27.4, 22.8.
acetate in hexane. Yield = 23 mg, 43%; H NMR (400 MHz,
CDCl3) δ 8.59 (s, 1H), 7.56-7.51 (m, 4H), 7.42-7.36 (m, 4H),
7.23 (dd, J = 10.7, 4.3 Hz, 2H), 6.59 (d, J = 2.6 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 133.2, 132.6, 129.0, 126.5,
123.9, 108.0.
2-Benzyl-5-phenyl-1H-pyrrole (3q):11b Following the general
procedure, the title product was obtained as a colourless solid
using silica-gel column chromatography eluting with 1% ethyl
(3k):11b
acetate in hexane. Yield = 26 mg, 46%; H NMR (400 MHz,
1
2-(4-Ethylphenyl)-5-isopropyl-1H-pyrrole
9
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 23 mg, 44%;
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.37 (d, J = 8.3 Hz,
2H), 7.18 (d, J = 8.2 Hz, 2H), 6.39-6.35 (m, 1H), 5.98 (t, J = 3.4
Hz, 1H), 3.03-2.92 (m, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.31 (d, J
= 6.9 Hz, 6H), 1.25 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 141.9, 140.0, 130.8, 130.7, 128.4, 123.7, 105.3,
104.8, 28.6, 27.3, 22.8, 15.7.
CDCl3) δ 8.03 (s, 1H), 7.41-7.37 (m, 2H), 7.36-7.29 (m, 4H),
7.28-7.23 (m, 3H), 7.16 (t, J = 7.3 Hz, 1H), 6.45 (t, J = 3.0 Hz,
1H), 6.06 (t, J = 3.0 Hz, 1H), 4.03 (s, 2H); 13C{H} NMR (100
MHz, CDCl3) δ 139.4, 132.9, 132.1, 131.6, 128.9, 128.8, 128.8,
126.6, 125.9, 123.6, 108.7, 106.2, 34.4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Benzyl-5-(naphthalen-2-yl)-1H-pyrrole (3r):11b Following
the general procedure, the title product was obtained as a
colourless solid using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 48 mg, 68%;
1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.81 (dd, J = 13.1,
5.7 Hz, 3H), 7.76 (s, 1H), 7.64 (dd, J = 8.5, 1.7 Hz, 1H), 7.49
(d, J = 6.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.39 (t, J = 7.4 Hz, 2H),
7.34-7.30 (m, 3H), 6.61 (t, J = 3.0 Hz, 1H), 6.14 (t, J = 2.9 Hz,
1H), 4.10 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 139.3,
133.8, 132.5, 131.9, 131.6, 130.2, 128.8, 128.7, 128.5, 127.7,
127.6, 126.6, 126.4, 125.2, 123.1, 120.4, 109.0, 106.9, 34.3.
2-Isopropyl-5-(naphthalen-2-yl)-1H-pyrrole
(3l):11b
Following the general procedure, the title product was obtained
as a colourless solid using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 28 mg, 49%;
1H NMR (400 MHz, CDCl3) δ 8.35 (dt, J = 7.3, 3.3 Hz, 1H),
8.14 (s, 1H), 7.92-7.83 (m, 1H), 7.77 (dd, J = 7.0, 3.2 Hz, 1H),
7.49 (dt, J = 7.2, 4.0 Hz, 4H), 6.43 – 6.39 (m, 1H), 6.12-6.07
(m, 1H), 3.10-2.96 (m, 1H), 1.35 (d, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 139.9, 134.2, 131.9, 131.4, 129.0,
128.5, 127.6, 126.3, 126.0, 125.9, 125.7, 125.6, 109.4, 104.4,
27.3, 22.8.
2-(4-Methoxyphenyl)-5-methyl-1H-pyrrole
(3s):11b
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 14 mg, 31%;
1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.35 (d, J = 9.1 Hz,
2H), 6.88 (d, J = 9.0 Hz, 2H), 6.30-6.24 (m, 1H), 5.95-5.88 (m,
1H), 3.81 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 158.0, 130.9, 128.4, 126.3, 124.9, 114.4, 107.7, 105.1,
55.4, 13.3.
2-(sec-Butyl)-5-(4-methoxyphenyl)-1H-pyrrole
(3m):11b
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 22 mg, 39%;
1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.37 (d, J = 8.8 Hz,
2H), 6.90 (d, J = 8.8 Hz, 2H), 6.30 (t, J = 3.0 Hz, 1H), 5.95 (t,
J = 3.0 Hz, 1H), 3.82 (s, 3H), 2.77-2.66 (m, 1H), 1.72 – 1.57
(m, 2H), 1.28 (d, J = 7.0 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 157.9, 138.5, 130.3, 126.3,
124.8, 114.3, 105.4, 104.7, 55.3, 34.4, 30.3, 20.1, 11.9.
2-Methyl-5-(naphthalen-2-yl)-1H-pyrrole (3t):11b Following
the general procedure, the title product was obtained as a
colourless solid using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 27 mg, 54%;
1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.81-7.76 (m, 4H),
7.62 (dd, J = 8.6, 1.7 Hz, 1H), 7.46-7.35 (m, 2H), 6.52 (t, J =
3.0 Hz, 1H), 6.00 (t, J = 5.8 Hz, 1H), 2.37 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 133.9, 131.9, 130.8, 130.4, 129.6,
128.5, 127.7, 127.6, 126.4, 125.1, 123.1, 120.1, 108.2, 107.0,
13.3.
8-Methoxy-2-methyl-4,5-dihydro-1H-benzo[g]indole (4a):
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 23 mg, 48%;
1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.15 (t, J = 7.1 Hz,
2H), 7.09-7.07 (m, 1H), 7.01-6.97 (m, 1H), 5.82 (d, J = 2.3 Hz,
1H), 2.90 (t, J = 7.6 Hz, 2H), 2.71-2.66 (m, 4H), 1.28 (t, J = 7.6
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 135.4, 134.5,
131.2, 129.6, 128.4, 126.4, 124.5, 120.7, 104.7, 104.6, 30.2,
22.0, 21.2, 13.8. HRMS (ESI-TOF) m/z [M]+ Calcd for C14H15N
197.1204, Found 197.1209.
2-(sec-Butyl)-5-(3-methoxyphenyl)-1H-pyrrole
(3n):11b
Following the general procedure, the title product was obtained
as a light brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 20 mg, 35%;
1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.25 (t, J = 8.0 Hz,
1H), 7.02 (ddd, J = 7.7, 1.5, 0.9 Hz, 1H), 6.98-6.95 (m, 1H),
6.71 (ddd, J = 8.2, 2.5, 0.6 Hz, 1H), 6.43-6.38 (m, 1H), 5.96 (t,
J = 2.9 Hz, 1H), 3.83 (s, 3H), 2.75-2.66 (m, 1H), 1.71-1.56 (m,
2H), 1.28 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 160.1, 139.3, 134.6, 130.2, 129.9,
116.1, 111.0, 109.4, 106.2, 105.7, 55.4, 34.5, 30.3, 20.1, 11.9.
2-(sec-Butyl)-5-phenyl-1H-pyrrole (3o):11b Following the
general procedure, the title product was obtained as a colourless
oil using silica-gel column chromatography eluting with 1%
1
ethyl acetate in hexane. Yield = 25 mg, 52%; H NMR (400
MHz, CDCl3) δ 8.12 (s, 1H), 7.46 (d, J = 7.7 Hz, 2H), 7.35 (t, J
= 7.7 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 6.45 (t, J = 2.9 Hz, 1H),
6.00 (t, J = 2.7 Hz, 1H), 2.79-2.69 (m, 1H), 1.66 (tdd, J = 20.7,
13.7, 7.1 Hz, 2H), 1.31 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 139.3, 133.1, 130.4,
128.9, 125.7, 123.5, 105.9, 105.8, 34.5, 30.4, 20.2, 12.0.
8-Methoxy-2-methyl-4,5-dihydro-1H-benzo[g]indole (4b):
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 30 mg, 55%;
1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.16 (t, J = 7.3 Hz,
2H), 7.09 (d, J = 7.3 Hz, 1H), 7.02-6.98 (m, 1H), 5.81 (d, J =
2.3 Hz, 1H), 2.91 (t, J = 7.6 Hz, 2H), 2.73-2.68 (m, 2H), 2.49
2,5-Diphenyl-1H-pyrrole (3p):11b Following the general
procedure, the title product was obtained as a colourless solid
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(d, J = 7.1 Hz, 2H), 1.94-1.84 (m, 1H), 0.98 (s, 3H), 0.97 (s,
= 39 mg, 62%; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.07
(d, J = 8.2 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.54 (dd, J = 8.2,
2.6 Hz, 1H), 5.79 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 2.83 (t, J =
7.6 Hz, 2H), 2.68-2.64 (m, 2H), 2.48 (d, J = 7.1 Hz, 2H), 1.91-
1.85 (m, 1H), 0.97 (s, 3H), 0.95 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 158.6, 133.1, 130.6, 128.9, 126.8, 126.2, 121.3,
108.8, 106.4, 104.4, 55.4, 37.6, 29.4, 29.2, 22.6, 22.2. HRMS
(ESI-TOF) m/z [M]+ Calcd for C17H21NO 255.1623, Found
255.1625.
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 134.4, 133.0, 129.7,
128.3, 126.5, 126.3, 124.4, 120.7, 117.6, 106.4, 37.6, 30.2, 29.4,
22.6, 22.0. HRMS (ESI-TOF) m/z [M]+ Calcd for C16H19N
225.1517, Found 225.1507.
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8-Methoxy-2-methyl-4,5-dihydro-1H-benzo[g]indole (4c):
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 39 mg, 64%;
1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.53 (d, J = 7.6 Hz,
2H), 7.39 (d, J = 7.5 Hz, 2H), 7.24-7.19 (m, 4H), 7.07 (t, J = 6.6
Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 2.96 (t, J = 7.1 Hz, 2H), 2.78
(s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 136.0, 135.1,
132.7, 129.0, 128.6, 128.4, 128.3, 126.7, 126.3, 125.3, 123.8,
122.3, 118.4, 106.1, 30.0, 21.9. HRMS (ESI-TOF) m/z [M]+
Calcd for C18H15N: 245.1204, Found 245.1209.
2-Benzyl-8-methoxy-4,5-dihydro-1H-benzo[g]indole (4i):11b
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 44 mg, 61%;
1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.36-7.28 (m, 2H),
7.28-7.23 (m, 3H), 7.06 (d, J = 8.1 Hz, 1H), 6.59-6.52 (m, 2H),
5.87 (d, J = 2.1 Hz, 1H), 4.00 (s, 2H), 3.77 (s, 3H), 2.83 (t, J =
7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 167.2, 139.4, 131.8, 129.0, 128.8, 128.8, 126.9, 126.6,
121.2, 109.8, 109.1, 107.0, 107.0, 104.5, 55.4, 34.5, 29.2, 22.2.
5-Isobutyl-3-methyl-2-phenyl-1H-pyrrole (4j):11b Following
the general procedure, the title product was obtained as a pale
brown oil using silica-gel column chromatography eluting with
1% ethyl acetate in hexane. Yield = 17 mg, 32%; 1H NMR (400
MHz, CDCl3) δ 7.76 (s, 1H), 7.41-7.34 (m, 4H), 7.21-7.16 (m,
1H), 5.83 (d, J = 2.8 Hz, 1H), 2.45 (d, J = 7.0 Hz, 2H), 2.24 (s,
3H), 1.92-1.80 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 134.1, 131.7, 128.7, 126.5, 125.9, 125.4,
116.4, 110.4, 37.4, 29.3, 22.6, 12.7.
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8-Methoxy-2-methyl-4,5-dihydro-1H-benzo[g]indole (4d):
Following the general procedure, the title product was obtained
as a pale brown oil using silica-gel column chromatography
eluting with 1% ethyl acetate in hexane. Yield = 33 mg, 51%;
1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.28-7.23 (m, 2H),
7.19 (t, J = 3.8 Hz, 3H), 7.09-7.03 (m, 2H), 6.95-6.92 (m, 2H),
5.80 (d, J = 2.2 Hz, 1H), 3.94 (s, 2H), 2.83 (t, J = 7.6 Hz, 2H),
2.62 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
139.3, 134.4, 131.6, 129.3, 128.6, 128.2, 127.1, 126.4, 126.3,
124.5, 120.5, 117.7, 106.9, 106.8, 34.4, 30.0, 21.8. HRMS (ESI-
TOF) m/z [M]+ Calcd for C19H17N: 259.1361, Found 282.1390.
8-Methoxy-2-methyl-4,5-dihydro-1H-benzo[g]indole
(4e):11b Following the general procedure, the title product was
obtained as a pale brown oil using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane. Yield
= 28 mg, 44%; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.09
(d, J = 8.2 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.57 (dd, J = 8.2,
2.5 Hz, 1H), 5.81 (d, J = 1.4 Hz, 1H), 3.81 (s, 3H), 2.84 (t, J =
7.6 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 158.6, 130.5, 129.0, 126.8, 126.5,
121.5, 108.9, 106.5, 106.4, 104.4, 55.4, 29.3, 22.2, 13.4.
2-Isopropyl-8-methoxy-4,5-dihydro-1H-benzo[g]indole
(4f):11b Following the general procedure, the title product was
obtained as a pale brown oil using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane. Yield
= 44 mg, 74%; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.06
(d, J = 8.1 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.54 (dd, J = 8.2,
2.6 Hz, 1H), 5.83 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H), 2.83 (t, J =
7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.17-2.01 (m, 1H), 1.29
(d, J = 6.9 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.6,
140.2, 130.5, 128.9, 126.9, 126.2, 121.0, 108.9, 104.4, 103.4,
55.5, 29.3, 27.5, 22.8, 22.2.
2-Benzyl-5-((3S,8S,9S,10R,13S,14S,17S)-3-methoxy-10,13-
dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1H-
pyrrole (5):11b Following the general procedure, the title
product was obtained as a pale yellow oil using silica-gel
column chromatography eluting with 1% ethyl acetate in
1
hexane. Yield = 18 mg, 41%; H NMR (500 MHz, CDCl3) δ
7.53 (s, 1H), 7.33 (dd, J = 10.2, 4.6 Hz, 2H), 7.23 (dd, J = 15.3,
7.7 Hz, 3H), 5.90 (t, J = 2.8 Hz, 1H), 5.87 (t, J = 2.9 Hz, 1H),
5.40-5.37 (m, 1H), 3.97 (s, 2H), 3.38 (s, 3H), 3.09 (ddd, J =
11.3, 6.8, 4.6 Hz, 1H), 2.55 (t, J = 9.8 Hz, 1H), 2.44-2.40 (m,
1H), 2.22-2.15 (m, 2H), 2.04-1.94 (m, 3H), 1.92-1.87 (m, 2H),
1.76-1.70 (m, 2H), 1.61-1.56 (m, 2H), 1.47 (ddd, J = 12.4, 9.7,
4.8 Hz, 3H), 1.31-1.27 (m, 1H), 1.26-1.21 (m, 1H), 1.14-1.07
(m, 2H), 1.02 (s, 3H), 0.52 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 141.0, 139.9, 132.3, 128.8, 128.6, 128.5, 126.3, 121.4,
106.2, 105.4, 80.3, 55.8, 55.6, 50.4, 50.2, 43.6, 38.7, 38.0, 37.2,
37.0, 34.2, 32.3, 31.9, 28.0, 26.3, 24.3, 20.9, 19.4, 13.0.
2-(sec-Butyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole
(4g):11b Following the general procedure, the title product was
obtained as a pale brown oil using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane. Yield
= 30 mg, 48%; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.06
(d, J = 8.2 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.2,
2.5 Hz, 1H), 5.81 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 2.83 (t, J =
7.6 Hz, 2H), 2.72-2.62 (m, 3H), 1.70-1.57 (m, 2H), 1.27 (d, J =
7.0 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 158.5, 139.1, 130.5, 128.8, 126.8, 126.0, 121.0, 108.7,
104.3, 104.0, 55.4, 34.6, 30.3, 29.2, 22.2, 20.1, 11.9.
ASSOCIATED CONTENT
Supporting Information
The supporting Information is available free of charge on the ACS
Publications website
Optimization studies, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: dbane.fcy@iitr.ac.in
2-(sec-Butyl)-8-methoxy-4,5-dihydro-1H-benzo[g]indole
(4h): Following the general procedure, the title product was
obtained as a pale brown oil using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane. Yield
ACKNOWLEDGMENT
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Page 8 of 8
Synthesis. Bull. Chem. Soc. Jpn. 1987, 60, 3456–3458. (f) Pridmore, S.
The authors thank SERB, India (ECR/2015/000600). IIT Roorkee
(SMILE-32) and FIST-DST are gratefully acknowledged for
instrument facilities. A. A. and S. B. thank IIT-R and INSPIRE
Fellowship (DST/2017/IF170766) for financial support. M. V.
Thank SERB-NPDF (PDF/2017/002784), India for a fellowship.
J.; Slatford, P. A.; Daniel, A.; Whittlesey, M. K.; Williams, J. M. J.
Ruthenium-Catalysed Conversion of 1,4-Alkynediols into Pyrroles.
Tetrahedron Lett. 2007, 48, 5115–5120. (g) Pridmore, S. J.; Slatford,
P. A.; Taylor, J. E.; Whittlesey, M. K.; Williams, J. M. J. Synthesis of
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4
5
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7
8
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Furans, Pyrroles and Pyridazines by
a Ruthenium-Catalysed
Isomerisation of Alkynediols and in situ Cyclisation. Tetrahedron
2009, 65, 8981–8986. (h) Siddiki, S. M. A. H.; Touchy, A.
S.; Chaudhari, C.; Kon, K.; Toyao, T.; Shimizu, K.-i. Synthesis of
2,5-Disubstituted Pyrroles via Dehydrogenative Condensation of
Secondary Alcohols and 1,2-Amino Alcohols by Supported Platinum
Catalysts. Org. Chem. Front. 2016, 3, 846–851.
(8) Selected recent examples with Ir-catalysts: (a) Michlik, S.;
Kempe, R. A Sustainable Catalytic Pyrrole Synthesis. Nat. Chem.
2013, 5, 140–144. (b) Forberg, D.; Obenauf, J.; Friedrich, M.; Hghne,
S. M.; Mader, W.; Motz, G.; Kempe, R. The Synthesis of Pyrroles via
Acceptorless Dehydrogenative Condensation of Secondary Alcohols
and 1,2-Amino Alcohols Mediated by a Robust and Reusable Catalyst
Based on Nanometer-sized Iridium Particles. Catal. Sci. Technol. 2014,
4, 4188–4192. (c) For an example with Re-catalysts, see: Mastalir, M.;
Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K. Rhenium-
Catalyzed Dehydrogenative Coupling of Alcohols and Amines to
Afford Nitrogen-Containing Aromatics and More. Org. Lett. 2019, 21,
1116–1120.
REFERENCES
(1) For selected recent reviews, see: (a) Hagfeldt, A.; Boschloo, G.;
Sun, L.; Kloo, L.; Pettersson, H. Dye-Sensitized Solar Cells. Chem.
Rev. 2010, 110, 6595–6663. (b) Estévez, V.; Villacampa, M.;
Menéndez, J. C. Multicomponent Reactions for the Synthesis of
Pyrroles. Chem. Soc. Rev. 2010, 39, 4402–4421. (c) Guillena, G.;
Ramón, D. J.; Yus, M. Hydrogen Autotransfer in the N-Alkylation of
Amines and Related Compounds using Alcohols and Amines as
Electrophiles. Chem. Rev. 2010, 110, 1611–1641.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) J. A. Joule and K. Mills, Heterocyclic Chemistry, 5th ed.; Wiley:
Chichester, U.K., 2010.
(3) (a) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R.
Biological Formation of Pyrroles: Nature's Logic and Enzymatic
Machinery. Nat. Prod. Rep. 2006, 23, 517–531. (b) Gulevich, A. V.;
Dudnik, A. S.; Chernyak, N. Gevorgyan, V. Transition Metal-Mediated
Synthesis of Monocyclic Aromatic Heterocycles. Chem. Rev. 2013,
113, 3084–3213.
(4) (a) Knorr, L. Synthese von Pyrrolderivaten. Ber. Dtsch. Chem.
Ges. 1884, 17, 1635–1642. (b) Paal, C. Synthese von Thiophen‐ und
Pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1885, 18, 367–371. (c)
Hantzsch, A. Neue Bildungsweise von Pyrrolderivaten. Ber. Dtsch.
Chem. Ges. 1890, 23, 1474–1483.
(5) Barta, K.; Ford, P. C. Catalytic Conversion of Nonfood Woody
Biomass Solids to Organic Liquids. Acc. Chem. Res. 2014, 47, 1503–
1512.
(6) For selected reviews, see: (a) Bähn, S.; Sebastian, I.; Neubert, L.;
Zhang, M.; Neumann, H.; Beller, M. The Catalytic Amination of
Alcohols. ChemCatChem 2011, 3, 1853–1864. (b) Dobereiner, G. E.;
Crabtree, R. H. Dehydrogenation as a Substrate-Activating Strategy in
Homogeneous Transition-Metal Catalysis. Chem. Rev. 2010, 110, 681–
703.
(7) (a) Srimani, D.; Ben-David, Y.; Milstein, D. Direct Synthesis of
Pyrroles by Dehydrogenative Coupling of β‐Aminoalcohols with
Secondary Alcohols Catalyzed by Ruthenium Pincer Complexes.
Angew. Chem. Int. Ed. 2013, 52, 4012–4015. Direct Synthesis of
Pyrroles by Dehydrogenative Coupling of β‐Aminoalcohols with
Secondary Alcohols Catalyzed by Ruthenium Pincer Complexes.
Angew. Chem. 2013, 125, 4104–4107. (b) Zhang, M.; Neumann, H.;
Beller, M. Selective Ruthenium-Catalyzed Three-Component
Synthesis of Pyrroles. Angew. Chem., Int. Ed. 2013, 52, 597–601.
Selective Ruthenium‐Catalyzed Three Component Synthesis of
Pyrroles. Angew. Chem. 2013, 125, 625–629. (c) Zhang, M.; Fang, X.;
Neumann, H.; Beller, M. General and Regioselective Synthesis of
Pyrroles via Ruthenium-Catalyzed Multicomponent Reactions. J. Am.
Chem. Soc. 2013, 135, 11384–11388. (d) Schley, N. D.; Dobereiner, G.
E.; Crabtree, R. H. Oxidative Synthesis of Amides and Pyrroles via
Dehydrogenative Alcohol Oxidation by Ruthenium Diphosphine
Diamine Complexes. Organometallics 2011, 30, 4174–4179. (e) Tsuji,
Y.; Yokoyama, Y.; Huh, K.-T.; Watanabe, Y. Ruthenium in Organic
(9) Bullock, R. M. Catalysis without Precious Metals, Eds.: Wiley-
VCH, Weinheim, 2010.
(10) For selected recent examples, see: (a) Kallmeier, F.; Dudziec, B.;
Irrgang, T.; Kempe, R. Manganese-Catalyzed Sustainable Synthesis of
Pyrroles from Alcohols and Amino Alcohols. Angew. Chem., Int. Ed.
2017, 56, 7261–7265. (b) Midya, S. P.; Landge, V. G.; Sahoo, M. K.;
Rana, J.; Balaraman, E. Cobalt-Catalyzed Acceptorless
Dehydrogenative Coupling of AminoAlcohols with Alcohols: Direct
Access to Pyrrole, Pyridine and Pyrazine Derivatives. Chem. Commun.
2018, 54, 90–93. (c) Zhang, M.-J.; Li, H.-X.; Young, D. J.; Lia, H.-Y.;
Lang, J.-P. Reaction Condition Controlled Nickel(II)-Catalyzed C–C
Cross-Coupling of Alcohols. Org. Biomol. Chem. 2019, 17, 3567–
3574. (d) Das, S.; Maiti, D.; Sarkar, S. D. Synthesis of Polysubstituted
Quinolines from α-2-Aminoaryl Alcohols Via Nickel-Catalyzed
Dehydrogenative Coupling. J. Org. Chem. 2018, 83, 2309−2316.
(11) (a) Vellakkaran, M.; Singh, K.; Banerjee, D. An Efficient and
Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with
Alcohols. ACS Catal. 2017, 7, 8152–8158. (b) Singh, K.; Vellakkaran,
M.; Banerjee, D.
A Nitrogen-Ligated Nickel-Catalyst Enables
Selective Intermolecular Cyclisation of β- and γ-Amino Alcohols with
Ketones: Access to Five and Six-Membered N-Heterocycles. Green
Chem. 2018, 20, 2250–2256. (c) Das, J.; Singh, K.; Vellakkaran, M.;
Banerjee, D. Nickel-Catalyzed Hydrogen-Borrowing Strategy for α-
Alkylation of Ketones with Alcohols: A New Route to Branched gem-
Bis(alkyl) Ketones. Org. Lett. 2018, 20, 5587–5591. (d) Singh, K.;
Kabadwal, L. M.; Bera, S.; Alanthadka, A.; Banerjee, D. Nickel-
Catalyzed Synthesis of N-Substituted Pyrroles Using Diols with Aryl-
and Alkylamines. J. Org. Chem. 2018, 83, 15406–15414.
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