Modular De novo Synthesis of Unsymmetrical BODIPY Dyes Possessing Four Different Aryl Substituents

Article abstract of DOI:10.1002/ejoc.201700773

A modular synthesis of unsymmetrical BODIPY dyes based on a [6π] electrocyclization to construct both pyrrole rings is presented. The products carry four aryl moieties in positions 1, 3, 5, and 7, which can be freely selected, as well as optional substitution in positions 2 and 8. The method employs acetophenones, benzaldehydes as well as glycine nitrile or glycine ethyl ester as the key building blocks.

Full text of DOI:10.1002/ejoc.201700773

A Journal of
Accepted Article
Title: Modular De Novo Synthesis of Unsymmetrical BODIPY Dyes
possessing four different Aryl Substituents
Authors: Natalie Netz, Carlos Díez-Poza, Asuncion Barbero, and Till
Opatz
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700773
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700773
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700773
Modular De Novo Synthesis of Unsymmetrical BODIPY Dyes possessing four different Aryl
Substituents
†
†,‡
‡
†,
Natalie Netz , Carlos Díez-Poza , Asunción Barbero , and Till Opatz *
†
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, 55128 Mainz,
Germany
‡
Departamento de Quimica Orgánica, Facultad de Ciencias, Campus Miguel Delibes, Paseo
Belen nº7, 47011 Valladolid, Spain
E-mail: opatz@uni-mainz.de
Abstract
A modular synthesis of unsymmetrical BODIPY dyes based on a [6π]-electrocyclization to
construct the two pyrrole rings is presented. The products carry four aryl moieties in positions 1,
3
, 5, and 7 which can be freely selected as well as optional substitution in positions 2 and 8. The
method employs acetophenones, benzaldehydes as well as glycine nitrile or glycine ethyl ester as
the key building blocks.
Introduction
4
,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) are fluorescence dyes with remarkable
properties, such as high fluorescence quantum yields, high extinction coefficients, good electron
transfer properties, thermal, chemical and photochemical stability, as well as a generally good
1
solubility. Moreover, lowering the HOMO-LUMO gap of the BODIPY dyes by the introduction
of aromatic substituents has shown to cause shift of its emission wavelength to the near Infrared
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
2
-6
7-9
region.
They have found numerous applications in photodynamic therapy, biological
1
0-12
13-15
labeling
and fluorescence sensing,
and the possibility of varying substituent patterns
1
6,17
18-23
confers widely tunable spectral characteristics.
Syntheses of symmetrical BODIPY dyes
2
4-34
as well as the functionalization of the BODIPY-core have been previously described.
Several
e.g. by
3
5,36
functionalization methods allow the desymmetrization of symmetrical BODIPY dyes,
3
7-39
stepwise halogenation and subsequent cross coupling reactions.
In contrast, the introduction
of more than one symmetry-breaking substituent requires a modular synthesis from two non-
identical pyrrole units and is generally underused and mostly relies on commercial coupling
1
,40-42
partners of limited structural diversity.
The synthesis of non-symmetrically substituted
BODIPYs is e.g. desirable for generating specific fluorescent ligands for biomolecules or for the
4
3-45
extension of electronic tuning properties.
Here, we demonstrate the synthesis of non-
symmetrical 1,3,5,7-tetraaryl-substituted BODIPY dyes through a modular approach in which
both pyrrole units are de novo synthesized in a [6π]-electrocyclization developed earlier in our
4
6-48
laboratory.
A major advantage of this method is the possibility of introducing at will four
different substituents in the BODIPY system in a simple and efficient manner and through a short
convergent synthetic sequence.
This cyclocondensation uses chalcones and glycine derivatives as the starting substrates and
4
6
converts them in high yield to 3,5-disubstituted pyrrole-2-carboxylates and pyrrole-2-
4
7,48
carbonitriles or 2,4-disubstituted pyrroles.
The syntheses of pyrrole-2-carboxylates and
pyrrole-2-carbonitriles were performed in a one-pot procedure which can be extended by an in
situ halogenation of the pyrrole core. Chalcones are readily available through aldol condensation
from aryl ketones and aromatic aldehydes commercially available with wide structural variety.
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European Journal of Organic Chemistry
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Scheme 1. Synthesis of Pyrroles from Enones.
To join the two individual pyrrole units in a Friedel-Crafts reaction, the pyrrole-2-carboxylates
and -nitriles are converted into the more electrophilic pyrrole-2-carbaldehydes and 2-
acylpyrroles. The facile access to halogenated pyrroles allows for a further functionalization of
the BODIPY core at a later stage.
Scheme 2. Modular Synthesis of BODIPYs.
Results and Discussion
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European Journal of Organic Chemistry
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To obtain the desired pyrrole-2-carbaldehydes 7a-g the DIBAL reduction of pyrrole-2-
carboxylate 1a was attempted first. Unfortunately, reduction of ethyl ester 1a in toluene or
dichloromethane did not produce the corresponding aldehyde but rather afforded small amount of
dipyrromethane 3 resulting from the formation of alcohol intermediate 2 which dimerizes in a
Friedel-Crafts/retro-Friedel-Crafts sequence mediated by the Lewis-acidic reductant (Scheme 3).
DIBAL reduction in THF also gave dipyrromethane 3, whereas NaBH reduction of 1a did not
4
result in any conversion. Reduction with LiAlH was tested in order to furnish alcohol 2 without
4
accompanying dimerization, which should then be oxidized to yield the desired carbaldehyde.
Employing 1.2 equivalents of LiAlH , the 2-methyl derivative 4 was obtained, while smaller
4
amounts of LiAlH again led to the formation of dipyrromethane 3.
4
Scheme 3. DIBAL- and LiAlH -reduction of 1a.
4
Based on these results, we chose to synthesize the Weinreb amides, from which the
carbaldehydes should be easily obtained via LiAlH or DIBAL reduction. Furthermore, the
4
Weinreb amides could alternatively be transformed into the corresponding ketones through
reaction with organolithium or magnesium compounds. Reaction of 1a with N,O-
Dimethylhydroxylamine hydrochloride (2 equiv) and isopropylmagnesium chloride in THF gave
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
a mixture of starting material 1a, amide 5a, and a high percentage of a by-product, which was
later identified as urea 6 (Scheme 4). Employing 3 equivalents of deprotonated
N,O-dimethylhydroxylamine, Weinreb amides 5a–g could be obtained in yields up to 89% (table
1
).
Table 1. Synthesis of Weinreb amides from pyrrole-2-carboxylates 1a–g.
1
2
entry
R
R
X
H
Yield %
89
Compound
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
Br
I
75
Ph
68
2-Naph
Br
Br
68
4-F-C H4 4-MeO-C H4
85
6
6
[a]
4-F-C H4
2-Cl-C H4
Br 44 (89 brsm)
Br 53
6
6
4-Cl-C H4 3-NO -C H
4
5g
6
2
6
[a]
brsm: based on recovered starting material..
The starting pyrrole-2-carboxylates 1a–b were synthesized via the previously published one-pot
4
6
procedure.
carboxylates by direct halogenation of the corresponding esters using N-halosuccinimides (Table
).
Halogenated pyrrole-2-carboxylates 1c–i were synthesized from pyrrole-2-
2
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European Journal of Organic Chemistry
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Table 2. Halogenation to generate pyrrole-2-carboxylates 1c–i.
1
2
entry
R
R
X
I
Yield % Compound
1
2
3
4
5
6
7
Ph
Ph
Ph
91
75
78
36
77
1c
1d
1e
1f
2-Naph
Br
Br
Br
Br
I
4-F-C H4
4-MeO-C H
6
6
4
4-F-C H4
2-Cl-C H
4
6
6
4-Cl-C H4
3-NO -C H
4
1g
1h
1i
6
2
6
[a]
4-Cl-C H4
3-NO -C H
4
54
6
2
6
3,4-(MeO) -C H 3,4-(MeO) -C H Br
79
2
6
3
2
6
3
[a]
1.9 equiv of NIS were added in 3 portions.
