Pd(II)/Bu4NBr/DMSO catalytic system for practical synthesis of indoles and pyrroles from imines through aerobic dehydrogenative cyclization

Article abstract of DOI:10.1055/s-0034-1379208

N-Aryl- and N-allylimines derived typically from substituted acetophenones undergo palladium(II)-catalyzed dehydrogenative cyclization reactions in the presence of tetrabutylammonium bromide and molecular oxygen in DMSO to afford indole and pyrrole deriva

Full text of DOI:10.1055/s-0034-1379208

PRACTICAL SYNTHETIC PROCEDURES
▌2727
practical synthetic procedures
Pd(II)/Bu4NBr/DMSO Catalytic System for Practical Synthesis of Indoles and
Pyrroles from Imines through Aerobic Dehydrogenative Cyclization
Indoles and Pyrroles from Imines
Wei Wen Tan, Xiaoya Hou, Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
Fax +6569711961; E-mail: nyoshikai@ntu.edu.sg
Received: 17.05.2014; Accepted after revision: 03.09.2014
Abstract: N-Aryl- and N-allylimines derived typically from substituted acetophenones undergo palladium(II)-catalyzed dehydrogenative
cyclization reactions in the presence of tetrabutylammonium bromide and molecular oxygen in DMSO to afford indole and pyrrole deriv-
atives, respectively, in moderate to good yields. The reactions are operationally simple and can be readily performed on multigram scales
(up to 55 mmol).
Key words: palladium, imines, indoles, pyrroles, C–H activation, Heck reaction
procedure 1
BocHN
Pd(OAc)2 (10 mol%)
Bu4NBr (2 equiv)
BocHN
CN
O2 (1 atm)
N
H
N
DMSO, 60 °C, 24 h
2 (84%)
CN
1 (55 mmol)
procedure 2
Pd(OAc)2 (5 mol%)
Bu4NBr (2 equiv)
3 Å MS, O2 (1 atm)
N
N
H
DMSO, r.t., 36 h
3 (7.5 mmol)
4 (63%)
Scheme 1 Aerobic dehydrogenative synthesis of indoles and pyrroles from imines under palladium catalysis
A common drawback in many of the existing synthetic
methods for indoles and pyrroles concerns the toxicity,
Introduction
Indole and pyrrole structural motifs are ubiquitously pres- cost, and availability of the starting materials. For exam-
ent in biologically active natural and unnatural com- ple, the Fischer indole synthesis uses carcinogenic arylhy-
pounds as well as in other functional molecules such as drazines, while the Larock’s method typically requires
dyes and pigments.1 The development of synthetic meth- expensive 2-iodoanilines. Furthermore, the range of com-
ods for these privileged heterocycles has therefore been an mercially available arylhydrazines and 2-haloanilines is
important subject in organic synthesis.2 While classical relatively limited. Thus, the development of indole/
synthetic methods, such as the Fischer indole synthesis pyrrole synthesis from inexpensive and readily available
and the Paal–Knorr pyrrole synthesis have played pivotal starting materials (e.g., simple anilines) through C–H
roles for more than a hundred years, transition metal-cat- functionalization has gained increasing attention from the
alyzed reactions have emerged and evolved into practical synthetic community.3–5
alternatives over the past several decades – the Larock in-
Building on pioneering works of Åkermark and Knölker
dole synthesis from 2-haloanilines and alkynes using a
on carbazole synthesis from diarylamines6 and of Glorius
palladium catalyst being one of the most successful exam-
on indole synthesis from N-arylenamines,7 we recently
developed a palladium(II)-catalyzed indole synthesis via
ples.
aerobic dehydrogenative cyclization of an N-arylimine
using Bu4NBr and DMSO as the key additive and solvent,
respectively (Scheme 1, Procedure 1).8–10 The reaction
features ready availability of the starting material, mild
conditions, and the use of molecular oxygen as the sole
SYNTHESIS 2014, 46, 2727–2733
Advanced online publication: 25.09.2014
DOI: 10.1055/s-0034-1379208; Art ID: ss-2014-z0303-psp
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2728
W. W. Tan et al.
PRACTICAL SYNTHETIC PROCEDURES
mmol). Herein we wish to describe our procedures for the
indole/pyrrole syntheses to demonstrate their utility on
preparatively useful scales (5–55 mmol).
(a)
N
R
N
R
H
1
1'
Pd(OAc)2
1/2O2 + H2O
H2O2
Scope and Limitations
O2, 2 AcOH
Pd0
PdOAc
R
As reported previously, a broad range of N-arylimines de-
rived from substituted anilines and acetophenones can be
converted into the corresponding 2-arylindoles in the
presence of Pd(OAc)2 (10 mol%), Bu4NBr (2 equiv), and
molecular oxygen (1 atm) in DMSO at 60 °C. Both the ad-
ditive and the solvent are crucial for the reaction, because
the yield significantly drops either in the absence of
Bu4NBr or in other solvent. N-Aryl imines derived from
2-arylacetophenones also undergo the dehydrogenative
cyclization to afford 2,3-diarylindoles, while the use of
Cu(OAc)2 instead of Bu4NBr and O2 is necessary to avoid
undesirable competing oxygenation of the benzylic posi-
tion. On the other hand, N-arylimines containing β-hydro-
gens, for example, those prepared from propiophenone
and tetralone, fail to give 2,3-disubstituted indoles but un-
dergo α,β-dehydrogenation presumably through β-hy-
dride elimination of α-palladated imine intermediates.14,15
A few alkyl methyl ketones, such as cyclopropyl methyl
ketone and pinacolone, can also be used to prepare the
corresponding 2-alkylindoles.
N
H+
–OAc
R
N
AcOH
2'
Pd
PdOAc
R
N
R
R
N
N
H
2
AcOH
(b)
N
R
N
R
H
3
3'
Pd(OAc)2
1/2O2 + H2O
H2O2
O2, 2 AcOH
Pd0
To examine the scalability of our indole synthesis, we first
examined the reaction of a benchmark substrate, that is,
imine 1a prepared from p-anisidine and acetophenone on
a 5 mmol scale (Table 1). The reaction under the standard
conditions for 24 hours afforded the desired indole 2a in
an excellent GC yield of 93% (Table 1, entry 1). The cat-
alyst loading could be reduced to 5 mol% without an ap-
parent problem (entry 2), while lowering the reaction
temperature to 40 °C led to a slight decrease in the product
yield (entry 3). Increase of the reaction concentration to
0.4 M did not have a positive influence (entry 4).
–OAc
PdOAc
N
R
H+
AcOH
OAc
Pd
R
R
AcOH
N
PdOAc
N
4'
R
N
R
N
H
4
Table 1 Cyclization of Imine 1a to Indole 2a
Scheme 2 Proposed catalytic cycles for dehydrogenative cyclization
to indole and pyrrole
Pd(OAc)2 (10 mol%)
Bu4NBr (2 equiv)
MeO
MeO
O2 (1 atm)
Ph
oxidant. A proposed catalytic cycle for this reaction in-
volves α-palladation of the imine through imine–enamine
tautomerization, intramolecular aromatic C–H activation,
and reductive elimination (Scheme 2, a). This mechanistic
consideration guided us and the groups of Glorius and Lei
to independently develop pyrrole synthesis from an N-al-
lylimine under a similar catalytic system (Scheme 1, Pro-
cedure 2), which likely involves α-palladation,
intramolecular alkene insertion, and β-hydride elimina-
tion (Scheme 2, b).11,12 In both of the catalytic cycles, the
palladium(II) catalyst is regenerated by reoxidation of
Pd(0) with molecular oxygen.13 The versatility of these
protocols has been demonstrated on small scales (0.2–0.4
N
DMSO (0.2 M)
60 °C, 24 h
N
Ph
H
1a (5 mmol)
2a
"standard conditions"
Entry
Variation from the ‘standard conditions’
Yield (%)a
1
2
3
4
none
93
90
79
84
loading of Pd(OAc)2: 5 mol%
temperature: 40 °C
concentration: 0.4 M
a Determined by GC using n-tridecane as an internal standard.
Synthesis 2014, 46, 2727–2733
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Indoles and Pyrroles from Imines
2729
Table 2 Indole Synthesis from N-Aryliminesa
Entry
Product
Small-scale yield (%)b,c Large-scale yield (%)b,d
MeO
MeO
84e,f
Ph
1
2a
89
N
H
CN
Br
2
3
2b
2c
91
77
91e
78e
N
H
MeO
MeO
Cl
N
H
OMe
4
5
2d
2e
2f
82
88
82
–
76
76
72
84g
64
32
80
N
H
Ph
N
H
EtO2C
BocHN
MeO
MeO
Ph
6
N
H
CN
7
2g
2h
2i
N
H
8
76
–
N
H
O
S
9
N
H
Ph
10
2j
72
N
F3C
H
Ph
11
2k
67
33
N
H
OMe
MeO
Ph
12h
2l
86
84
84
81
Ph
N
H
MeO
13
2m
N
H
a Reaction conditions: imine 1, Pd(OAc)2 (10 mol%), Bu4NBr (2 equiv), O2 (1 atm), DMSO (0.2 M), 60 °C, 24 h.
b Yield of isolated product.
c Reaction was conducted on a 0.2 mmol scale.
d Reaction was conducted on a 5 mmol scale, unless otherwise noted.
e Reaction was conducted on a 10 mmol scale.
f Average of three runs (84%, 84%, and 83%).
g Reaction was conducted on a 55 mmol scale.
h Cu(OAc)2 (3 equiv) was used instead of Bu4NBr and O2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2727–2733

2730
W. W. Tan et al.
PRACTICAL SYNTHETIC PROCEDURES
Having confirmed the applicability of the original catalyt-
ic system to a preparative scale reaction, the reaction of
representative N-arylimines was next examined. The lat-
ter and a few others have been used previously by us on a
0.2 mmol scale (Table 2). Cyclization of imine 1a took
place smoothly on a 10 mmol scale to produce the indole
2a in an average yield of 84% for three runs, which was
comparable to the yield obtained by the small-scale reac-
tion (Table 2, entry 1). The yields of the individual runs
were uniform (84%, 84%, and 83%), demonstrating high
reproducibility of the reaction. Electron-withdrawing and
-donating groups on the acetophenone moiety could be
tolerated, as demonstrated by the preparation of indoles
2b–d in good yields (entries 2–4). Electronic perturba-
tions on the aniline moiety did not interfere with the reac-
tion (entries 5–7). Notably, cyclization of imine bearing
cyano and Boc-protected amino groups was achieved on a
55 mmol scale (entry 7). The corresponding indole prod-
uct 2g could be isolated in an analytically pure form in
84% yield just by washing the crude solid with ethyl ace-
tate. Imine derived from 2-acetylfuran was efficiently
converted into the corresponding indole 2h in 64% yield
(entry 8). By contrast, the reaction of imine derived from
2-acetylthiophene was rather sluggish, affording the de-
sired product 2i in only 32% yield (entry 9).
Pd(OAc)2 (10 mol%)
Bu4NBr (2 equiv)
MeO
MeO
O2 (1 atm)
Ph
Ph
N
N
DMSO (0.2 M)
60 °C, 24 h
H
H
2a
72% recovery
94% recovery without Pd(OAc)2
2a (1 mmol)
Scheme 3 Stability of indole 2a to aerobic conditions
With slight modification, the Pd(OAc)2/Bu4NBr/DMSO
system allows aerobic dehydrogenative cyclization of N-
allylimines to pyrroles. Thus, imine derived from ace-
tophenone and allylamine (0.4 mmol) was converted into
2-phenyl-4-methylpyrrole (4a) in 76% yield in the pres-
ence of Pd(OAc)2 (5 mol%), Bu4NBr (2 equiv), and 3 Å
MS (400 mg) under 1 atm of O2 in DMSO at room tem-
perature (Table 3, entry 1). The same reaction could be
achieved on a 7.5 mmol scale in an average yield of 63%
Table 3 Pyrrole Synthesis from N-Allyliminesa
Entry Product
Small-scale Large-scale
yield (%)b,c yield (%)b,d
Imine derived from m-trifluoromethylaniline underwent
cyclization exclusively onto the less hindered position, af-
fording 7-trifluoromethylindole 2j in 80% yield (entry
10). The reaction of imine derived from o-anisidine on a
0.2 mmol scale afforded the desired indole 2k in 67%
yield, demonstrating the tolerance of the present reaction
to the blockage of one of the ortho-positions of the N-aryl
group (entry 11). However, unlike other cases, the yield of
this reaction dropped significantly (33%) on a 5 mmol
scale. Cyclization of imine derived from 2-phenylace-
tophenone could be achieved using Cu(OAc)2 (3 equiv) as
an oxidant instead of Bu4NBr and molecular oxygen, af-
fording the corresponding 2,3-diphenylindole 2l in 84%
yield (entry 12). The reaction of imine derived from cy-
clopropyl methyl ketone was also amenable to the scale-
up to 5 mmol, affording the product 2m in 81% yield (en-
try 13).
1
2
3
4
4a
4b
4c
76
75
57
57
63e
70
69
38
Ph
N
H
N
H
CF3
N
H
Br
4d
N
H
OMe
We briefly examined the stability of the isolated indole
product 2a to oxidation (Scheme 3). A prolonged (24 h)
exposure of 2a to the standard reaction conditions caused
its gradual decomposition, leading to the recovery of 2a in
72% yield. The palladium catalyst appears to play a cru-
cial role in this decomposition process, because the degree
of decomposition was much smaller in its absence (94%
recovery). Thus, in order to achieve the highest yield,
practitioners of the present indole synthesis are advised to
carefully monitor the progress of the reaction. Note that
we did not observe any apparent decomposition of 2a and
other indole products during purification on silica gel.
O
5
4e
4f
49
61
41
33
N
H
6f
N
H
a Reaction conditions: imine 3, Pd(OAc)2 (5 mol%), Bu4NBr (2
equiv), 3 Å MS (100 mg per 0.1 mmol of 3), O2 (1 atm), DMSO (0.2
M), r.t., 24–36 h.
b Yield of isolated product.
c Reaction was conducted on a 0.4 mmol scale.
d Reaction was conducted on a 5 mmol scale, unless otherwise noted.
e Reaction was conducted on a 7.5 mmol scale. Average of two runs
(67% and 59%).
f Powdered 4 Å MS was used instead of 3 Å MS.
Synthesis 2014, 46, 2727–2733
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PRACTICAL SYNTHETIC PROCEDURES
Indoles and Pyrroles from Imines
2731
tion from a hexane–EtOAc mixture to afford the desired N-aryl-
imine.
(two runs), while the degree of the fluctuation of the
yields (67% and 59%) was greater compared with the case
of the indole synthesis (vide supra). This fluctuation is not
due to product decomposition, because, unlike the indole
2a, the isolated product 4a did not undergo noticeable de-
composition upon exposure to the catalytic conditions for
24 hours (96% recovery). Like the indole cyclization re-
action, this catalytic system was applicable to N-allyl-
imines derived from aryl and heteroaryl methyl ketones
(entries 2–5) and pinacolone (entry 6). The reaction could
be performed on a 5 mmol scale, while some cases led to
a significant decrease in the product yield (entries 4 and
6). Unfortunately, N-allylimine prepared from 2-phenyl-
acetophenone failed to give the desired pyrrole. Not unex-
pectedly, tetralone-derived imine also failed to participate
in the reaction because of α,β-dehydrogenation. Note that
(E)-tert-Butyl (4-{[1-(4-Cyanophenyl)ethylidene]amino}phe-
nyl)carbamate (1g)
Yield: 17.5 g (87%; 60 mmol scale); yellow solid; mp 189–191 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.31 (s, 1 H), 8.12 (d, J = 8.5
Hz, 2 H), 7.94 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.6 Hz, 2 H), 6.75
(d, J = 8.7 Hz, 2 H), 2.25 (s, 3 H), 1.48 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 164.1, 152.9, 144.9, 143.1,
135.6, 132.3 (2 C), 127.8 (2 C), 119.9 (2 C), 118.8 (2 C), 118.6,
112.6, 78.9, 28.1 (3 C), 17.1.
HRMS (ESI): m/z calcd for C20H21N3O2 [M + H]+: 336.1712; found:
336.1718.
(E)-4-Methoxy-N-[1-(thiophen-2-yl)ethylidene]aniline (1i)
Yield: 1.66 g (72%; 10 mmol scale); yellow solid; mp 81–83 °C.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.43 (m, 2 H), 7.08 (dd, J =
besides imines bearing parent allyl group, those bearing α- 5.1, 3.7 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2
H), 3.81 (s, 3 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.7, 159.4, 147.0, 143.9, 129.9,
128.5, 127.7, 121.6 (2 C), 114.4 (2 C), 55.7, 17.6.
branched allyl groups have also been reported to partici-
pate in the dehydrogenative cyclization.11,12
In summary, palladium(II)-catalyzed aerobic dehydroge-
native cyclization reactions of N-arylimines and N-al-
lylimines to indole and pyrrole derivatives, respectively,
have been developed. The catalytic systems employ
Bu4NBr and DMSO as the key additive and solvent, re-
spectively, and feature operational simplicity and mild
conditions. With successful demonstration of a series of
gram-scale experiments, the present protocols are now
ready for practical synthesis of some classes of indole and
pyrrole derivatives.
HRMS (ESI): m/z calcd for C13H13NOS [M + H]+: 232.0792; found:
232.0788.
Preparative Scale Indole Synthesis (5 mmol Scale); General
Procedure
A 100 mL 2-necked round-bottomed flask equipped with a stirrer
bar was charged with the appropriate N-arylimine (5 mmol),
Pd(OAc)2 (112 mg, 0.50 mmol, 10 mol%), and Bu4NBr (3.2 g, 10
mmol, 2 equiv), followed by the addition of DMSO (25 mL). The
flask was quickly evacuated and then refilled three times with O2
using an O2 balloon (3 L). The resulting mixture was stirred at a stir-
ring rate of 600 rpm at 60 °C for 24 h. Upon cooling to r.t., the re-
action mixture was diluted with EtOAc (30 mL), followed by
filtration through a pad of silica gel using EtOAc (150 mL) as an
eluent. The filtrate was washed with H2O (3 × 30 mL), dried
(Na2SO4), and then concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography on silica gel afforded
the indole product.
Analytical TLC was performed on Merck 60 F254 silica gel plates.
1H and 13C NMR spectra were recorded on Bruker AV-400 (400
MHz) NMR spectrometers. 1H and 13C NMR spectra are reported in
parts per million (ppm) downfield from an internal standard, TMS
(0 ppm) or DMSO (2.50 ppm) and CHCl3 (77.0 ppm) or DMSO
(39.5 ppm), respectively. Gas chromatographic analysis was per-
formed on a Shimadzu GC-2010 system equipped with an FID de-
tector and a capillary column DB-5 (Agilent J & W, 0.25 mm i.d. ×
30 m). High-resolution mass spectra (HRMS) were obtained with a
Waters Q-Tof Premier LC HR mass spectrometer. Melting points
were determined using a capillary melting point apparatus and are
uncorrected. Pd(OAc)2 was purchased from Strem (min 98%, 99.9+
% Pd) or Alfa Aesar (Pd 45.9–48.4%) and was used as received. No
apparent difference in the performance of the Pd catalysts from
these suppliers was observed during the present study. Bu4NBr
(98+%) was purchased from Alfa Aesar and was used as received.
O2 cylinder (99.7%) was purchased from National Oxygen and was
used as received. Unless otherwise noted, all other materials were
purchased from commercial suppliers and were used as received.
Anhydrous DMSO was distilled over CaH2 and stored under N2 or
purchased from Aldrich and used without further purification.
Imines were prepared from the corresponding amines and ketones.
Except for 1g and 1i, their analytical data can be found in the appro-
priate reference.8,11
Analytical data for representative and/or new indole products 2a,
2g, 2i, and 2m are provided below. Data for other products can be
found in the appropriate reference.8
5-Methoxy-2-phenyl-1H-indole (2a)
The reaction of (E)-4-methoxy-N-(1-phenylethylidene)aniline (1a;
2.25 g, 10 mmol) was performed in a 100 mL 2-necked round-bot-
tomed flask following the general procedure, proportionally scaling
up the quantities of other reagents and solvents except for the size
of the O2 balloon. After the workup according to the general proce-
dure, the crude product was purified by flash chromatography on
silica gel (eluent: hexane–EtOAc, 90:10) to afford the title com-
pound as an off-white solid; yield: 1.87 g (84%); Rf = 0.21 (hexane–
EtOAc, 90:10); mp 169–170 °C (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.26 (br s, 1 H), 7.66–7.64 (m, 2
H), 7.44 (t, J = 7.2 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.27 (d, J =
8.6 Hz, 1 H), 7.12 (d, J = 2.3 Hz, 1 H), 6.90 (dd, J = 8.7, 2.4 Hz, 1
H), 6.77 (d, J = 1.9 Hz, 1 H), 3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.5, 138.6, 132.4, 132.0, 129.7,
129.0, 127.7, 125.1, 112.6, 111.6, 102.3, 99.8, 55.8.
N-Arylimines; General Procedure
A 100 mL round-bottomed flask equipped with a stirrer bar was
charged with activated molecular sieves 4Å (9.0 g), the respective
ketone (10 mmol), and the appropriate aniline (12 mmol). Toluene
(10 mL) was added, and the reaction mixture was stirred for 24 h.
The reaction mixture was then diluted with EtOAc (40 mL), fol-
lowed by filtration through a pad of Celite, and concentration under
reduced pressure. The crude product was purified by recrystalliza-
HRMS (ESI): m/z calcd for C15H13NO [M + H]+: 224.1075; found:
224.1069.
tert-Butyl [2-(4-Cyanophenyl)-1H-indol-5-yl]carbamate (2g)
The reaction of 1g (18.4 g, 55 mmol) was performed in a 500 mL 3-
necked round-bottomed flask following the general procedure, pro-
portionally scaling up the quantities of other reagents and solvents
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2727–2733

2732
W. W. Tan et al.
PRACTICAL SYNTHETIC PROCEDURES
except for the size of the O2 balloon. Upon cooling to r.t., the reac-
tion mixture was diluted with EtOAc (150 mL), followed by filtra-
tion through a pad of silica gel with EtOAc (250 mL) as an eluent.
The treatment of the filtrate with H2O (200 mL) resulted in poorly
soluble brown precipitates, which were extracted with EtOAc (5 ×
400 mL). The combined organic layers were washed with H2O (600
mL) and brine (300 mL), dried (Na2SO4), and concentrated under
reduced pressure. The solid residue was treated with EtOAc (50
mL), filtered through a Büchner funnel, and washed with additional
EtOAc (50 mL) to afford the title compound as a brown solid in an
analytically pure form; yield: 15.5 g (84%); Rf = 0.21 (hexane–EtOAc,
70:30). Further purification could be performed by recrystallization
from hot EtOAc affording yellow crystals; mp 213–215 °C.
1H NMR (400 MHz, DMSO-d6): δ = 11.58 (s, 1 H), 9.11 (s, 1 H),
8.01 (d, J = 7.7 Hz, 2 H), 7.89 (d, J = 7.6 Hz, 2 H), 7.72 (s, 1 H),
7.30 (d, J = 8.3 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 1 H), 7.05 (s, 1 H),
1.49 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 153.1, 136.6, 135.9, 134.0,
132.8 (2 C), 132.3, 128.3, 125.2 (2 C), 119.0, 116.2, 111.4, 109.5,
109.0, 101.4, 78.4, 28.2 (3 C).
Preparative Scale Pyrrole Synthesis (5 mmol Scale); General
Procedure
A 100 mL 2-necked round-bottomed flask equipped with a stirrer
bar was charged with activated molecular sieves 3Å (5.0 g),
Pd(OAc)2 (56 mg, 0.25 mmol, 5 mol%), and Bu4NBr (3.2 g, 10
mmol, 2 equiv). The flask was evacuated and refilled three times
with O2 using a balloon, followed by the addition of the requisite N-
allylimine (5.0 mmol) and anhydrous DMSO (25 mL). The result-
ing mixture was stirred at r.t. for 36 h. The reaction mixture was di-
luted with EtOAc (30 mL), followed by filtration through a short
pad of silica gel with EtOAc (150 mL) as an additional eluent. The
filtrate was washed with sat. aq NaHCO3 (3 × 50 mL) and brine (40
mL), and then concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel to afford
the desired pyrrole product.
Analytical data for representative pyrrole products 4b and 4e are
provided below. Data for other products can be found in the appro-
priate reference.10
4-Methyl-2-[4-(trifluoromethyl)phenyl]-1H-pyrrole (4b)
The reaction of (E)-N-{1-[4-(trifluoromethyl)phenyl]ethyl-
idene}prop-2-en-1-amine (3b; 1.14 g, 5 mmol) was performed ac-
cording to the general procedure. The crude product was purified by
flash chromatography on silica gel (eluent: hexane–EtOAc, 90:10)
to afford the title compound as a light red solid; yield: 0.79 g (70%);
Rf = 0.34 (hexane–EtOAc, 90:10); mp 169–171 °C (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.57 (d, J = 8.4
Hz, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 6.66 (s, 1 H), 6.46 (s, 1 H), 2.15
(s, 3 H).
HRMS (ESI): m/z calcd for C20H19N3O2 [M + H]+: 334.1556; found:
334.1553.
5-Methoxy-2-(thiophen-2-yl)-1H-indole (2i)
The reaction of 1i (1.16 g, 5 mmol) was performed according to the
general procedure. The crude product was purified on silica gel
(eluent: hexane–EtOAc, 90:10) to afford the title compound as a
grey solid; yield: 0.37 g (32%); Rf = 0.18 (hexane–EtOAc, 90:10);
mp 137–139 °C (EtOAc).
2
13C NMR (100 MHz, CDCl3): δ = 136.0, 130.4, 127.8 (q, JC,F
=
1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.29–7.22 (m, 3 H),
7.08 (dd, J = 5.0, 3.6 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 6.85 (dd,
J = 8.8, 2.5 Hz, 1 H), 6.65 (d, J = 1.4 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.9, 136.0, 133.3, 131.9, 129.9,
128.1, 124.7, 123.0, 113.0, 111.7, 102.5, 100.6, 56.1.
3
1
33.0 Hz), 127.1, 125.8 (q, JC,F = 3.0 Hz), 124.3 (q, JC,F = 270.0
Hz), 123.3, 118.1, 109.1, 11.8.
HRMS (ESI): m/z calcd for C12H11F3N [M + H]+: 226.0844; found:
226.0846.
HRMS (ESI): m/z calcd for C13H11NOS [M + H]+: 230.0640; found:
2-(Furan-2-yl)-4-methyl-1H-pyrrole (4e)
The reaction of (E)-N-[1-(furan-2-yl)ethylidene]prop-2-en-1-amine
(3e; 0.75 g, 5 mmol) was performed according to the general proce-
dure. The crude product was purified by flash chromatography on
silica gel (eluent: hexane–EtOAc, 90:10) to afford the title com-
pound as a green solid; yield: 0.30 g (41%); Rf = 0.36 (hexane–EtOAc,
90:10); mp 40–42 °C (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.23 (br s, 1 H), 7.32 (d, J = 1.2
Hz, 1 H), 6.54 (s, 1 H), 6.40 (dd, J = 3.2, 2.0 Hz, 1 H), 6.29 (d, J =
3.2 Hz, 1 H), 6.26 (s, 1 H), 2.12 (s, 3 H).
230.0632.
2-Cyclopropyl-5-methoxy-1H-indole (2m)
The reaction of (E)-N-(1-cyclopropylethylidene)-4-methoxyaniline
(1m; 0.95 g, 5 mmol) was performed according to the general pro-
cedure. The crude product was purified on silica gel (eluent: hex-
ane–EtOAc, 92:8) to afford the title compound as a yellow oil;
yield: 0.76 g (81%); Rf = 0.24 (hexane–EtOAc, 90:10).
1H NMR (400 MHz, CDCl3): δ = 7.85 (br s, 1 H), 7.15 (d, J = 8.7
Hz, 1 H), 7.00 (d, J = 2.4 Hz, 1 H), 6.78 (dd, J = 8.8, 2.5 Hz, 1 H),
6.09 (d, J = 2.0 Hz, 1 H), 3.85 (s, 3 H), 1.97–1.90 (m, 1 H), 0.99–
0.94 (m, 2 H), 0.80–0.75 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 154.2, 142.6, 130.9, 129.2, 110.9,
110.8, 101.9, 97.6, 55.9, 9.0, 7.4.
13C NMR (100 MHz, CDCl3): δ = 148.4, 140.2, 123.9, 120.3, 116.0,
111.4, 106.8, 101.9, 11.8.
HRMS (ESI): m/z calcd for C9H10NO [M + H]+: 148.0762; found:
148.0764.
HRMS (ESI): m/z calcd for C12H13NO [M + H]+: 188.1075; found:
188.1082.
Acknowledgment
This work was supported by Singapore National Research Founda-
tion (NRF-RF-2009-05) and Nanyang Technological University.
N-Allylimines; General Procedure
A 100 mL round-bottomed flask equipped with a stirrer bar was
charged with the respective ketone (10 mmol), the corresponding
allylamine (50 mmol), and anhydrous toluene or Et2O (20 mL). To
this mixture was added a solution of TiCl4 in CH2Cl2 (1.0 M, 6.4
mL, 6.4 mmol) at 0 °C in a dropwise manner over a period of 40
min. The reaction mixture was allowed to stir at r.t. for 2 h, followed
by filtration through a pad of Celite with EtOAc (40 mL) as an elu-
ent. The filtrate was washed with brine (2 × 25 mL), dried (Na2SO4),
and concentrated under reduced pressure. The yellow residue was
purified by Kugelrohr distillation or used as such.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2727–2733