Passerini/tsuji–trost strategy towards pyrrole derivatives

Article abstract of DOI:10.1002/ejoc.201700653

The Passerini reaction of α,β-unsaturated aldehydes affords suitable substrates for a Tsuji–Trost reaction with NH-enamines. The latter behave as a 1,3-bisnucleophile, which leads to the formation of pyrrole derivatives with five points of diversity through a Tsuji–Trost/Michael addition/aromatization cascade.

Full text of DOI:10.1002/ejoc.201700653

A Journal of
Accepted Article
Title: Passerini/Tsuji-Trost strategy towards pyrrole derivatives
Authors: laurent El Kaim and Noisette Narboni
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European Journal of Organic Chemistry
10.1002/ejoc.201700653
COMMUNICATION
Passerini/Tsuji-Trost strategy towards pyrrole derivatives
[a]
Noisette Narboni and Laurent El Kaim,*
[a]
Abstract: The Passerini reaction of α,β-unsaturated aldehydes
affords suitable substrates for a Tsuji-Trost reaction with NH-
enamines. The latter behave as a 1,3-bisnucleophile leading to
pyrrole derivatives with 5 points of diversity through a Tsuji-
Trost/Michael addition/aromatization cascade.
Introduction
Isocyanides are mostly known in organic synthesis for their
[1]
involvement in the Ugi and Passerini reactions. Even though
the Passerini coupling was discovered nearly forty years before
its Ugi extension, it has been the object of a reduced number of
studies probably due to its lower diversity and efficiency. Indeed,
its three component nature together with a more difficult
electrophilic activation of the aldehydes compared to their
related imines in the Ugi reactions may explain the lower interest
[
2]
of the chemists community for this reaction.
Scheme 1. Tsuji-Trost reactions on Passerini adducts.
However, Passerini adducts has found interesting specific
applications such as the potential transformations of the newly
formed ester moiety as highlighted in the Passerini Amine
[
3]
Deprotection-Acyl Migration (PADAM) protocole. Recently, we
disclosed the use of Passerini adducts of cinnamaldehyde
derivatives in various Tsuji-Trost reactions. Following a first
Passerini/reduction cascade using formic acid as acidic
Tsuji-Trost type allylations of enamine derivatives have been
the object of a limited number of studies mainly focused on
enantioselective couplings. In the case of NH enamines,
allylation with simple allylic derivatives was observed on the β-
carbon nucleophilic position without any attack on nitrogen. To
evaluate the feasibility of our project, we selected enamine 2a
obtained from methyl acetoacetate and aniline due to its stability
and easy preparation under Lewis acid triggered conditions.
When an equimolar mixture of 2a and Passerini adduct 1a
(obtained from cinnamaldehyde, tert-butylisocyanide and acetic
acid under solvent free conditions in 73 % yield) was treated
[
4]
component in the Passerini step, we applied these Tsuji-Trost
transformations of Passerini adducts to the formation of cyclic
derivatives by the use of 1,3-bisnucleophiles such as
[
5]
[6]
bismalonates
or hydrazones (Scheme 1).
Stimulated by
these results we now wish to present the use of enamines in a
new approach toward pyrroles (Scheme 1).
2 3
with a Pd(OAc) /PPh couple in toluene under microwave
conditions, we observed the formation of the new pyrrole 3a in
moderate 54% isolated yield (Scheme 2).
Results and Discussion
When 1,3 bis-malonates are used as nucleophiles in Tsuji-
Trost reaction of cinnamaldehyde Passerini adducts,
the
synthetic sequence towards cyclopentane starts with a Tsuji-
Trost addition at the γ position of the amide followed by an
intramolecular Michael addition of the resulting α,β-unsaturated
amide. In the case of N-arylhydrazones, a more complex
cascade is settled taking advantage of the azaenamine
behaviour of hydrazones. Enamines prepared from primary
amines could behave as well as 1,3 bis-nucleophiles in a related
strategy towards hydropyrroles.
[a]
L. El Kaim, N. Narboni
Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique,
ENSTA ParisTech- UMR 7652, Université Paris-Saclay, 828 Bd des
Maréchaux, 91128 Palaiseau. France.
E-mail: laurent.elkaim@ensta-paristech.fr;
Scheme 2. Optimization toward the pyrrole 3a.
Supporting information for this article is given via a link at the end of
the document.
At this stage of the study, the structure was proposed
assuming a behavior close to the one observed in the Tsuji-
Trost reaction of Passerini adduct 1a with hydrazone. C13 and
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European Journal of Organic Chemistry
10.1002/ejoc.201700653
COMMUNICATION
proton NMR data as well as NOESY experiments were not
conclusive enough to conclude on the regioselectivity of the
reaction between 1a and 2a.
We went further on the
optimization of reaction expecting that related compounds
obtained later in the study would furnish better structural
indications. Slightly lower temperature under thermal conditions
3
(
toluene reflux) gave a much lower yield as well as working at
0°C with a Pd dba /PPh couple (Scheme 2). Changing the
5
2
3
3
phosphine allowed to improve the reaction conditions with dppe
giving the highest 65% yield. Surprisingly best yields were
obtained with a slightly higher Pd/phosphine ratio than observed
in the standard conditions for Tsuji-Trost type reactions. The
4
2
use of Pd(OAc) (5 mol%)/dppe (5 mol%) in toluene under
microwave conditions at 120°C was finally selected for the
examples performed with the various Passerini adducts 1 and
enamines 2 displayed in Table 1.
When acetic acid was replaced by pivalic acid (Table 1, entry
1), the resulting Passerini adduct 1a’ afforded pyrrole 3a in
comparable yield. However, as the first Passerini step was much
less efficient with pivalic acid, acetic acid was preferred for all
other examples. Overall, the yields are good to moderate. The
reaction is not limited to enamines derived from anilines as
shown by the formation of pyrroles 3f and 3g (Table 1, entries 6,
5
7) obtained from benzyl amine and thiophenylmethylamines.
Tert-butyl isocyanide may be replaced by p-methoxybenzyl
isocyanide leading to a slightly lower yield in the pyrrole
formation (Table 1, entry 4). Various 3-aryl and heteroaryl
pyrroles were obtained changing the aryl moiety of the
cinnamaldehyde Passerini partner (Table 1, entries 2, 3, 5).
Whereas β-ketoesters derived enamines afforded pyrroles in
reasonable yields, β-diketones were not suitable for this cascade
leading to poor yield of ketopyrrole (Table 1, entry 8).
Rewardingly pyrrole 3f gave us conclusive NOESY correlation
6
7
2
between the two CH groups of the molecule confirming the
proposed structures for pyrroles 3a to 3h.
Table 1. Pyrrole synthesis through Tsuji-Trost/oxidation cascade.
8
Entry
Passerini
Enamine
Pyrrole
Following our previous reports on Tsuji-Trost reactions of
Passerini adducts, we can propose a three-step mechanism for
this new pyrrole formation from enamines (Scheme 3).
Formation of palladium(0) is followed by the generation of a π-
allyl palladium intermediate A from Passerini adduct 1. The latter
is attacked by the enamines 2 at the γ position of the amide as
observed for malonate addition on the same compound. The
resulting imine B rearrange to enamine C which undergo an
1
[
7]
intramolecular Michael addition to afford the dihydropyrrole D.
2
In opposition to what was observed in the Passerini conversion
to dihydropyrazole, D is not stable in the medium and undergo a
final oxidation to pyrrole 3 in agreement with similar redox
processes observed in the literature.
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European Journal of Organic Chemistry
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COMMUNICATION
[
5]
General procedure A for Passerini reaction: A mixture of aldehyde
1.0 equiv), acid (1.0 equiv) and isocyanide (1.0 equiv) was stirred under
(
argon at room temperature for 2 days. The crude was purified by flash
chromatography on silica gel.
[
14]
General procedure B for enamine synthesis: A mixture of carbonyle
derivative (1.0 equiv), amine (1.0 equiv) and zinc triflate (20 mol%) was
stirred at room temperature for 15min. the crude was purified by flash
chromatography on silica gel with AcOEt/EP (20/80) as eluant.
Scheme 3. Proposed mechanism for the pyrrole formation.
General procedure C for pyrrole synthesis: To a 0.25 M solution of
Passerini adduct 1 (1.0 equiv) in toluene were added enamine 2 (1.0
2 3 2
equiv), Cs CO (1.2 equiv), dppe (5 mol%) and Pd(OAc) (5 mol%). The
resulting mixture was hated under microwave at 120°C during 30 minutes.
The solvent was removed afterwards under reduced pressure and the
crude was purified by flash chromatography on silica gel.
Compared to indoles, their benzofused derivatives, the
applications of pyrroles in medicinal chemistry may be
considered rather limited. However pyrroles may be found in
various natural compounds and many uses of pyrroles as
anticancer, antitubercular or anti-inflammatory agents are
(E)-1-(tert-butylamino)-1-oxo-4-phenylbut-3-en-2-yl pivalate (1a'):
Compound 1a' was prepared according to general procedure A starting
from 264mg (2mmol, 1equiv) trans-cinnamaldehyde, 1equiv (2mmol) tert-
butyl isocyanide and 1equiv (2mmol) pivalic acid. Purification by flash
chromatography with a gradient AcOEt/EP (10/90 to 30/70) gave the
[8]
reported in the literature. In particular, families of pyrroles with
similar structural patterns as the products prepared in our study
have shown potential as cytosolic phospholipase A2 inhibitor (4,
[
9]
[10]
scheme 4),
histone deacetylase inhibitor (5, Scheme 4) or
[11]
prostaglandin synthetase inhibitor (6, Scheme 4). Numerous
synthetic approaches have been proposed for pyrroles since
their first preparation at the end of the XIX century with
enamines being key components as shown by their involvement
1
desired product (190mg, 30%) as a white solid. Mp 110°C ; H-NMR
(
CDCl
3
, 400 MHz) (δ, ppm) 7.44 (d, J = 7.6 Hz, 2H, HAr), 7.36 (t, J = 7.4
Hz, 2H, HAr), 7.31 (d, J = 5.6 Hz, 1H, HAr), 6.73 (d, J = 16.1 Hz, 1H),
6
1
.35 (dd, J = 16.0, 6.3 Hz, 1H), 5.95 (s, 1H, NH), 5.71 (d, J = 6.3 Hz, 1H),
13
.42 (s, 9H, tBu(C=O)), 1.35 (s, 9H, tBuNH) ; C-NMR (CDCl , 100.6
3
[
12]
in Hantzsch pyrrole synthesis.
palladium catalyzed process in particular are well represented
Organometallic chemistry and
MHz) (δ, ppm) 176.42 (Cq, OC=O), 167.42 (Cq, NC=O), 135.88 (Cq,
CAr), 133.78 (CH), 128.59 (2CH, CAr), 128.29 (CH, CAr), 126.83 (2CH,
[
13]
among modern accesses to these scaffolds.
CAr), 123.04 (CH), 74.17 (CH), 51.41 (Cq, tBu(C=O)), 38.89 (Cq, tBuNH),
-1
Me
N
Me
N
Ph
N
2
8.72 (3CH , tBu(C=O)), 27.16 (3CH
3
3
, tBuNH) ; IR (ν, cm ) 3320, 2967,
Me
O
Me
O
OH
CONHOH
OH
1731, 1668, 1518, 1478, 1450, 1393, 1364, 1272, 1223, 1126, 964 ;
HRMS (EI) Calcd. for C19 : 317.1991 found : 317.1979
O
O
H27NO
3
Me
C17H35
O
Me
C11H23
4
5
6
Ph
(
E)-1-(tert-butylamino)-4-(furan-2-yl)-1-oxobut-3-en-2-yl acetate (1b):
Compound 1b was prepared according to general procedure A starting
Scheme 4. Some biologically relevant pyrrole derivatives.
from 366mg (3mmol, 1equiv) (2E)-3-(furan-2-yl)prop-2-enal, 1equiv
(
3mmol) tert-butyl isocyanide and 1equiv (3mmol) acetic acid. Purification
by flash chromatography with a gradient AcOEt/EP (10/90 to 30/70) gave
Conclusion
the desired product (643mg, 81%) as a brown solid. Mp 119 - 120°C ;
1
H-NMR (CDCl , 400 MHz) (δ, ppm) 7.36 (s, 1H, HFur), 6.53 (d, J = 15.8
3
As a conclusion, we have disclosed a new three-steps, one-
pot synthesis of pyrroles starting from Passerini adduct and
enamines derivatives. Both starting materials were prepared
under neat conditions making the sequence even more
appealing. Overall the process allow the preparation of pyrroles
with five points of diversity, the scaffold obtained being close to
some biologically relevant compounds. Further optimization will
be required to raise the diversity of the enamine partner in
particular for cyclohexanone derivatives which might afford an
interesting route towards indoles.
Hz, 1H), 6.37 (s, 1H), 6.32 (s, 1H), 6.15 (dd, J = 15.8, 7.0 Hz, 1H), 5.82
(
s, 1H, NH), 5.58 (d, J = 7.0 Hz, 1H), 2.19 (s, 3H, Me), 1.37 (s, 9H, tBu) ;
13
C-NMR (CDCl
NC=O), 151.4 (Cq), 142.7 (CH), 122.8 (CH), 121.1 (CH), 111.5 (CH),
09.8 (CH), 74.5 (CH), 51.6 (Cq, tBu), 28.7 (3CH , tBu), 21.1 (CH , Me) ;
IR (ν, cm ) 3291, 3080, 2966, 1741, 1661, 1487, 1364, 1218, 1012,
59 ; HRMS (EI) Calcd. for C14 : 265.1314 found : 265,1310
3
, 100.6 MHz) (δ, ppm) 169.2 (Cq, OC=O), 167.0 (Cq,
1
3
3
-1
9
H19NO
4
(
E)-1-(tert-butylamino)-4-(2-nitrophenyl)-1-oxobut-3-en-2-yl acetate
(1e): Compound 1e was prepared according to general procedure A
starting from 354mg (2mmol, 1equiv) of (2E)-3-(2-nitrophenyl)prop-2-enal,
1equiv (2mmol) of tert-butyl isocyanide and 1equiv (2mmol) of acetic acid.
Purification by flash chromatography with a gradient AcOEt/EP (10/90 to
1
0/70) gave the desired product (403mg, 63%) as a yellow oil. H-NMR
3
Experimental Section
(
CDCl , 400 MHz) (δ, ppm) 7.98 (d, J = 8.3 Hz, 1H, HAr), 7.67 - 7.56 (m,
3
2
=
3
1
H, HAr), 7.49 - 7.37 (m, 1H, HAr), 7.15 (d, J = 15.9 Hz, 1H), 6.33 (dd, J
General Methods: Commercially available reagents and solvents were
15.9, 5.9 Hz, 1H), 5.93 (s, 1H, NH), 5.69 (d, J = 5.9 Hz, 1H), 2.24 (s,
13
H, Me), 1.38 (s, 9H, tBu) ; C-NMR (CDCl , 100.6 MHz) (δ, ppm)
3
1
13
used without further purification. H and C NMR were recorded on a
Bruker Avance 300 and 400 MHz. Chemical shifts (δ) are reported in part
per million (ppm) relative to internal TMS. High-Resolution Mass spectra
69.16 (Cq, OC=O), 166.47 (Cq, NC=O), 147.73 (Cq, CAr), 133.46 (CH,
CAr), 131.87 (Cq, CAr), 129.07 (CH, CAr), 128.83 (CH, CAr), 128.71
(
HRMS) were carried out with JEOL JMSGCmateII spectrometer. IR
(
(
CH), 128.58 (CH), 124.74 (CH, CAr), 73.89 (CH), 51.76 (Cq, tBu), 28.68
-1
spectra were performed on a Perkin-Elmer FT 1600 spectrometer with
3CH
3 3
, tBu), 21.03 (CH , Me) ; IR (ν, cm ) 3312, 3073, 2969, 1742,
-1
wavelengths in cm . Column chromatography was performed on silica
gel (70–230 mesh ASTM) using the reported eluents. Thin layer
1
666, 1519, 1343, 1217, 1100, 1042, 965 ; HRMS (EI) Calcd. for
C
16 20 2
H N O
5
: 320.1372 found : no pic found
chromatography (TLC) was performed using plates of silica 60 F254
.
Melting points (Mp) were determined on a Stuart SMP3 apparatus and
(
Z)-methyl
3-((thiophen-2-ylmethyl)amino)but-2-enoate
(2c):
[
were left uncorrected. Products 1a, 1c, 1d, have been prepared
5]
[5]
[5]
Compound 2c was prepared according general procedure B starting from
23µL (3mmol, 1 equiv) of methyl acetoacetate and 1equiv (3mmol) 2-
[
following the procedure described in the literature as well as 2a, 2b
14]
[14]
,
3
[
14]
and 2d
.
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European Journal of Organic Chemistry
10.1002/ejoc.201700653
COMMUNICATION
1
thenylamine. Purification afforded 562mg of colorless oil (89% yield). H-
-1
cm ) 3301, 2931, 1660, 1511, 1447, 1287, 1244, 1159, 1083, 1033 ;
HRMS (EI) Calcd. for C27 : 468.2049 found : 468,2060
NMR (CDCl
3
, 400 MHz) (δ, ppm) 8.90 (s, 1H, NH), 7.22 (d, J = 4.3 Hz,
), 4.54 (s, 1H), 3.63 (s, 3H,
, 100.6 MHz) (δ, ppm) 170.8
Cq, C=O), 161.2 (Cq), 142.0 (Cq), 127.0 (CH), 124.9 (CH), 124.8 (CH),
32 2 4
H N O
1
H), 6.94 (s, 2H), 4.58 (d, J = 6.2 Hz, 2H, CH
2
13
OMe), 1.97 (s, 3H, Me) ; C-NMR (CDCl
3
Methyl 5-(2-(tert-butylamino)-2-oxoethyl)-2-methyl-4-(2-nitrophenyl)-
-phenyl-1H-pyrrole-3-carboxylate (3e): Compound 3e was prepared
(
1
-
1
8
3.4 (CH), 50.09 (CH
289, 3104, 2945, 1650, 1595, 1433, 1238, 1169, 1096, 1007, 929 ;
S : 211.0667 found : 211.0666
3 2 3
, OMe), 42.08 (CH ), 19.31 (CH , Me) ; IR (ν, cm )
according general procedure C starting from 100mg (0.31mmol, 1 equiv)
3
of 1e and 1equiv (0.31mmol) of 2a. Purification by flash chromatography
HRMS (EI) Calcd. for C10H13NO
2
with a gradient Et
2
O/EP (10/90 to 30/70) gave the desired product (51mg,
1
3
5%) as a yellow oil. H-NMR (CDCl , 400 MHz) (δ, ppm) 8.06 (d, J = 9.1
3
Methyl 5-(2-(tert-butylamino)-2-oxoethyl)-2-methyl-1,4-diphenyl-1H-
pyrrole-3-carboxylate (3a): Compound 3a was prepared according
general procedure C starting from 100mg (0.36mmol, 1equiv) of 1a and
Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.54 - 7.45 (m, 4H), 7.39 - 7.32 (m, 2H),
7.25 - 7.24 (m, 1H), 5.75 (s, 1H), 3.55 (s, 3H), 3.22 (dd, J = 132.8, 17.3
13
3
Hz, 2H), 2.33 (s, 3H), 1.17 (s, 9H) ; C-NMR (CDCl , 100.6 MHz) (δ,
1
equiv (0.36mmol) of 2a. Purification by flash chromatography with a
gradient Et O/EP (10/90 to 30/70) gave the desired product (96mg, 65%)
as a yellow oil. H-NMR (CDCl
ppm) 167.98 (Cq), 165.16 (Cq), 150.22 (Cq), 138.38 (Cq), 136.45 (Cq),
133.02 (CH), 132.97 (CH), 130.91 (Cq), 129.85 (CH), 129.69 (CH),
129.52 (CH), 128.53 (CH), 128.27(CH), 128.15(CH), 124.51 (Cq),
2
1
3
, 400 MHz) (δ, ppm) 7.54 - 7.45 (m, 3H),
.41 - 7.28 (m, 6H), 7.24 (s, J = 6.4 Hz, 1H), 5.07 (s, 1H), 3.62 (s, 3H),
7
3
124.27(CH), 121.20 (Cq), 110.21 (Cq), 51.31 (Cq), 50.73 (CH
3
), 34.15
) ; IR (ν, cm ) 3328, 2965, 1700, 1658,
1525, 1450, 1362, 1280, 1225, 1194, 1162, 1093 ; HRMS (EI) Calcd. for
13
-1
.14 (s, 2H), 2.32 (s, 3H), 1.16 (s, 9H) ; C-NMR (CDCl
3
, 100.6 MHz) (δ,
2 3 3
(CH ), 28.47 (3CH ), 12.93 (CH
ppm) 168.33 (Cq), 166.11 (Cq), 137.31 (Cq), 136.91 (Cq), 135.51 (Cq),
1
1
30.08 (2CH), 129.63 (2CH), 129.20 (CH), 128.52 (2CH), 127.91 (2CH),
26.69 (CH), 125.05 (Cq), 124.98 (Cq), 111.27 (Cq), 51.07 (Cq), 50.65
C
25
H
27
N
3
O
5
} : 449.1951 found : 449.1938
-
1
(
CH
3
), 34.08 (CH
963, 1655, 1505, 1448, 1363, 1264, 1240, 1221, 1193, 1082 ; HRMS
: 404.2100 found : 404,2107
2 3 3
), 28.53 (3CH ), 12.90 (CH ) ; IR (ν, cm ) 3335, 3055,
Methyl
1-benzyl-5-(2-(tert-butylamino)-2-oxoethyl)-2-methyl-4-
2
phenyl-1H-pyrrole-3-carboxylate (3f): Compound 3f was prepared
according general procedure C starting from 100mg (0.36mmol, 1 equiv)
of 1a and 1equiv (0.36mmol) of 2b. Purification by flash chromatography
(
EI) Calcd. for C25
28 2
H N O
3
Methyl 5-(2-(tert-butylamino)-2-oxoethyl)-4-(furan-2-yl)-2-methyl-1-
phenyl-1H-pyrrole-3-carboxylate (3b): Compound 3b was prepared
according general procedure C starting from 100mg (0.38mmol, 1equiv)
of 1b and 1equiv (0.38mmol) of 2a. Purification by flash chromatography
with a gradient Et
51%) as a yellow oil. H-NMR (CDCl
8H), 6.93 (d, J = 7.4 Hz, 2H), 5.27 (s, 2H, CH
2
O/EP (10/90 to 30/70) gave the desired product (77mg,
1
3
, 400 MHz) (δ, ppm) 7.40 - 7.21 (m,
), 5.02 (s, 1H), 3.58 (s, 3H),
3.20 (s, 2H), 2.51 (s, 3H), 1.15 (s, 9H) ; C-NMR (CDCl , 100.6 MHz) (δ,
2
13
3
with a gradient Et
2
O/EP (10/90 to 30/70) gave the desired product (90mg,
ppm) 168.78 (Cq), 166.08 (Cq), 136.74 (Cq), 136.67 (Cq), 136.01 (Cq),
1
1%) as a yellow oil. H-NMR (CDCl
6
3
2
3
, 400 MHz) (δ, ppm) 7.54 - 7.47 (m,
130.24 (2CH), 129.00 (2CH), 127.91 (2CH), 127.57 (CH), 126.69 (CH),
H), 7.46 (dt, J = 7.1, 3.5 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.50 - 6.45 (m,
125.65 (2CH), 125.04 (Cq), 124.52 (Cq), 111.10 (Cq), 51.22 (CH
(Cq), 47.29 (CH ), 34.05 (CH ), 28.53 (3CH ), 11.81 (CH ) ; IR (ν, cm )
3330, 2965, 1651, 1527, 1448, 1267, 1225, 1162, 1095, 1069 ; HRMS
(EI) Calcd. for C26 : 418.2256 found : 418,2258
3
), 50.56
-
1
H), 5.42 (s, 1H), 3.76 (s, 3H), 3.25 (s, 2H), 2.28 (s, 3H), 1.22 (s, 9H) ;
2
2
3
3
1
3
C-NMR (CDCl
3
, 100.6 MHz) (δ, ppm) 168.24 (Cq), 165.64 (Cq), 148.27
(
Cq), 141.55 (CH), 137.60 (Cq), 136.50 (Cq), 129.73 (2CH), 129.43 (CH),
30 2 3
H N O
1
28.35 (2CH), 127.25 (Cq), 114.14 (Cq), 111.16 (Cq), 110.97 (CH),
08.97 (CH), 51.12 (Cq), 51.01 (CH ), 34.99 (CH ), 28.58 (3CH ), 12.91
) ; IR (ν, cm ) 3328, 2926, 1661, 1498, 1392, 1416, 1364, 1222,
085 ; HRMS (EI) Calcd. for C23 : 394.1893 found : 394,1900
1
3
2
3
Methyl
thiophen-2-ylmethyl)-1H-pyrrole-3-carboxylate (3g): Compound 3g
was prepared according general procedure C starting from 100mg
0.36mmol, 1 equiv) of 1a and 1equiv (0.36mmol) of 2c. