Phosphine-Free Palladium-Catalyzed Direct Bisarylation of Pyrroles with Aryl Iodides on Water

Article abstract of DOI:10.1021/acs.joc.5b00451

(Chemical Presented). The Pd-catalyzed bisarylation of pyrroles with aryl iodides on water is described. The reaction proceeds under mild reaction conditions, i.e., relatively low temperature (40 C) and phosphine-free.

Full text of DOI:10.1021/acs.joc.5b00451

Note
pubs.acs.org/joc
Phosphine-Free Palladium-Catalyzed Direct Bisarylation of Pyrroles
with Aryl Iodides on Water
Beom Shin Cho, Hyun Jung Bae, and Young Keun Chung*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
S
* Supporting Information
ABSTRACT: The Pd-catalyzed bisarylation of pyrroles with aryl iodides on water is described. The reaction proceeds under
mild reaction conditions, i.e., relatively low temperature (40 °C) and phosphine-free.
nspired by nature’s ability to utilize C−H bonds as latent
Ifunctional groups, transition metal-catalyzed selective
cleavage of C−H bond, followed by its functionalization into
a C-X bond, has long been studied and developed.1 This type of
direct C−H bond functionalization has become a potentially
applicable and powerful class of organic transformations in
organic synthesis. The application of this strategy helps in over-
coming the drawbacks of stoichiometrically employed organo-
metallic reagents, which have a relatively high price, toxicity,
and sensitivity to air and moisture. Among the transition metal-
catalyzed C−H arylation, Pd(0)-catalyzed C−H arylation
reactions has been comprehensibly studied by several groups,
especially by the groups of Doucet,2 Fagnou,3 and Daugulis.4
However, most of these reactions proceed under rather harsh
reaction conditions, which significantly lowers their appeal.
Since Ohta and his co-workers reported5 the Pd-catalyzed
arylation of several heteroarenes through C−H bond activation
with moderate to good yields, the Pd-catalyzed direct C−H
arylation of heteroarenes has been proven to be a very powerful
method for the synthesis of a variety of arylated heteroarenes.
Owing to the widespread applications of arylated pyrroles,6−9
the development of new and more convenient synthetic
methods is a topic of ongoing interest.10 Recently, Gryko et
al. reported10c the arylation of pyrroles without Pd catalyst.
They found that lithium tert-butoxide alone could promote the
arylation of pyrroles with aryl iodides and bromide. However,
they used a large excess (15 equiv) of pyrroles and carried out
the reaction at 145 °C. The Pd-catalyzed direct C-2 arylation of
pyrroles by a C−H bond activation using aryl halides has
met with great success in recent years, allowing the one-step
synthesis of a wide variety of arylated pyrroles.11 However,
most of the reported studies directed on direct arylation
reactions of heterocyclic compounds to deal with monoar-
ylations.2−4 In contrast, multiple C−H activation is rare,12 and
hence, we examined the possibility of double C−H activation
reactions of different N-substituted pyrroles.
medium in the arylation of pyrroles has not been reported.
While we were attempting to establish greener reaction
conditions for the Pd-catalyzed arylation of pyrroles, we
discovered that a bisarylation of pyrroles can be carried out
on water at 40 °C. The low temperature required implied that
the reaction was highly activated on water, though the reason
for this behavior is not yet clear. We report herein our
preliminary results on the environmentally friendly direct
bisarylation of pyrroles on water.
We expected that the reactivity of pyrroles seemed to be
similar to that of its benzo analogue, indole. Therefore, we
selected the reaction conditions developed for indole as the
starting point of our study.14 Initially, the reaction of
N-benzylpyrrole (1a) with iodobenzene (2a) affording the C-2
arylated product, 1-benzyl-2-phenylpyrroles, (3aa), “on water”
was chosen as the model reaction in the presence of Pd(OAc)2
(5 mol %), Ag2CO3 (1 equiv), and pivalic acid (PivOH)
(1 equiv) in water (3 mL) at room temperature for 24 h (eq 1).
In the Pd-catalyzed direct arylation of pyrroles, the most reactive
positions are generally the carbons C2 and C5, whereas the
positions C3 and C4 exhibit a poor reactivity.15 Thus, we
expected the formation of 1-benzyl-2-phenylpyrrole (3aa) and/
or 1-benzyl-2,5-diphenylpyrrole (5aa) as (a) major product(s).
However, surprisingly, a mixture of regioisomers was formed,
presumably due to an activation on water.16,17 The formation of
two monoarylated and four bisarylated products was confirmed
by GC-MS and NMR studies. Even when 1.2 equiv iodo-
benzene was used, a considerable amount of bisarylated prod-
ucts was formed. Thus, we decided to optimize the reaction
conditions for the regioselective bisarylation of pyrroles.
Several years ago, Greaney et al. reported13 the first Pd-
catalyzed direct arylation of thioles on water at 60 °C. To the
best of our knowledge, reports on the use of water as a reaction
Received: February 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00451
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Reaction Condition Optimization
a
b
Pd(OAc)2 (mol %)
2a (eq)
[Ag] (eq)
[Acid] (eq)
yield (%)
selectivity
1
7.5
7.5
7.5
7.5
7.5
5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
3.5
2.5
4.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
0
1
2
4
6
6
6
6
6
6
6
6
6
1
75
60
67
87
42
24
N.R.
72
0
100:0:0:0
53:0:28:19
86:0:7:7
91:0:4:4
95:0:3:2
94:2:2:2
94:0:3:3
2
3
4
5
6
7
3
8
0
9
7.5
7.5
7.5
7.5
7.5
87:0:4:9
10
11
12
13
0
1.5
1.5
1.5
73
63
94:0:3:3
94:0:4:2
88:2:4:6
c
68
a
b
The total isolated yield of bisarylated pyrroles. For the yields of all compounds, see the Supporting Information. The selectivies for bisarylated
c
pyrroles based on GC analysis. For the selectivities of all compounds, see the Supporting Information. The reaction was carried out at room
temperature. [Ag] = Ag2CO3, [Acid] = PivOH.
Scheme 1. Bisarylation of 1a with Iodobenzenes
a
General conditions: 1a (0.5 mmol), 2a−j (4.5 equiv), Pd(OAc)2 (7.5 mol %), Ag2CO3 (1.5 equiv), PivOH (6 equiv) in H2O (3 mL) at 40 °C for
b
c
24 h. Isolated yield. Run at 60 °C.
The amounts of PivOH, Ag2CO3, Pd(OAc)2, and iodoben-
zene were screened in order to maximize the yield of 5aa
(Table 1).
determined to be 6 equiv. The regioselectivity and the total
yield of bisarylated pyrroles were decreased with a decrease in
the amount of Pd(OAc)2 (entries 5−8). In the absence of
Pd(OAc)2, no reaction was observed (entry 8). Similarly, the
regioselectivity and the total yield of the bisarylated pyrroles
deteriorated with a decrease in the amount of Ag2CO3 (entries
5, 9, and 10). Without the silver salt, a monoarylated pyrrole
was formed in only 6% yield (entry 10).These results showed
that the presence of Pd(OAc)2, a silver salt (Ag2CO3), and an
acid (PivOH) was essential for the reaction. Decreasing the
amount of iodobenzene used did not influence the
We first investigated the effect of PivOH on the reaction
(entries 1−5). Without PivOH, a negligible amount of a
monoarylated pyrrole was formed (entry 1). As the amount of
PivOH was increased, the regioselectivity and the total yield of
bisarylated pyrroles (5aa−8aa) were increased. When 6 equiv
of PivOH was used, the ratio of the bisarylated pyrroles
5aa:6aa:7aa:8aa was 95:0:3:2 and their total yield was to 87%
(entry 5). Thus, the optimal amount of pivalic acid used was
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DOI: 10.1021/acs.joc.5b00451
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The Journal of Organic Chemistry
Note
regioselectivity of the reaction, but decreased the yield of the
reaction (entries 5, 11, and 12). Moreover, the regioselectivity
and the yields of bisarylated pyrroles were highly temperature
dependent (entries 4, 13). Therefore, the optimized reaction
conditions were as follows: 1 mmol of pyrrole, 4.5 mmol of
iodobenzene, 7.5 mol % Pd(OAc)2, 6 mmol of PivOH, and
1.5 mol of Ag2CO3 in 3 mL H2O at 40 °C. With the optimum
reaction conditions in hands, we studied the effect of different
Pd catalysts, such as Pd(MeCN)2Cl2 (71%; 5aa:6aa:7aa:8aa =
96:0:2:2) and PdCl2 (12%; 5aa:6aa:7aa:8aa = 88:6:0:6), on
the efficiency of the catalyst system. Then, Pd(OAc)2 was
chosen as the catalyst. Silver salts, such as silver acetate
(AgOAc), and carboxylic acids, such as o-nitrobenzoic acid,
have been proven to be efficient additives for the direct C-2
arylation of indoles that increase the rate of the palladation
step, thus enhancing the electrophilicity of the cationic Pd
species.18 Thus, silver salts and carboxylic acids were screened
(see the Supporting Information). When AgOAc or Ag2O was
used in the presence of PivOH and Pd(OAc)2, both the
regioselectivity and yield were diminished. When acetic acid
was used in the presence of Ag2CO3 and Pd(OAc)2, the yield of
the bisarylated pyrroles was abruptly dropped to 3%. Inter-
estingly, the use of trifluoroacetic acid (TFA) in the presence of
Ag2CO3 and Pd(OAc)2 led to the exclusive formation of 5aa in
79% yield. However, in the case of TFA, the yield of the 5 was
highly substrate dependent. Pd(OAc)2 was used as a homo-
geneous catalyst under the optimized conditions in different
organic solvents, such as DMF (no reaction), dichloro-
methane (52% yield), toluene (65% yield), and ethanol
(15% yield). Thus, the activation of the C−H bond by the Pd
catalyst system was less efficient in organic solvents than
water. Interestingly, when the reaction was carried out without
a solvent, the corresponding product 5aa was formed in 72%
yield.
Scheme 2. Bisarylation of N-Substituted Pyrroles with 2a
a
General conditions: 1b−g (0.5 mmol), 2a (4.5 equiv), Pd(OAc)2
(7.5 mol %), Ag2CO3 (1.5 equiv), PivOH (6 equiv) in H2O (3 mL) at
40 °C for 24 h. Isolated yield.
b
substrate for the bisarylation19 and only monoarylated products
were formed in poor yields (12−19%).20 In the case of free
pyrrole or indole, only decomposition products were detected
under the reaction conditions.14 These results suggest that a
sufficient electron density on the pyrrole ring is necessary to
facilitate substitution.21
Subsequently, the influence of the substituent at the
benzyl group on the direct arylation was also was examined
(Scheme 3). N-Benzylpyrroles were found to react smoothly
Scheme 3. Bisarylation of Substituted Benzylpyrroles with 2a
Using the optimized reaction conditions, the substrate scope
of the reaction was examined (Scheme 1). Broad functional
group compatibility was observed among the substituted aryl
iodides: both electron-donating (compounds 5ab, 5ac, 5ag,
5ah, and 5aj) and electron-withdrawing substituents (com-
pounds 5ad, 5ae, 5af, and 5ai) were tolerated. On the contrary,
the reaction yields were significantly influenced by the steric
effects of the iodobenzene derivatives. Thus, when 1-iodo-2-
methylbenzene was used, the corresponding product was 5aj
isolated in a poor yield (17%). Interestingly, with 1-bromo-
4-iodobenzene, the yield of 5ad was highly temperature
dependent. In fact, operating at 40 °C, 5ad was isolated in
24% yield, whereas, when the reaction was carried out 60 °C,
the yield dramatically increased to 64%. Iodoarenes having an
acidic proton, such as 4-iodophenol and 4-iodoaniline, were not
good substrates under our reaction conditions. Moreover,
1-benzyl-2,5-dimethylpyrole did not give any arylation product.
This result may provide indirect evidence for the direct
arylation to the 2,5-position. This method is particularly advan-
tageous because of the large pool of commercially available aryl
iodides. We also attempted to extend our arylation protocol to
aryl bromides and chlorides, but the corresponding products
were not formed.
a
General conditions: 1a′-g′ (0.5 mmol), 2a (4.5 equiv), Pd(OAc)2
(7.5 mol %), Ag2CO3 (1.5 equiv), PivOH (6 equiv) in H2O (3 mL) at
40 °C for 24 h. Isolated yield.
b
with iodobenzene to afford the corresponding bisarylated prod-
ucts in good yields, irrespective of the electronic or steric effect
of the (a) substituent(s) on the benzene ring.
We also investigated the arylation of the pyrrole 1h having an
electron-withdrawing group at the 3-position (eq 2). Under
Subsequently, we investigated the bisarylation of different
N-substituted pyrroles with iodobenzene (Scheme 2). Pyrroles
bearing an electron-donating substituent (TIPS, Et) were
efficiently bisarylated. In contrast, a relatively lower yield (48%)
was observed for N-methylpyrrole. Pyrroles containing
N-electron-withdrawing groups (Ts, Boc, Ph) were not good
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DOI: 10.1021/acs.joc.5b00451
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Note
1-(4-Chlorobenzyl)pyrrole (1a′). Dark yellow oil. 1H NMR
(400 MHz, CDCl3): δ 7.21 (dd, J = 5.0, 3.4 Hz, 2 H), 6.99−6.94 (m,
2 H), 6.61 (dd, J = 3.7, 1.8 Hz, 2 H), 6.18 (dt, J = 4.2, 2.1 Hz, 2 H),
4.93 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 136.7, 133.4, 128.8,
128.3, 121.1, 108.8, 52.5. HRMS (EI+) m/z: Calcd for C11H10NCl:
191.0502, found: 191.0501.
the standard reaction conditions (at 40 °C for 24 h), only
monoarylated products (C-2 and C-5 adducts) were isolated in
low yield (7%) with a recovery of most of the reactant. When
the reaction was carried out at 60 °C, monoarylated products
were isolated in 40% yield22 (see Supporting Information).
Finally, it is worth noting that the reaction may be scaled up:
the reaction of 1.57 g of N-benzylpyrrole (10 mmol) gave
2.53 g (82% yield) of 5aa (eq 3).
1-(4-Bromobenzyl)pyrrole (1b′). Dark yellow oil. 1H NMR
(400 MHz, CDCl3): δ 7.28 (dd, J = 10.6, 4.6 Hz, 2 H), 6.81 (t, J =
7.3 Hz, 2 H), 6.55−6.49 (m, 2 H), 6.12−6.05 (m, 2 H), 4.83 (d, J =
6.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ 137.3, 131.8, 128.6,
121.5, 121.1, 108.8, 52.6. HRMS (EI+) m/z: Calcd for C11H10NBr:
234.9997, found: 234.9998.
1-(4-Methoxybenzyl)pyrrole (1c′). Dark yellow oil. 1H NMR
(400 MHz, CDCl3): δ 7.11−7.05 (m, 2 H). 6.86 (dd, J = 8.8, 2.3 Hz,
2 H), 6.70−6.66 (m, 2 H), 6.20−6.15 (m, 2 H), 5.00 (s, 2 H), 3.79 (s,
3 H). 13C NMR (100 MHz, CDCl3): δ 159.3, 130.3, 128.6, 121.1,
114.2, 108.5, 55.4, 52.9. HRMS (EI+) m/z: Calcd for C12H13NO:
187.0997, found: 187.0996.
Although the exact reaction pathway is not clear at this stage,
our experimental observation suggests the electrophilic
activation of the pyrrole C−H bonds by the PdII species as
described previously by other research groups.11c,22
In conclusion, we have developed the first direct bis-arylation
of pyrroles on water in the absence of phosphine ligand at
40 °C. The direct C−H arylation of pyrroles with aryl iodides
gives 2,5-diarylpyrroles in good yields. The pyrrole arylation
reaction is carried out under conditions much milder than those
commonly described in the literature for pyrrole arylation. The
application of this methodology to the arylation of other
heteroarene molecules is currently being investigated in our
laboratory.
1
1-(4-(tert-Butyl)benzyl)pyrrole (1d′). Yellow oil. H NMR (400
MHz, CDCl3): δ 7.34 (d, J = 8.3 Hz, 2 H), 7.07−7.03 (m, 2 H), 6.69
(d, J = 1.1 Hz, 2 H), 6.18 (dd, J = 2.1, 1.2 Hz, 2 H), 5.04 (s, 2 H),
1.31−1.29 (m, 9 H). 13C NMR (100 MHz, CDCl3): δ 150.8, 135.3,
126.9, 125.8, 121.3, 108.5, 53.2, 34.7, 31.5. HRMS (EI+) m/z: Calcd
for C15H19N: 213.1517, found: 213.1516.
1
1-(3,5-Dimethylbenzyl)pyrrole (1e′). Yellow oil. H NMR (400
MHz, CDCl3): δ 6.88 (s, 1 H), 6.72 (d, J = 0.5 Hz, 2 H), 6.64 (t, J =
2.1 Hz, 2 H), 6.16 (t, J = 2.1 Hz, 2 H), 4.92 (s, 2 H), 2.25 (s, 6 H). 13C
NMR (100 MHz, CDCl3): δ 138.3, 138.1, 129.3, 125.0, 121.1, 108.4,
53.3, 21.3. HRMS (EI+) m/z: Calcd for C13H15N: 185.1204, found:
185.1203.
1
1-(2-Fluorobenzyl)pyrrole (1f′). Dark yellow oil. H NMR (400
MHz, CDCl3): δ 7.27−7.20 (m, 1 H), 6.92 (t, J = 8.4 Hz, 1 H), 6.85
(d, J = 7.6 Hz, 1 H), 6.75 (d, J = 9.6 Hz, 1 H), 6.65 (d, J = 2.0 Hz,
2 H), 6.19 (d, J = 2.0 Hz, 2 H), 5.00 (s, 2 H). 13C NMR (100 MHz,
CDCl3): δ 163.2 (d, J = 246.6 Hz), 141.0 (d, J = 7.1 Hz), 130.3 (d, J =
8.2 Hz), 122.5 (d, J = 2.9 Hz), 121.2, 114.6 (d, J = 21.1 Hz), 113.9 (d,
J = 22.0 Hz), 108.9, 52.8, 52.8. HRMS (EI+) m/z: Calcd for
C11H10NF: 175.0797, found: 175.0797.
EXPERIMENTAL SECTION
■
All reactions for preparation of novel compounds were conducted
under nitrogen using standard Schlenk-type flasks. NMR spectra were
recorded at 25 °C on 400 or 300 MHz spectrometers: 1H NMR (300
or 400 MHz) and 13C NMR (75 or 100 MHz). 1H NMR spectra were
taken in CDCl3 and were referenced to residual TMS (0 ppm) and
reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, dd = doublet of doublet, m = multiplet). Chemical
shifts of the 13C NMR spectra were measured relative to CDCl3
(77.16 ppm). High-resolution mass spectra were obtained using the
electronic impact (EI) mode using a magnetic sector−electric sector
focusing mass analyzer. GC-MS analyses were performed with a HP-5
capillary column (30 m × 0.25 mm; coating thickness 0.25 μm):
analytical conditions: initial temperature, 50 °C; raising temperature,
10 °C/min; final temperature, 300 °C; He gas, pressure 7.56 psi; total
flow, 53.7 mL/min. Reactions were monitored by thin-layer chro-
matography on 0.25 mm E. Merck silica gel plates. The TLC plates
were visualized by UV-light (254 nm). Workup procedures were done
in air. Flash column chromatography was carried out on silica gel
(230−400 mesh). Substrates, 1a, 1f, 1h, 1a′-g′, were prepared
according to the literature procedure.23
1-(2-methylbenzyl)pyrrole (1g′). Yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.00 (m, 3 H), 6.68 (t, J = 7.8 Hz, 1 H), 6.48−6.43 (m, 2 H),
6.06−6.00 (m, 2 H), 4.82 (d, J = 4.8 Hz, 2 H), 2.08 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ 136.0, 135.8, 130.3, 127.8, 126.3, 121.1, 108.4,
51.3, 18.9. HRMS (EI+) m/z: Calcd for C12H13N: 171.1048, found:
171.1050.
General Procedure for Palladium-Catalyzed Bisarylation of
N-Substituted Pyrroles. Reactions were performed in a Schlenk
tube equipped with a stirring bar and capped with a rubber septum.
The followings were placed in the tube flask in order: 0.0375 mmol of
catalyst, 2.25 mmol of iodobenzenes, 0.75 mmol of silver salt, 3 mmol
of carboxylic acid, 0.5 mmol of N-benzylpyrrole, and 3 mL of water.
The mixture was stirred at 40 °C for 24 h. The mixture was extracted
with ethyl acetate, filtered to remove catalyst residue, and finally
evaporated under reduced pressures. The mixture was purified by flash
chromatography on silica gel (n-hexane/ethyl acetate) to afford the
product. Ratios of bisarylated isomers were determined by GC-MS.
Compounds 3aa,24 4aa,25 6aa,26 7aa,27 and 8aa28 were known.
1-Benzyl-2,5-diphenylpyrrole (5aa). White solid. Mp: 144 °C
(0.26 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, 10 H), 7.13−
7.06 (m, 3 H), 6.65 (d, J = 7.0 Hz, 2 H), 6.36 (d, J = 2.5 Hz, 2 H), 5.22
(s, 2 H). 13C NMR (100 MHz, CDCl3): δ 139.4, 136.9, 133.8, 129.2,
128.44, 128.40, 127.1, 126.9, 126.0, 109.8, 48.8. HRMS (EI+) m/z:
Calcd for C23H19N: 309.1517, found: 309.1514.
1-Benzylpyrrole (1a). Yellow oil. 1H NMR (400 MHz, CDCl3): δ
7.34−7.24 (m, 3 H), 7.13−7.09 (m, 2 H), 6.70−6.66 (m, 2 H), 6.20−
6.16 (m, 2 H), 5.07 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 138.3,
128.8, 127.76, 127.12, 121.3, 108.6, 53.5. HRMS (EI+) m/z: Calcd for
C11H11N: 157.0891, found: 157.0889.
1-(tert-Butoxycarbonyl)pyrrole (1f). Colorless oil. 1H NMR
(400 MHz, CDCl3): δ 7.15 (s, 2 H), 6.12 (s, 2 H), 1.51 (s, 9 H). 13
C
NMR (100 MHz, CDCl3): δ 149.0, 120.0, 111.9, 83.61, 28.1. HRMS
(EI+) m/z: Calcd for C9H13NO2: 167.0946, found: 167.0948.
Benzyl 1-Benzyl-1H-pyrrole-3-carboxylate (1h). White solid.
Mp: 69 °C. 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 6.9 Hz, 2H),
7.37−7.27 (m, 7H), 7.10 (d, J = 6.6 Hz, 2H), 6.66−6.62 (m, 1H),
6.60−6.57 (m, 1H), 5.24 (s, 2H), 4.99 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 164.6, 136.8, 136.7, 128.9, 128.5, 128.2, 128.1, 128.0, 127.3,
126.6, 122.2, 116.1, 110.7, 65.5, 53.9. HRMS (EI+) m/z: Calcd for
C19H17NO2: 291.1259, found: 291.1257.
1-Benzyl-2,5-di-p-tolylpyrrole (5ab). White solid. Mp: 160 °C
1
(0.26 g, 78%). H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 8.0 Hz,
4 H), 7.10 (t, J = 9.0 Hz, 7 H), 6.68 (d, J = 6.6 Hz, 2 H), 6.31 (s, 2 H),
5.20 (s, 2 H), 2.31 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ 139.7,
136.8, 136.6, 131.0, 129.12, 129.05, 128.3, 126.8, 126.0, 109.4, 48.7,
21.3. HRMS (EI+) m/z: Calcd for C25H23N: 337.1830, found:
337.1828.
D
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The Journal of Organic Chemistry
Note
1-Benzyl-2,5-bis(4-methoxyphenyl)pyrrole (5ac). White solid.
Mp: 126 °C (0.18 g, 48%). 1H NMR (400 MHz, CDCl3): δ 7.25−7.22
(m, 4 H), 7.16−7.10 (m, 3 H), 6.84−6.81 (m, 4 H), 6.71−6.67 (m, 2
H), 6.27 (t, J = 1.9 Hz, 2 H), 5.15 (s, 2 H), 3.77−3.76 (m, 6 H). 13C
NMR (100 MHz, CDCl3): δ 158.8, 139.7, 135.9, 130.5, 128.4, 126.84,
126.48, 126.0, 113.8, 109.0, 55.4, 48.6. HRMS (EI+) m/z: Calcd for
C25H23NO2: 369.1729, found: 369.1727.
1-Benzyl-2,5-bis(4-bromophenyl)pyrrole (5ad). White solid.
Mp: 159 °C (0.11 g, 24%, 299 mg, 64% at 60 °C). 1H NMR
(400 MHz, CDCl3): δ 7.44−7.37 (m, 4 H), 7.21−7.10 (m, 7 H), 6.65
(d, J = 7.0 Hz, 2 H), 6.34 (d, J = 2.3 Hz, 2 H), 5.15 (s, 2H). 13C NMR
(100 MHz, CDCl3): δ 139.0, 136.0, 132.4, 131.7, 130.5, 128.7, 127.2,
125.8, 110.4, 48.7. HRMS (EI+) m/z: Calcd for C23H17NBr2:
464.9728, found: 464.9727.
2,5-Diphenyl-1-(triisopropylsilyl)pyrrole (5da). Pale purple
solid. Mp: 131 °C (0.27 g, 72%). H NMR (400 MHz, CDCl3): δ
1
7.52−7.49 (m, 4 H), 7.32 (dd, J = 7.0, 0.9 Hz, 4 H), 7.29 (s, 2 H), 6.29
(s, 2 H), 1.08−1.01 (m, 3 H), 0.92 (d, J = 7.9 Hz, 18 H). 13C NMR
(100 MHz, CDCl3): δ 144.0, 137.5, 129.4, 129.2, 128.0, 127.8, 127.0,
115.3, 19.3, 14.9. HRMS (EI+) m/z: Calcd for C25H33NSi: 375.2382,
found: 375.2381.
1-(4-Chlorobenzyl)-2,5-diphenylpyrrole (5a′a). White solid.
Mp: 120 °C (0.19 g, 56%). 1H NMR (400 MHz, CDCl3): δ 7.34−7.28
(m, 8 H), 7.25 (d, J = 6.8 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H), 6.52 (d,
J = 8.3 Hz, 2 H), 6.35 (s, 2 H), 5.17 (s, 2 H). 13C NMR (100 MHz,
CDCl3): δ 137.8, 136.9, 133.6, 132.6, 129.1, 128.5, 127.4, 127.3, 110.1,
48.2. HRMS (EI+) m/z: Calcd for C23H18NCl: 343.1128, found:
343.1125.
1-Benzyl-2,5-bis(4-(trifluoromethyl)phenyl)pyrrole (5ae).
White solid. Mp: 136 °C (0.34 g, 76%). 1H NMR (400 MHz,
CDCl3): δ 7.55 (d, J = 8.3 Hz, 4 H), 7.45 (d, J = 8.3 Hz, 4 H), 7.14
(dd, J = 6.0, 4.6 Hz, 3 H), 6.67 (dd, J = 7.2, 1.8 Hz, 2 H), 6.45 (s, 2 H),
5.22 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 138.7, 136.9, 136.5,
129.4, 129.0, 128.8, 127.4, 125.8, 125.4 (q, J = 3.7 Hz), 124.4, 123.0,
111.4, 49.2. HRMS (EI+) m/z: Calcd for C25H17F6N: 445.1265, found:
445.1263.
1-(4-Bromobenzyl)-2,5-diphenylpyrrole (5b′a). White solid.
Mp: 113 °C (0.19 g, 50%). 1H NMR (400 MHz, CDCl3): δ 7.32−7.19
(m, 12 H), 6.49−6.44 (m, 2 H), 6.35−6.32 (m, 2 H), 5.15 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ 138.3, 136.9, 133.6, 131.5, 129.1,
128.5, 127.8, 127.3, 120.8, 110.1, 48.3. HRMS (EI+) m/z: Calcd for
C23H18NBr: 387.0623, found: 387.0623.
1-(4-Methoxybenzyl)-2,5-diphenyl-pyrrole (5c′a). White solid.
Mp: 113 °C (0.26 g, 76%). 1H NMR (400 MHz, CDCl3): δ 7.37−7.33
(m, 4 H), 7.31−7.26 (m, 4 H), 7.25−7.19 (m, 2 H), 6.62 (d, J =
8.8 Hz, 2 H), 6.54 (d, J = 8.4 Hz, 2 H), 6.34 (d, J = 1.1 Hz, 2 H), 5.16
(s, 2 H), 3.65 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 158.4, 136.8,
133.9, 131.4, 129.1, 128.4, 127.2, 127.0, 113.8, 109.8, 55.2, 48.2.
HRMS (EI+) m/z: Calcd for C24H21NO: 339.1623, found: 339.1624.
1-(4-(tert-Butyl)benzyl)-2,5-diphenylpyrrole (5d′a). White
1-Benzyl-2,5-bis(4-chlorophenyl)pyrrole (5af). White solid.
1
Mp: 137 °C (0.26 g, 69%). H NMR (400 MHz, CDCl3): δ 7.27−
7.22 (m, 8 H), 7.14 (d, J = 6.9 Hz, 3 H), 6.65 (d, J = 6.0 Hz, 2 H), 6.33
(s, 2 H), 5.15 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 139.0, 136.0,
133.2, 132.0, 130.3, 128.7, 128.6, 137.2, 125.8, 110.3, 48.8. HRMS
(EI+) m/z: Calcd for C23H17NCl2: 377.0738, found: 377.0741.
1-Benzyl-2,5-bis(3,5-dimethylphenyl)pyrrole (5ag). Colorless
1
solid. Mp: 110 °C (0.23 g, 63%). H NMR (400 MHz, CDCl3): δ
1
oil (0.31 g, 85%). H NMR (400 MHz, CDCl3): δ 7.14−7.07 (m,
7.36−7.33 (m, 4 H), 7.28 (t, J = 7.6 Hz, 4 H), 7.23 (d, J = 7.3 Hz,
2 H), 7.10 (d, J = 8.2 Hz, 2 H), 6.56 (d, J = 8.2 Hz, 2 H), 6.34 (s, 2 H),
5.19 (s, 2 H), 1.21 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ 149.7,
136.9, 136.3, 133.9, 129.2, 128.4, 127.0, 125.9, 125.2, 109.8, 48.6, 34.5,
31.4. HRMS (EI+) m/z: Calcd for C27H27N: 365.2143, found:
365.2141.
3 H), 6.95 (s, 4 H), 6.87 (s, 2 H), 6.68 (d, J = 7.6 Hz, 2 H), 6.30 (s,
2 H), 5.20 (s, 2 H), 2.24 (s, 12 H). 13C NMR (100 MHz, CDCl3): δ
139.8, 137.8, 137.0, 133.7, 128.7, 128.3, 127.1, 126.7, 126.2, 109.5,
49.0, 21.4. HRMS (EI+) m/z: Calcd for C27H27N: 365.2143, found:
365.2141.
1-Benzyl-2,5-bis(3-methoxyphenyl)pyrrole (5ah). Pale red oil
1-(3,5-Dimethylbenzyl)-2,5-diphenylpyrrole (5e′a). Colorless
oil (0.20 g, 60%). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J = 7.1 Hz,
4 H), 7.28 (dd, J = 11.1, 4.1 Hz, 4 H), 7.22 (d, J = 6.6 Hz, 2 H), 6.72
(s, 1 H), 6.35 (d, J = 1.8 Hz, 2 H), 6.30 (s, 2 H), 5.14 (s, 2 H), 2.13
(s, 6 H). 13C NMR (100 MHz, CDCl3): δ 139.3, 137.9, 136.7, 133.9,
129.2, 128.6, 128.4, 127.0, 124.0, 109.7, 48.7, 21.4. HRMS (EI+) m/z:
Calcd for C25H23N: 337.1830, found: 337.1832.
1
(0.29 g, 78%). H NMR (400 MHz, CDCl3): δ 7.21−7.15 (m, 4 H),
7.13−7.09 (m, 1 H), 6.97−6.94 (m, 2 H), 6.87−6.85 (m, 2 H), 6.82−
6.76 (m, 4 H), 6.39−6.36 (m, 2 H), 5.23 (s, 2 H), 3.57 (s, 6 H). 13C
NMR (100 MHz, CDCl3): δ 159.5, 139.9, 136.8, 134.9, 129.4, 128.5,
126.9, 126.0, 121.6, 113.9, 113.4, 109.8, 55.0, 49.0. HRMS (EI+) m/z:
Calcd for C25H23NO2: 369.1729, found: 369.1727.
1-Benzyl-2,5-bis(3-benzaldehyde)pyrrole (5ai). White solid.
1-(3-Fluorobenzyl)-2,5-diphenylpyrrole (5f′a). White solid.
1
1
Mp: 86 °C (0.15 g, 40%). H NMR (400 MHz, CDCl3): δ 9.94 (s,
Mp: 110 °C (0.19 g, 59%). H NMR (400 MHz, CDCl3): δ 7.35−
2H), 7.85 (s, 2 H), 7.78 (d, J = 7.5 Hz, 2 H), 7.62 (d, J = 7.5 Hz, 2 H),
7.49 (t, J = 7.6 Hz, 2 H), 7.17−7.08 (m, 3 H), 6.64 (d, J = 5.2 Hz,
2 H), 6.45 (s, 2 H), 5.24 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ
192.2, 138.7, 136.7, 136.2, 134.7, 134.5, 130.3, 129.3, 128.7, 128.3,
127.4, 125.8, 111.0, 49.2. HRMS (EI+) m/z: Calcd for C25H19NO2:
365.1416, found: 365.1414.
1-Benzyl-2,5-di-o-tolylpyrrole (5aj). Colorless oil (0.06 g, 17%).
1H NMR (400 MHz, CDCl3): δ 7.22−7.19 (m, 7 H), 7.16−7.13 (m,
2 H), 7.03−7.01 (m, 2 H), 6.43 (dd, J = 6.6, 1.4 Hz, 2 H), 6.20 (s, 2
H), 4.70 (s, 2 H), 2.18 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ
138.9, 138.2, 134.0, 133.6, 131.7, 130.1, 128.01, 127.98, 126.8, 126.7,
125.6, 109.0, 48.4, 20.2. HRMS (EI+) m/z: Calcd for C25H23N:
337.1830, found: 337.1828.
7.22 (m, 10 H), 7.03 (td, J = 8.0, 6.0 Hz, 1 H), 6.75 (td, J = 8.5,
2.4 Hz, 1 H), 6.40 (d, J = 7.7 Hz, 1 H), 6.36 (s, 2 H), 6.31 (d, J = 9.8
Hz, 1 H), 5.19 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ 162.9 (d, J =
246.0 Hz), 141.9 (d, J = 7.0 Hz), 136.9, 133.6, 129.8 (d, J = 8.3 Hz),
129.1, 128.5, 127.3, 121.6 (d, J = 2.8 Hz), 113.8 (d, J = 21.2 Hz), 113.0
(d, J = 22.2 Hz), 110.1, 48.39, 48.37. HRMS (EI+) m/z: Calcd for
C23H18NF: 327.1423, found: 327.1423.
1-(2-Methylbenzyl)-2,5-diphenylpyrrole (5g′a). White solid.
1
Mp: 132 °C (0.19 g, 60%). H NMR (400 MHz, CDCl3): δ 7.31 (d,
J = 7.1 Hz, 4 H), 7.24 (d, J = 7.8 Hz, 6 H), 7.05 (dd, J = 5.6, 3.4 Hz,
2 H), 7.00−6.97 (m, 1 H), 6.57−6.53 (m, 1 H), 6.40 (s, 2 H), 5.13 (s,
2 H), 1.99 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 137.9, 136.5,
133.7, 133.6, 129.7, 128.9, 128.3, 127.0, 126.7, 126.3, 125.9, 109.6, 46.7,
18.8. HRMS (EI+) m/z: Calcd for C24H21N: 323.1674, found: 323.1672.
Benzyl 1-Benzyl-5-phenyl-1H-pyrrole-3-carboxylate (3ha-1).
Colorless oil (0.02 g, 6%, 0.11 g, 30% at 60 °C). 1H NMR (300 MHz,
CDCl3): δ 7.48−7.42 (m, 3H), 7.34−7.23 (m, 11H), 7.18 (d, J = 7.4
Hz, 2H), 6.66−6.63 (m, 1H), 5.19 (s, 2H), 5.03 (s, 2H). 13C NMR
(75 MHz, CDCl3): δ 164.42, 137.18, 136.73, 136.47, 134.74, 129.41,
129.09, 128.48, 128.36, 128.17, 127.91, 127.86, 127.66, 127.52, 126.62,
121.69, 113.27, 65.43, 54.03. HRMS m/z: Calcd for C25H21NO2:
367.1572, found: 367.1571.
1-Methyl-2,5-diphenylpyrrole (5ba). White solid. Mp: 200 °C
1
(0.11 g, 48%). H NMR (400 MHz, CDCl3): δ 7.49−7.46 (m, 4 H),
7.42 (td, J = 7.5, 3.4 Hz, 4 H), 7.32 (d, J = 7.3 Hz, 2 H), 6.32 (s, 2 H),
3.61 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 137.0, 133.7, 128.9,
128.6, 127.0, 108.8, 34.5. HRMS (EI+) m/z: Calcd for C17H15N:
233.1204, found: 233.1203.
1-Ethyl-2,5-diphenypyrrole (5ca). Pale red solid. Mp: 68 °C
1
(0.21 g, 87%). H NMR (400 MHz, CDCl3): δ 7.49−7.44 (m, 4 H),
7.42−7.37 (m, 4 H), 7.33−7.27 (m, 2 H), 6.29−6.24 (m, 2 H), 4.12−
4.07 (m, 2 H), 0.86−0.81 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ
136.0, 134.2, 129.2, 129.1, 128.53, 128.51, 127.1, 109.64, 109.62, 40.0,
16.2. HRMS (EI+) m/z: Calcd for C18H17N: 247.1361, found:
247.1358.
Benzyl 1-Benzyl-2-phenyl-1H-pyrrole-3-carboxylate (3ha-2).
Colorless oil (0.06 g, 2%, 0.04 g, 10% at 60 °C). 1H NMR (300 MHz,
CDCl3): δ 7.42−7.27 (m, 14H), 7.01−6.96 (m, 2H), 6.70 (d, J =
1.8 Hz, 1H), 5.28 (s, 2H), 5.11 (s, 2H). 13C NMR (75 MHz, CDCl3): δ
E
DOI: 10.1021/acs.joc.5b00451
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
164.73, 137.47, 136.87, 132.15, 129.28, 128.97, 128.65, 128.61, 128.21,
128.07, 127.96, 127.90, 126.79, 115.86, 110.23, 65.65, 51.32. HRMS
m/z: Calcd for C25H21NO2: 367.1572, found: 367.1573.
Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468. (c) Donohoe, T. J.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for products. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b00451.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ykchung@snu.ac.kr.
Notes
■
The authors declare no competing financial interest.
(12) (a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am.
Chem. Soc. 2009, 131, 14622. (b) Nakano, M.; Tsurugi, H.; Isatoh, T.;
Miura, M. Org. Lett. 2008, 10, 1851. (c) Shibahara, F.; Yamaguchi, E.;
Murai, T. Chem. Commun. 2010, 46, 2471.
(13) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int.
Ed. 2007, 46, 7996.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government
(2014R1A5A1011165 and 2007-0093864). B.S.C. and H.J.B.
are recipients of BK21 plus Fellowship.
(14) Islam, S.; Larrosa, I. Chem.Eur. J. 2013, 19, 15093.
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5, 255. (b) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem
2010, 2, 20.
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DOI: 10.1021/acs.joc.5b00451
J. Org. Chem. XXXX, XXX, XXX−XXX