When batch sizes were increased (ca. 4 mmol), the same side reaction caused by the excess of
deprotonated N,O-dimethylhydroxylamine was observed (Scheme 4). A possible explanation for
this reaction is the nucleophilic attack of excess N,O-dimethylhydroxylamide at the carbonyl
group to produce a tetrahedral intermediate which undergoes 1,2-migration of the pyrrole core
while cleaving the weak N–O bond and the expulsion of methanolate to produce the urea
derivative 6 (Scheme 5).
Scheme 4. Structure elucidation of side product 6.
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European Journal of Organic Chemistry
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Scheme 5. Possible mechanism for the formation of urea 6.
While reduction of 5a with DIBAL did not furnish aldehyde 7a but rather a complex product
mixture, the use of LiAlH (1.0 equiv) gave N,O-dimethylhydroxylamine 8 (Scheme 6). Smaller
4
amounts (0.6 equiv) of the same reductant gave a mixture of 5a, 7a and 8 in a ratio of 1:2.5:3.6.
Addition of the amide 5a to a solution of LiAlH (3 equiv) in THF (–78 °C) and raising the
4
temperature to –30 °C within 2.5 h gave better results (table 3, entry 2).
Employing 0.6 equivalents of LiAlH , Weinreb amides 5b–g were easily transformed into the
4
corresponding pyrrole-2-carbaldehydes 7b–g in yields ranging between 42 and 62% (table 3).
The synthesis via the Weinreb amides was particularly suitable for preparing the 4-halogenated
pyrrole-2-carbaldehydes, which could not be accomplished by any other method tested.
Scheme 6. Attempted reduction of Weinreb amide 5a.
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European Journal of Organic Chemistry
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Table 3. Synthesis of pyrrole-2-carbaldehydes 7a–g from Weinreb amides 5a–g.
1
2
entry
R
R
X
H
H
Br
I
Yield %
Compound
[a]/[b]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
35
7a
7a
7b
7c
7d
7e
7f
[a]/[c]
70
Ph
62
42 (57 brsm)
48
[
d]
Ph
2-Naph
Br
4-F-C H4 4-MeO-C H4 Br
57
6
6
[d]
4-F-C H4
2-Cl-C H4
Br 53 (62 brsm)
6
6
4-Cl-C H4 3-NO -C H Br
55
7g
6
2
6
4
[
a]
1
[b]
[c]
yield judged by H NMR.
Mixture of 5a, 8a and 7 was yielded (1:2.5:3.6).
3 equiv LiAlH4,
[d]
warming to –30 °C. brsm: based on recovered starting material.
The conversion of Weinreb amides into the corresponding ketones was attempted using
AllylMgBr, PhMgBr, and PhLi in THF, unfortunately without any appreciable conversion.
4
7,48
Based on the methods developed by Bergner et al. and Kücükdisli et al.
two further
cyanopyrrolines, 2,4-disubstituted pyrroles and pyrrole-2-carbonitriles were synthesized (table 4).
Enone 9b could not be transformed into the cyanopyrroline, since elimination of HCN already
took place during the cyclocondensation. Microwave-induced elimination of HCN worked for
pyrrole 11d, but this compound could not be purified due to its instability.
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European Journal of Organic Chemistry
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Table 4. Synthesis of cyanopyrrolines and pyrroles.
Starting
1
2
R
R
Yield % Product
material
[
a]
9
a
3,4-(MeO)
2
-C
6
H
3
3
3
3,4-(MeO)
4-NO -C
Indol-3-yl
3,4-(MeO) -C
Indol-3-yl
4-Cl-C
3,4-(MeO)
Indol-3-yl
2
-C
6
H
3
3
3
45
10a
10b
10c
11a
11c
11d
12a
12c
[
b]
9b
4-NO -C
2
H
6
4
2
H
6
4
–
9
c
Ph
3,4-(MeO)
Ph
41
44
41
1
0a
0c
0d
0a
0c
-C
2
6
H
2
H
6
1
[
c]
1
3-NO
2
-C
H
6
4
6
H
4
–
1
3,4-(MeO)
Ph
-C
2
6
H
-C
2
H
6
50
56
1
[a]
[b]
[c]
1.75 equiv aminoacetonitrile hydrochloride/7 h.
Concomitant HCN-elimination took place.
Purification unsuccessful.
4
7,48
Furthermore, the procedure by Kücükdisli et al.
was modified for implementation in a one-
pot procedure. Therefore the amounts of aminoacetonitrile hydrochloride were reduced to 1.2
equivalents. The one-pot procedure could also be extended by an in situ bromination with NBS
while the 4-iodo-derivative was obtained by direct halogenation of 12d. The results are
summarized in table 5.
Table 5. One-pot synthesis of pyrrole-2-carbonitriles.
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European Journal of Organic Chemistry
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1
2
entry
R
R
X
H
Br
I
Yield % Compound
1
2
3
4
5
6
7
Ph
Ph
60
40
82
49
53
47
38
12d
12e
Ph
Ph
Ph
[a]
Ph
12f
2-Naph
Ph
H
H
H
H
12g
12h
12i
4-Cl-C H4
3-NO -C H
4
6
2
6
Ph
2,3-Cl -C H
2 6 3
4-F-C H4
4-MeO-C H4
12j
6
6
[a]
direct halogenation of 12d.
The conversion of pyrrole-2-carbonitriles 12 into pyrrole-2-carbaldehydes 7 with DIBAL
proceeded smoothly in the case of the phenyl-substituted compound 12d while lower yields were
observed for more complex substitution patterns (table 6). An encountered difficulty was the
surprisingly high stability of the imine intermediates to hydrolysis. In addition, the sensitivity of
the aldehydes towards oxidative and acidic conditions (homocondensation) complicated their
handling and further reduced the overall yields of the procedure. Treatment of 4-halogenated
pyrrole-2-carbonitriles with DIBAL resulted in complex mixtures of undesired products.
The conversion of pyrrole-2-carbonitriles 12d,e,h,i into the corresponding ketones 13a-e could be
achieved with the corresponding Grignard reagents, while organolithium reagents did not result
in any appreciable conversion. Possibly, a certain Lewis acidity of the metal is required in this
case. The resulting imines had to be hydrolyzed with 4N sodium hydroxide/ethanol/80 °C to
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
yield the ketones 13a–e in yields ranging from 55 to 87% while acid hydrolysis was
unsuccessful.
Table 6. Synthesis of pyrrole-2-carbaldehydes 7 and ketones 13 from pyrrole-2-carbonitriles 12.
1
2
3
entry
R
R
R
X
H
Yield % Compound
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
H
67
7a
13a
7b
[a]
H
62
[b]
Ph
Br
Br
–
Ph
Ph
88
82
–
13b
13c
Ph
Thienyl Br
Vinyl Br
Ph
2-Naph
H
H
H
H
H
H
H
H
H
H
26
43
41
7h
7i
4-F-C H4
4-MeO-C H
6
6
4
4-F-C H4
2-Cl-C H4
H
7j
6
6
[
c]
1
1
1
1
1
0
1
2
3
4
4-Cl-C H4
3-NO -C H
4
Ph
H
–
13d
7k
13e
7l
6
2
6
Ph
Ph
2,3-Cl -C H
54
75
30
35
2
6
3
2,3-Cl -C H
Ph
H
2
6
3
3,4-(MeO) -C H 3,4-(MeO) -C H
2
6
3
2
6
3
Ph
Indol-3-yl
H
7m
[
a]
[b]
Two-step synthesis, imine was purified via column chromatography.
A complex mixture was
[c]
obtained. Side reaction, see Scheme 7.
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European Journal of Organic Chemistry
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The reaction of 12h with phenylmagnesium bromide (4 equiv) not only led to the ketone
formation, but also the nitro substituent was reduced to the secondary amine in this case (Scheme
4
9
7
).
Scheme 7. Reaction of 12h with PhMgBr.
For the BODIPY synthesis, pyrrole-2-carbaldehydes 7 and 2,4-disubstituted pyrroles 11 were
dissolved in dichloromethane and 1 equiv of TFA or POCl was added. The desired
3
unsymmetrical BODIPY dyes 14a-n were obtained after reaction of the dipyrromethenes with
BF ·OEt in situ in 23–80% yield. Remarkably, symmetrically substituted BODIPYs 16a–b and
3
2
1
5a were also isolated from the reaction mixture in certain cases (table 7, entries 2–5 and 12–13).
The mechanism of the formation of these side products probably involves an intermediate
tripyrrylmethane, which is formed from one molecule of pyrrole carbaldehyde and two molecules
2
3
of the disubstituted pyrrole or a deformylation in the case of the “aldehyde dimers” 15.
Elimination of one pyrrole moiety then affords the symmetrical BODIPY 16a–b. The synthesized
BODIPYs, including the isolated symmetrical byproducts are depicted in table 7.
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European Journal of Organic Chemistry
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Table 7. Synthesis of BODIPYs.
1
2
3
4
[a]
entry
R
R
R
R
X
Br
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
Yield %
80
37
40
45
45
76
22
40
42
9
Compound
1
2
Ph
Ph
Ph
Ph
14a
14b
16a
14c
16a
14d
15a
16b
14e
16b
14f
2-Naph
Ph
4-F-C H
2-Cl-C H
6
4
4
4
4
4
6
4
4
4
4
–
Ph
–
–
4-F-C H
2-Cl-C H
6
6
3
4
Ph
–
4-F-C H
2-Cl-C H
6
6
4-F-C H
2-Cl-C H
6
6
Ph
Ph
–
2,3-Cl -C H
4-F-C H
4-MeO-C H
2
6
3
6
6
4
2,3-Cl -C H
–
–
2
6
3
–
4-F-C H
4-MeO-C H
6
4
4
4
4
4
4
6
4
4
4
4
4
5
Ph
–
Ph
–
4-F-C H
4-MeO-C H
6
6
4-F-C H
4-MeO-C H
6
6
6
7
9
Ph
Ph
4-F-C H
4-MeO-C H
40
55
43
58
51
32
43
49
47
25
6
6
4-F-C H4
2-Cl-C H4
4-F-C H
4-MeO-C H
14g
16a
14h
14i
6
6
6
6
4-F-C H4
2-Cl-C H4
4-F-C H
2-Cl-C H
4
6
6
6
6
1
1
1
0
1
2
4-F-C H4
2-Cl-C H4
Ph
Indol-3-yl
6
6
4-F-C H4
2-Cl-C H4
3,4-(MeO) -C H 3,4-(MeO) -C H
6
6
2
6
3
2
6
3
2-Naph
Ph
–
4-F-C H
4-MeO-C H
14j
6
4
4
4
4
6
4
–
Ph
4-F-C H
4-MeO-C H
16b
14k
16a
15a
6
6
4
13
2,3-Cl -C H
4-F-C H
2-Cl-C H
2
6
3
6
6
4
–
–
4-F-C H
2-Cl-C H
6
6
4
Ph
2,3-Cl -C H
–
–
2
6
3
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European Journal of Organic Chemistry
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1
1
1
4
5
7
Ph
Ph
Indol-3-yl
Indol-3-yl
Ph
2,3-Cl -C H
3
H
H
44
23
14l
14m
14n
2
6
4-F-C H
4-MeO-C H
6
4
6
4
4-Cl-C H4 3-NO -C H
4
Ph
Indol-3-yl
Br 56
6
2
6
[
a]
The yields of the cross-coupling products and the symmetrical by-products partly originate
from separate reations, see experimental section for details.
2
-Acylpyrroles 13 were also condensed with 2,4-disubstituted pyrroles 11, but the above-
mentioned conditions did not provide the desired dipyrromethenes in this case. The use of larger
amounts of TFA or POCl or heating also did not improve the conversion. A model reaction was
3
5
0
instead accomplished employing a modified procedure by Liras et al. The ketone 13c and
phosphorous oxychloride were stirred together for 30 min and after addition of 2,4-
diphenylpyrrole, the mixture was heated to 40 °C. An inseparable mixture of cross condensation
product 17a and symmetrical products 17b was obtained in a 1:2 ratio (Scheme 8).
Scheme 8. Reaction of ketone 13c with 2,4-diphenylpyrrole.
The selective construction of 2-halogenated BODIPYs offers the possibility of further and
selective stepwise functionalization. BODIPYs 14a, 14e and 14n were further functionalized via
Suzuki and Stille-cross coupling-reactions, to yield 18a and 18b (Scheme 9). Unfortunately, the
reaction with tributyl(ethynyl)stannane did not afford the desired compound 18c. Subsequent
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
bromination and functionalization could render 1,2,3,5,6,7-trisubstituted BODIPYs with
completely selectable substituent patterns.
Scheme 9. Functionalization of BODIPY dyes via Suzuki and Stille-cross coupling.
UV-Vis-absorbing and fluorescence properties of the synthesized compounds were determined in
MeCN solution, the results are shown in Table 8. Molar extinction-coefficients are mostly larger
−
1
−1
than 30,000 L·mol ·cm . Replacing the phenyl substituents by 4-fluorophenyl, 2-chlorophenyl,
2
,3-dichlorophenyl or 4-methoxyphenyl-substituents had little influence on absorption- and
emission wavelength whereas naphthalen-2-yl- and indol-3-yl-substituents as well as 3,4-
dimethoxyphenyl-substituents led to a more or less pronounced red shift. Vinyl-substitution of
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European Journal of Organic Chemistry
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the 2-position of the BODIPY-core results in bathochromic, 2-bromo- or furan-3-yl-substitution
on the other hand to hypsochromic shift of the absorption- and emission maxima. Although
fluorescence quantum yields were not determined, the presence of an indole moiety clearly leads
to fluorescence quenching.
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European Journal of Organic Chemistry
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Table 8. Absorption and emission maxima for synthesized BODIPY dyes in acetonitrile.
Stokes-
Compound
λ
max abs/nm
λmax emiss/nm
Shift/nm
1
4a
4b
4c
4d
4e
4f
4g
4h
556
564
562
564
560
564
564
574
586
572
562
576
578
568
556
572
562
562
568
586
604
30
1
40
29.5
31
1
591.5
595
1
1
585
25
1
593.5
594
29.5
30
1
1
1
606.5
620
32.5
34
1
4i
4j
606
34
1
4k
4l
4m
4n
595
33
1
622
46
1
633.5
603
55.5
35
1
1
8a
580
24
1
8b
608.5
595
36.5
33
1
1
5a
6a
593
31
1
6b
596
28
In summary, an easy and efficient modular synthesis of BODIPY dyes from easy accessible or
commercially available starting materials has been developed. A total of 16 non-symmetrically
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
substituted and three symmetrically substituted BODIPY dyes were synthesized and
characterized. Since the synthetic scheme is general, pyrrole building blocks prepared along other
routes may also be incorporated to further increase the structural diversity of the products.
Experimental Section
All reactions involving air or moisture sensitive reagents or intermediates were performed under
an inert atmosphere of argon in oven dried glassware. Pyrrole building blocks, the synthesis of
4
6,48
which are not described herein, were prepared as described previously.
All reagents and
solvents were obtained from commercial suppliers and used without further purification unless
stated otherwise. Anhydrous toluene, THF, and diethyl ether were distilled from sodium /
benzophenone under argon. Dichloromethane was distilled from calcium hydride. NMR spectra
1
13
were recorded with a Bruker AV-III 400 (400 MHz H and 100.6 MHz C) or with a Bruker
1
13
AV-III 600 spectrometer (600 MHz H and 151 MHz C) equipped with 5 mm probes (BBFO
for AV 400, TCI cryoprobe for AV 600). The chemical shifts were referenced to the residual
5
1
solvent signal (CHCl , 7.26 ppm or DMSO, 2.50 ppm). IR spectra were recorded on a Bruker
3
Tensor 27 instrument using a diamond ATR. UV-VIS spectra were recorded on a Perkin Elmer
Lambda 16 spectrometer, a Perkin Elmer LS 50B instrument was used for measuring the
fluorescence spectra. ESI-HRMS spectra were recorded on a Waters Q-TOF Ultima-III
instrument with a dual source and a suitable external calibrant. Thin-layer chromatography (TLC)
was carried out on 0.25 mm silica gel plates with fluorescence indicator. Flash chromatography
was performed on 35–70 μm silica gel (Acros) using the solvent systems indicated.
Ethyl 4-Iodo-3,5-diphenyl-1H-pyrrole-2-carboxylate (1c). Ethyl 3,5-diphenyl-1H-pyrrole-2-
4
6
carboxylate (1a , 46 mg, 0.501 mmol) was dissolved in pyridine (10 mL) and NIS (125 mg,
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
0
.556 mmol, 1.1 equivequiv) was added. After 19 h of stirring at room temperature, another
portion of NIS (30 mg, 0.13 mmol, 0.26 equivequiv) was added After 3 h of stirring at room
temperature, the solvent was removed in vacuo. Purification by flash column chromatography
(cylcohexane/EtOAc, 10:1) yielded the title compound (191 mg, 91%) as a colorless solid. mp
–
1
1
1
7
7
49.6–152.0 °C. R = 0.56 (silica, cylcohexane/EtOAc, 2:1). IR (ATR) (cm ) = 3269, 1669,
f
1
434, 1290, 1265, 1155, 762, 696. H NMR (400 MHz, CDCl )  (ppm) = 9.74 (s , 1H, NH),
3
br
.75–7.70 (m, 2H, H-2’’/6’’), 7.51–7.35 (m, 8H), 4.08 (q, J = 7.1 Hz, 2H, CH ), 1.05 (t, J =
2
1
3
.1 Hz, 3H, CH ). C NMR (100.6 MHz, CDCl )  (ppm) = 160.8 (C=O), 136.8 (C 5), 136.1
3
3
q
(
(
[
C ), 135.4 (C ), 131.7 (C ), 130.7 (2C), 128.8 (1C), 128.7 (2C), 128.5 (2C), 127.6 (1C), 127.6
q q q
2C), 120.5 (C 2), 69.9 (C 4), 60.7 (CH ), 14.0 (CH ). ESI-HRMS calcd for
q
q
2
3
127
+
C H NO I + Na] 440.0124, found 440.0122.
1
9
16
2
Ethyl
corresponding ester (118 mg, 0.346 mmol) was dissolved in pyridine (7 mL) and NBS
80.0 mg, 0.449 mmol) was added. After 3 h of stirring at room temperature the solvent was
4-Bromo-5-(naphthalen-2-yl)-3-phenyl-1H-pyrrole-2-carboxylate
(1d).
The
4
6
(
removed in vacuo. Purification by flash column chromatography (cylcohexane/EtOAc, 10:1)
yielded the title compound (108.9 mg, 0.259 mmol, 75%) as a colorless solid. mp 193.3–
–
1
1
1
94.1 °C. R = 0.50 (silica, cylcohexane/EtOAc, 4:1). IR (ATR)  (cm ) = 3334, 1652, 1431,
f
1
262, 1243, 1165, 1020, 895, 722, 748, 698. H NMR, COSY (400 MHz, CDCl )  (ppm) = 9.71
3
(s, 1H, NH), 8.23 (d, J = 1.7 Hz, 1H, H-1‘‘), 7.94 (d, J = 8.6 Hz, 1H, H-4‘‘), 7.93–7.86 (m, 2H,
Naph), 7.87 (dd, J = 8.6, 1.7 Hz, 1H, H-3‘‘), 7.57–7.51 (m, 2H, Naph), 7.48–7.36 (m, 5H, Ph),
13
4
.10 (q, J = 7.1 Hz, 2H, CH ), 1.06 (t, J = 7.1 Hz, 3H, CH ). C NMR, HSQC, HMBC (100.6
2 3
MHz, CDCl )  (ppm) = 161.0 (C=O), 133.4 (C ), 133.3 (2×C ), 133.1 (C ), 132.5 (C 3), 130.8
3
q
q
q
q
(
C2‘/6‘), 128.6 (1C, Naph), 128.4 (1C, Naph), 128.1 (C ), 127.9 (1C, Naph), 127.7 (C4‘), 127.6
q
(
C3‘/5‘), 127.2 (C1‘‘), 126.9 (1C, Naph), 126.8 (1C, Naph), 125.2 (C3‘‘), 119.5 (C 2), 99.3
q
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
79
+
(
C 4), 60.8 (CH ), 14.0 (CH ). ESI-HRMS calcd for [C H BrNO + Na] 442.0419, found
q
2
3
23 18
2
4
42.0430.
Ethyl 4-Bromo-5-(4-fluorophenyl)-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (1e). The
4
6
corresponding ester (93.6 mg, 0.28 mmol) was dissolved in pyridine (5.6 mL) and NBS (64mg,
.36 mmol, 1.3 equivequiv) was added. After 3 h of stirring at room temperature, the solvent was
0
removed in vacuo. Purification by flash column chromatography (cylcohexane/EtOAc, 6:1)
yielded the title compound (91.4 mg, 0.219 mmol, 78%) as a colorless solid. mp 167.1–167.9 °C.
–1
R = 0.33 (silica, cylcohexane/EtOAc, 4:1). IR (ATR)  (cm ) = 3284, 1658, 1505, 1439, 1290,
f
1
1
1
248, 1221, 1034, 837, 812, 774, 721. H NMR, COSY (400 MHz, CDCl )  (ppm) = 9.52 (s ,
3
br
H, NH), 7.77–7.66 (m, 2H, H-2‘‘/6‘‘), 7.41–7.31 (m, 2H, H-2‘/6‘), 7.22–7.11 (m, 2H,
H-3‘‘/5‘‘), 7.00–6.92 (m, 2H, H-3‘/5‘), 4.14 (q, J = 7.2 Hz, 2H, CH ), 3.86 (s, 3H, OCH ), 1.14
2
3
1
3
(
t, J = 7.2 Hz, 3H, CH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 162.9 (d,
3
3
1
JC,F = 249.3 Hz, C 4‘‘), 160.9 (C=O), 159.2 (C 4‘), 132.3 (C 5), 132.0 (C 3), 131.9 (C2‘/6‘),
q
q
q
q
3
4
1
1
29.8 (d, J = 8.2 Hz, C2‘‘/6‘‘), 126.9 (d, J = 3.4 Hz, C 1‘‘), 125.5 (C 1‘), 119.2 (C 2),
C,F C,F q q q
2
16.0 (d, J = 21.8 Hz, C3‘‘/5‘‘), 113.1 (C3‘/5‘), 99.3 (C 4), 60.8 (CH ), 55.4 (OCH ), 14.2
C,F
q
2
3
7
9
+
(
CH ). ESI-HRMS calcd for [C H BrFNO + Na] 440.0274, found 440.0276.
3 20 17 3
Ethyl 4-Bromo-3-(2-chlorophenyl)-5-(4-fluorophenyl)-1H-pyrrole-2-carboxylate (1f). The
4
6
corresponding ester (163 mg, 0.47 mmol) was dissolved in pyridine (9.4 mL) and NBS
110 mg, 0.62 mmol, 1.3 equivequiv) was added. After 3 h of stirring at room temperature, the
solvent was removed in vacuo. Purification by flash column chromatography
cylcohexane/EtOAc, 3:2) yielded the title compound (72 mg, 0.17 mmol, 36%) as a colorless
(
(
–
1
solid. mp 180.5–181.1°C. R = 0.22 (silica, cylcohexane/EtOAc, 2:1). IR (ATR)  (cm ) = 3280,
f
1
1
666, 1441, 1290, 1259, 1228, 1160, 1016, 839, 753, 733, 661. H NMR, COSY (400 MHz,
CDCl )  (ppm) = 9.82 (s , 1H, NH), 7.79–7.72 (m, 2H, H-2‘‘/6‘‘), 7.50–7.45 (m, 1H, H-6‘),
3
br
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
7
7
.37–7.30 (m, 3H, H-3‘,4‘,5‘), 7.20–7.13 (m, 2H, H-3‘‘/5‘‘), 4.17–3.96 (m, 2H, CH ), 1.00 (t, J =
2
13
.1 Hz, 3H, CH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 162.9 (d, J = 249.2
3
3
Hz, C 4‘‘), 160.9 (C=O), 134.6 (C 1‘), 133.3 (C 2‘), 132.4 (C 5), 132.2 (1C), 129.7 (d, J = 8.2
q
q
q
q
Hz, C2‘‘/6‘‘), 129.5 (C 3), 129.3 (1C), 129.2 (C6‘), 126.7 (d, J = 3.4 Hz, C 1‘‘), 126.2 (C4‘),
q
q
1
20.2 (C 2), 116.0 (d, J = 21.8 Hz, C3‘‘/5‘‘), 99.1 (C 4), 60.9 (CH ), 13.8 (CH ). ESI-HRMS
q q 2 3
7
14
9
+
calcd for [C H BrClFNO + Na] 443.9778, found 443.9788.
19
2
Ethyl 4-Bromo-5-(4-chlorophenyl)-3-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (1g). The
4
6
corresponding ester (174.5 mg, 0.471 mmol) was dissolved in pyridine (9.4 mL) and NBS
108.6 mg, 0.610 mmol, 1.3 equivequiv) was added. After 3 h of stirring at room temperature the
solvent was removed in vacuo. Purification by flash column chromatography
cylcohexane/EtOAc, 6:1) yielded the title compound (163 mg, 0.362 mmol, 77%) as a colorless
(
(
–1
solid. mp 197.3–198.4 °C. R = 0.47 (silica, cylcohexane/EtOAc, 3:1). IR (ATR) (cm ) = 3300,
f
1
1
670, 1537, 1518, 1443, 1344, 1285, 1255, 1175, 1092, 827, 693. H NMR, COSY (400 MHz,
CDCl )  (ppm) = 9.75 (s , 1H, NH), 8.36–8.30 (m, 1H, H-2‘), 8.25 (ddd, J = 8.3, 2.3, 1.1 Hz,
3
br
1
H, H-4‘), 7.77 (ddd, J = 7.7, 1.7, 1.1 Hz, 1H, H-6‘), 7.72–7.64 (m, 2H, 4-Cl-Ph), 7.59 (pseudo-t,
J = 8.0 Hz, 1H, H-5‘), 7.50–7.41 (m, 2H, 4-Cl-Ph), 4.12 (q, J = 7.1 Hz, 2H, CH ), 1.08 (t, J = 7.1
2
13
Hz, 3H, CH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 160.4 (C=O), 147.8
3
3
(
C 3‘), 137.0 (C6‘), 135.1 (C ), 134.9 (C 1‘), 132.7 (C ), 129.5 (C 3), 129.3, 129.2 (2×2C,
q q q q q
C2‘‘/3‘‘/5‘‘/6‘‘), 128.6 (2C, C5‘C ), 126.2 (C2‘), 122.7 (C4‘), 119.9 (C 2), 98.9 (C 4), 61.3
q
q
q
7
9
+
(
CH ), 14.0 (CH ). ESI-HRMS calcd for [C H BrClN O + Na] 470.9723, found 470.9734.
2 3 19 14 2 4
Ethyl 4-Iodo-5-(4-chlorophenyl)-3-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (1h). The
4
6
corresponding ester (136 mg, 0.368 mmol) was dissolved in pyridine (7.4 mL) and NIS
(107.5 mg, 0.478 mmol, 1.3 equivequiv) was added. After 3 h of stirring at room temperature the
TLC did not show complete conversion. Another portion of NIS (24.8 mg, 0.11 mmol,
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
0
.3 equivequiv) was added. After 3 h of stirring at room temperature, starting material could still
be detected (TLC) and another portion of NIS (24.8 mg, 0.11 mmol, 0.3 equivequiv) was added.
After stirring at room temperature overnight, the solvent was removed in vacuo. Purification by
flash column chromatography (cylcohexane/EtOAc, 10:1) yielded the title compound (99 mg,
0
.19 mmol, 54%) as a colorless solid. mp 194.0–194.8°C. R = 0.32 (silica, cylcohexane/EtOAc,
f
–
1
5
:1). IR (ATR)  (cm ) = 3305, 1671, 1534, 1516, 1440, 1343, 1284, 1253, 1171, 826, 694, 661.
1
H NMR, COSY (400 MHz, CDCl )  (ppm) = 9.81 (s , 1H, NH), 8.28 (ddd, J = 2.2, 1.6, 0.6 Hz,
3
br
1
7
H, H-2‘), 8.26 (ddd, J = 8.1, 2.2, 1.2 Hz, 1H, H-4‘), 7.72 (ddd, J = 7.7, 1.6, 1.2 Hz, 1H, H-6‘),
.69–7.61 (m, 2H, H-2‘‘/6‘‘), 7.60 (ddd, J = 8.1, 7.7, 0.6 Hz, 1H, H-5‘), 7.51–7.42 (m, 2H,
1
3
H-3‘‘/5‘‘), 4.09 (q, J = 7.1 Hz, 2H, CH ), 1.05 (t, J = 7.1 Hz, 3H, CH ). C NMR, HSQC,
2
3
HMBC (100.6 MHz, CDCl )  (ppm) = 160.2 (C=O), 147.8 (C 3‘), 137.1 (C6‘), 136.8 (C 1‘),
3
q
q
1
36.3 (C 5), 135.3 (C 4‘‘), 133.2 (C 3), 129.8 (C2‘‘/6‘‘), 129.7 (C 1‘‘), 129.2 (C3‘‘/5‘‘), 128.6
q q q q
(
C5‘), 126.2 (C2‘), 122.7 (C4‘), 121.1 (C 2), 69.5 (C 4), 61.2 (CH ), 14.0 (CH ). ESI-HRMS
q q 2 3
127
+
calcd for [C H Cl IN O + Na] 518.9585, found 518.9583.
19
14
2
4
Ethyl
corresponding ester (30 mg, 73 mol) was dissolved in pyridine (2 mL) and NBS (14 mg,
9 mol) was added. After 20.5 h of stirring at room temperature the solvent was removed in
4-Bromo-3,5-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylate
(1i).
The
4
6
7
vacuo. Purification by flash column chromatography (cylcohexane/EtOAc, 3:2) yielded the title
compound (28 mg, 79%) as a yellow oil. R = 0.21 (silica, cylcohexane/EtOAc, 1:1). IR (ATR)
f
–1
1

(cm ) = 3287, 2836, 1688, 1666, 1510, 1463, 1433, 1226, 1136, 1025, 913, 730. H NMR (400
MHz, CDCl )  (ppm) = 9.40 (s, 1H, NH), 7.30 (d, J = 2.0 Hz, 1H, H-2’’), 7.25 (dd, J = 8.3.
3
2
4
1
.0 Hz, 1H, H-6’’), 7.00 (dd, J = 8.2, 1.9 Hz, 1H, H-6’), 6.98–6.91 (m, 3H, H-5’’, H-2’, H-5’),
.16 (q, J = 7.1 Hz, 2H, CH ), 3.94 (s, 3H, OCH ), 3.93 (s, 6H, 2 x OCH ), 3.90 (s, 3H, OCH ),
2
3
3
3
13
.14 (t, J = 7.1 Hz, 3H, CH ). C NMR (100.6 MHz, CDCl )  (ppm) = 160.9 (C=O), 149.5
3
3
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
(
COMe), 149.1 (COMe), 148.6 (COMe), 148.0 (COMe), 133.3 (C 5), 132.1 (C 3), 125.8 (C 1’),
q q q
1
1
23.4 (C6’), 123.3 (C 1’’), 120.4 (C6’’), 118.7 (C 2), 114.2 (C5’’), 111.3 (C2’), 111.1 (C2’’),
q q
10.3 (C5’), 98.7 (C 4), 60.7 (CH ), 56.2 (OCH ), 56.1 (OCH ), 56.0 (OCH ), 55.3 (OCH ), 14.3
q
2
3
3
3
3
7
9
+
(
CH ). ESI-HRMS calcd for [C H NO Br + H] 490.0865, found 490.0848.
3 23 24 6
4
6
2
0
0
-Methyl-3,5-diphenyl-1H-pyrrole (4). In a Schlenk flask, compound 1a
(146 mg,
.501 mmol) was dissolved in dry THF (1 mL), lithium aluminum hydride (2M in THF, 0.3 mL,
.6 mmol) was added and the mixture was heated to reflux for 17.5 h. After cooling to 0 °C, the
mixture was quenched with 1n aqueous NaOH and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried with MgSO and concentrated in vacuo to yield the
4
title compound (116 mg, 0.497 mmol, quant.) as a colorless to light pink oil. R = 0.51 (silica,
f
1
cyclohexane/EtOAc, 2:1). H NMR (400 MHz, CDCl )  (ppm) = 8.18 (s , 1H, NH), 7.52–7.44
3
br
(m, 4H), 7.42–7.34 (m, 4H), 7.25–7.17 (m, 2H), 6.63 (d, J = 2.9 Hz, 1H, H-4), 2.48 (s, 3H, CH3).
4
7,52
The spectroscopic data were in accordance with the literature.
General procedure for the synthesis of Weinreb amides 5a–g. A Schlenk flask was charged
with N,O-dimethylhydroxylamine hydrochloride (2–3 equivequiv) under argon, dry THF
n
(
10 mL/mmol ester) was added and the homogeneous solution was cooled to 78 °C. BuLi
(2.5M in hexane, 4–6 equivequiv) was slowly added. The mixture was stirred for 35 minmin at

78 °C and for 1 h at room temperature. After cooling to 78 °C, a solution of ester 1a–g
(1 equivequiv) in dry THF was added followed by stirring at 78 °C for 1 h and at room
temperature overnight (10–16 h). The mixture was quenched with sat. NH Cl-solution and
4
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over
MgSO and concentrated in vacuo. Flash column chromatography yielded the desired product.
4
N-Methoxy-N-methyl-3,5-diphenyl-1H-pyrrole-2-carboxamide (5a). According to the general
n
procedure using N,O-dimethylhydroxylamine hydrochloride (301 mg, 3.09 mmol), BuLi (2.5M
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
4
6
in hexane, 2.5 mL, 6.25 mmol) and 1a (292 mg, 1.00 mmol). Purification by flash column
chromatography (cyclohexane/EtOAc, 3:2) yielded the title compound (280 mg, 89%) as a light
–1
yellow foam. R = 0.26 (silica, cyclohexane/EtOAc, 1:1). IR (ATR)cm ) = 3216, 1599, 1478,
f
1
1

7
3
457, 1439, 1368, 1263, 1083, 908, 759, 728, 695. H NMR, COSY (400 MHz, CDCl )
3
(ppm) = 10.68 (s , 1H, NH), 7.62–7.58 (m, 2H, H-2’’/6’’), 7.50–7.46 (m, 2H, H-2’/6’), 7.42–
br
.35 (m, 4H, H-3’/5’, H-3’’/5’’), 7.34–7.30 (m, 1H, H-4’), 7.30–7.24 (m, 1H, H-4’’), 6.60 (d, J =
1
3
.0 Hz, 1H, H-4), 3.60 (s, 3H, OCH ), 3.07 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6
3
3
MHz, CDCl3)  (ppm) = 162.7 (C=O), 136.4 (Cq1’), 135.0 (Cq5), 131.7 (C 1’’), 130.7 (C 3),
q
q
1
29.0, 128.5, 128.3 (3×2C, C3’/5’, C2’/6’, C3’’/5’’), 127.4 (C4’’), 126.9 (C4’), 124.8 (2C,
C2’’/6’’), 120.3 (C 2), 108.3 (C4), 60.7 (OCH ), 35.5 (NCH ). ESI-HRMS calcd for
q
3
3
+
[
C H N O + Na] 329.1266, found 329.1258.
19 18 2 2
N-(3,5-Diphenyl-1H-pyrrole-2-yl)-N'-methoxy-N,N'-dimethylurea (6). The title compound
was prepared according to the general procedure using N,O-dimethylhydroxylamine
n
hydrochloride (1.15 g, 11.8 mmol, 3.1 equivequiv), BuLi (2.5M in hexane, 9.5 mL, 24 mmol,
4
6
6
.2 equivequiv) and 1a (1.12 g, 3.84 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 3:2) yielded the title compound (707 mg, 2.11 mmol, 55%) as a colorless
–
1
foam. R = 0.48 (silica, cyclohexane/EtOAc, 1:1). IR (ATR) (cm ) = 3258, 2932, 1648, 1605,
f
1
1
593, 1501, 1458, 1441, 1375, 909, 759, 732, 695. H NMR, COSY (400 MHz, CDCl )
3

(ppm) = 10.17 (s, 1H, NH), 7.77–7.68 (m, 4H, H-2‘/6‘/2‘‘/6‘‘), 7.48–7.40 (m, 4H,
H-3‘/5‘/3‘‘/5‘‘), 7.30–7.24 (m, 2H, H-4‘/4‘‘), 6.84 (d, J = 3.0 Hz, 1H, H-4), 3.24 (s, 3H, NCH3),
1
3
3
.08 (s, 3H, NCH (OCH )), 3.04 (s, 3H, OCH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )
3 3 3 3

(ppm) = 163.0 (C=O), 134.7 (C 1‘), 132.3 (C 1‘‘), 129.1 (2C), 129.0 (C 2), 128.7 (2C), 128.6
q q q
(
C 5), 126.3 (C4‘‘), 126.2 (C2‘/6‘), 125.8 (C4‘), 123.5 (C2‘‘/6‘‘), 117.2 (C 3), 104.4 (C4), 60.1
q
q
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
+
(
OCH ), 39.0 (NCH ), 36.1 (NCH ). ESI-HRMS calcd for [C H N O + Na] 358.1531, found
3
3
3
20 21
3
2
3
4
58.1531.
-Bromo-N-methoxy-N-methyl-3,5-diphenyl-1H-pyrrole-2-carboxamide (5b). The title
compound was prepared according to the general procedure using N,O-dimethylhydroxylamine
n
hydrochloride (303 mg, 3.11 mmol), BuLi (2.5M in hexane, 2.5 mL, 6.3 mmol, 6.3 equivequiv)
4
6
and 1b
(371 mg, 1.00 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 3:2) yielded the title compound (287 mg, 75%) as a light yellow foam.
–1
R = 0.23 (silica, cyclohexane/EtOAc, 1:1). IR (ATR) (cm ) = 3181, 1615, 1600, 1480, 1438,
f
1
1
1
263, 1094, 1025, 908, 766, 729, 696. H NMR, COSY (400 MHz, CDCl )  (ppm) = 12.22 (s,
3
H, NH), 7.76–7.71 (m, 2H, H-2’’/6’’), 7.51–7.46 (m, 2H, H-3’’/5’’), 7.44–7.33 (m, 6H, Ph’,
1
3
H-4’’), 3.44 (s, 3H, OCH ), 2.96 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )
3
3
3

(ppm) = 161.2 (C=O), 133.6 (C 1’), 130.7 (C 1’’), 130.6 (C 5), 129.5 (C3’/5’), 128.4
q q q
(
C3’’/5’’), 128.1(C3’/5’), 127.8 (C2’’/6’’), 127.7 (C4’’), 127.0 (C4’), 125.7 (C 3), 122.6 (C 2),
q q
79
+
9
4.9 (C 4), 60.2 (OCH ), 34.1 (NCH ). ESI-HRMS calcd for [C H N O Br + H] 385.0549,
q 3 3 19 17 2 2
found 385.0552.
-Iodo-N-methoxy-N-methyl-3,5-diphenyl-1H-pyrrole-2-carboxamide
4
(5c).
The
title
compound was prepared according to the general procedure using N,O-dimethylhydroxylamine
n
hydrochloride (120 mg, 1.13 mmol), BuLi (2.5M in hexane, 1.0 mL, 2.5 mmol, 6.2 equivequiv)
and 1c (169 mg, 0.405 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 2:1→3:2). yielded the title compound (119 mg, 68%) as a colorless foam.
–1
R = 0.08 (silica, cyclohexane/EtOAc, 2:1) IR (ATR) (cm ) = 3176, 1614, 1600, 1480, 1437,
f
1
1
1
261, 1092, 1024, 909, 765, 730, 697. H NMR, COSY (400 MHz, CDCl )  (ppm) = 10.72 (s ,
3
br
H, NH), 7.64–7.56 (m, 2H, H-2‘‘/6‘‘), 7.46–7.34 (m, 8H, Ph), 3.49 (s, 3H, OCH ), 2.96 (s, 3H,
3
13
NCH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 161.3 (C=O), 136.1 (C 5),
3
3
q
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
1
36.0 (C ), 133.4 (C ), 132.0 (C ), 130.3 (2C, Ph), 128.7 (2C, Ph), 128.5 (3C, C2‘‘/6‘‘, Ph),
q q q
1
28.1 (2C, Ph), 127.6 (1C, Ph), 122.0 (C 2), 60.8 (OCH ), 35.0 (NCH ). C4 could not be
q 3 3
127

identified. ESI-HRMS calcd for [C H
IN O  I] 455.0232, found 455.0225.
19
17
2
2
4
-Bromo-N-methoxy-N-methyl-5-(naphthalen-2-yl)-3-phenyl-1H-pyrrole-2-carboxamide
(5d). The title compound was prepared according to the general procedure using
n
N,O-dimethylhydroxylamine hydrochloride (69 mg, 0.71 mmol), BuLi (2.2M in hexane,
0
.64 mL, 1.4 mmol) and 1d (99 mg, 0.24 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 3:2) yielded the title compound (87 mg, 0.20 mmol, 85%) as a colorless
–
1
oil. R = 0.11 (silica, cyclohexane/EtOAc, 2:1). IR (ATR)  (cm ) = 3188, 1730, 1600, 1491,
f
1
1

7
7
462, 1371, 1239, 1093, 1023, 819, 748, 699. H NMR, COSY (400 MHz, CDCl )
3
(ppm) = 10.99 (s , 1H, NH), 8.15 (d, J = 1.7 Hz, 1H, H-1‘‘), 7.88 (d, J = 8.8 Hz, 1H, H-4‘‘),
br
.87–7.84 (m, 2H, Naph), 7.79 (dd, J = 8.5, 1.8 Hz, 1H, H-3‘‘), 7.55–7.44 (m , 2H, Naph), 7.40–
C
13
.28 (m, 5H, Ph), 3.46 (s, 3H, OCH ), 2.95 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6
3
3
MHz, CDCl )  (ppm) = 161.7 (C=O), 134.3 (C ), 133.3 (C ), 133.0 (C ), 132.6 (C ), 130.1 (2C,
3
q
q
q
q
Ph), 129.5 (C 3), 128.4 (2×1C, Naph+C ), 128.1 (2C, Ph), 127.8 (1C), 127.5 (1C), 127.1 (C1‘‘),
q
q
1
26.6 (2C, Naph), 125.5 (C3‘‘), 121.1 (C 2), 97.8 (C 4), 60.7(OCH ), 35.2 (NCH ). One carbon
q q 3 3
7
19
9
+
resonane is missing due to overlap. ESI-HRMS calcd for [C H BrN O + Na] 457.0528,
23
2
2
found 457.0523.
-Bromo-5-(4-fluorophenyl)-N-methoxy-3-(4-methoxyphenyl)-N-methyl-1H-pyrrole-2-
4
carboxamide (5e). The title compound was prepared according to the general procedure using
n
N,O-dimethylhydroxylamine hydrochloride (36 mg, 0.37 mmol), BuLi (2.2M in hexane, 0.3 mL,
0
.66 mmol) and 1e (75 mg, 0.18 mmol). After purification by flash column chromatography
(cyclohexane/EtOAc, 10:1→3:2) 38 mg (91 mol) of ethyl carboxylate 1e could be recovered.
The title compound (34 mg, 78 µmol, 44%, 89% brsm) was obtained as a colorless amorphous
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
–
1
solid. R = 0.09 (silica, cyclohexane/EtOAc, 2:1). IR (ATR)  (cm ) = 3247, 2933, 1714, 1670,
f
1
1

7
2
2
606, 1510, 1252, 1177, 1162, 1032, 838, 732. H NMR, COSY (400 MHz, CDCl )
3
(ppm) = 10.96 (s , 1H, NH), 7.60–7.55 (m, 2H, H-2’’/6’’), 7.30–7.26 (m, 2H, H-2‘/6‘), 7.12–
br
.05 (m, 2H, H-3‘‘/5‘‘), 6.99–6.94 (m, 2H, H-3‘/5‘), 3.86 (s, 3H, OCH ), 3.51 (s, 3H, NOCH ),
3
3
1
3
1
.94 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 162.6 (d, J
=
3
3
C,F
3
48.4 Hz, C 4‘‘), 161.8 (C=O), 159.2 (C 4‘), 131.7 (C 5), 131.1 (C2‘/6‘), 129.8 (d, J = 8.1
q
q
q
C,F
4
Hz, C2‘‘/6‘‘), 128.9 (C 3), 127.3 (d, J = 3.4 Hz, C 1‘‘), 126.4 (C 1‘), 120.7 (C 2), 115.7 (d,
q
C,F
q
q
q
2
JC,F = 21.8 Hz, C3‘‘/5‘‘), 113.7 (C3‘/5‘), 97.5 (C 4), 60.8 (NOCH ), 55.4 (OCH ), 35.5 (NCH ).
q
3
3
3
79
+
ESI-HRMS calcd for [C H BrFN O + H] 433.0563, found 433.0572.
2
0
18
2
3
4
-Bromo-3-(2-chlorophenyl)-5-(4-fluorophenyl)-N-methoxy-N-methyl-1H-pyrrole-2-
carboxamide (5f). The title compound was prepared according to the general procedure using
n
N,O-dimethylhydroxylamine hydrochloride (32 mg, 0.325 mmol), BuLi (2.2M in hexane,
0
.30 mL, 6.6 mmol) and 1f (44 mg, 0.10 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 3:2 und 3:1) yielded the title compound (24 mg, 55 mol, 53%) as a
–1
colorless oil. R = 0.17 (silica, cyclohexane/EtOAc, 3:1). IR (ATR)  (cm ) = 3196, 1608, 1594,
f
1
1

7
569, 1482, 1458, 1437, 1234, 1161, 838, 756. H NMR, COSY (400 MHz, CDCl )
3
(ppm) = 10.00 (s , 1H, NH), 7.77–7.67 (m, 2H, H-2‘‘/6‘‘), 7.53–7.44 (m, 1H, 2-Cl-Ph), 7.37–
br
.26 (m, 3H, 2-Cl-Ph), 7.22–7.11 (m, 2H, H-3‘‘/5‘‘), 3.51 (s, 3H, OCH ), 3.16 (s, 3H, NCH ).
3
3
1
3
C NMR, HSQC, HMBC (100.6 MHz, CDCl )  (ppm) = 162.7 (d, J = 248.9 Hz, C 4’’), 160.7
3
q
(
C=O), 134.3 (C ), 134.2 (C ), 132.2 (1C, 2-Cl-Ph), 131.0 (C 5), 129.5 (d, J = 8.3 Hz, C2’’/6’’),
q q q
1
29.4 (1C, 2-Cl-Ph), 129.1 (1C, 2-Cl-Ph), 128.3 (C 3), 127.0 (d, J = 3.2 Hz, C 1’’), 126.4 (1C, 2-
q q
Cl-Ph), 121.6 (C ), 116.0 (d, J = 21.8 Hz, C3’’/5’’), 99.0 (C 4), 61.5 (OCH ), 34.0 (NCH ).
q
q
3
3
1
9
F NMR (376.3 MHz, CDCl ) δ (ppm) = 113.66 (tt, J = 8.5, 5.5 Hz). ESI-HRMS calcd for
3
79
15
+
[
C H BrClFN O + H] 437.0068, found 437.0066.
1
9
2
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
4
-Bromo-5-(4-chlorophenyl)-N-methoxy-N-methyl-3-(3-nitrophenyl)-1H-pyrrole-2-
carboxamide (5g). The title compound was prepared according to the general procedure using
n
N,O-dimethylhydroxylamine hydrochloride (34 mg, 0.35 mmol), BuLi (2.2M in hexane,
0
.31 mL, 0.68 mmol) and 1g (52 mg, 0.12 mmol). Purification by flash column chromatography
(cyclohexane/EtOAc, 3:2) yielded the title compound (25 mg, 54 µmol, 47%) as a yellow oil.
–1
R = 0.10 (silica, cyclohexane/EtOAc, 2:1). IR (ATR) (cm ) = 3189, 1620, 1534, 1517, 1478,
f
1
1
442, 1347, 1092, 832, 754, 726. H NMR, COSY (400 MHz, CDCl )  (ppm) = 10.67 (s , 1H,
3
br
NH), 8.23–8.19 (m, 2H, H-2‘, H-4‘), 7.67–7.54 (m, 4H, H-5‘, H-6‘, Ph‘), 7.45–7.40 (m, 2H,
13
Ph‘),3.52 (s, 3H, OCH ), 3.11 (s, 3H, NCH ). C NMR, HSQC, HMBC (100.6 MHz, CDCl ) 
3
3
3
(
ppm) = 160.7 (C=O), 148.0 (C 3‘), 136.1 (C C6‘), 134.7 (C ), 131.4 (C ), 129.1 (2×2C,
q
q
q
q
C2‘‘/3‘‘/5‘‘/6‘‘), 128.9 (C C5‘), 128.1 (C 3), 124.9 (C2‘), 122.4 (C4‘), 121.3 (C 2), 97.9 (C 4),
q
q
q
q
6
1.4 (NOCH ), 34.1 (NCH ). One carbon resonance missing due to overlap. ESI-HRMS calcd for
3 3
79
+
[
C H BrClN O + Na] 485.9832, found 485.9836.
19 15 3 4
1
-(3,5-Diphenyl-1H-pyrrol-2-yl)-N-methoxy-N-methylmethanamine (8). In a Schlenk flask 5a
(31 mg, 0.10 mmol, 1.0 equivequiv) was put under argon, dissolved in dry THF (2 mL) and
cooled to –78 °C. Lithium aluminum hydride (2M in THF, 0.05 mL, 0.1 mmol, 1 equivequiv) was
added and the reaction mixture stirred for 20 minmin at –78 °C, then slowly warmed to room
temperature. After stirring a room temperature for 1.5 h the reaction was quenched with 1N
aqueous NaOH and extracted with ethyl acetate. The combined organic phases were washed with
brine, dried with MgSO4 and concentrated in vacuo. Purification by flash column
chromatography (cylcohexane/EtOAc, 10:1) yielded the title compound (24 mg, 82 mol, 82%)
–1
as a light pink oil. R = 0.31 (silica, cyclohexane/EtOAc, 2:1). IR (ATR) (cm ) = 3436, 1607,
f
1
1
497, 1454, 1440, 1350, 1075, 1044, 1007, 810, 758, 699. H NMR, COSY (400 MHz, DMSO-
d6)  (ppm) = 11.30 (s, 1H, NH), 7.72 (d, J = 7.6 Hz, 2H, H-2‘‘/6‘‘), 7.66 (d, J = 7.7 Hz, 2H,
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European Journal of Organic Chemistry
10.1002/ejoc.201700773
H-2‘/6‘), 7.36 (t, J = 7.7 Hz, 4H, H-3‘/5‘/3‘‘/5‘‘), 7.22–7.14 (m, 2H, H-4‘/4‘‘), 6.74 (d, J =
1
3
2
.8 Hz, 1H, H-4), 3.86 (s, 2H, CH ), 3.35 (s, 3H, OCH ), 2.57 (s, 3H, NCH ). C NMR, HSQC,
2 3 3
HMBC (100.6 MHz, DMSO-d )  (ppm) = 136.5, 132.5 (C1‘, C1‘‘), 130.6 (C5), 128.7
6
(
(
[
C3‘‘/5‘‘), 128.3 (C3‘/5‘), 127.4 (C2‘/6‘), 125.6 (2C, C2/4‘‘), 125.2 (C4‘), 123.9 (C3), 123.6
C2‘‘/6‘‘), 105.6 (C4), 59.3 (OCH ), 55.2 (CH ), 44.5 (NCH ). ESI-HRMS calcd for
3
2
3
+
C H N O – N(CH )OCH ] 232.1121, found 232.1126.
1
9
20
2
3
3
General procedure for the synthesis of pyrrole-2-carbaldehydes 7a–g from Weinreb
amides. A Schlenk flask was charged with Weinreb amide under argon, dry THF (ca.
2
mL/0.1 mmol) was added and the solution was cooled to 78 °C. Lithium aluminum hydride
(solution in THF, 0.6 equiv) was slowly added. When conversion was completed, the reaction
was cooled to 0 °C, quenched with 1N aqueous NaOH and extracted with ethyl acetate. The
combined organic phases were washed with brine, dried with MgSO and concentrated in vacuo.
4
Flash column chromatography yields the desired product.
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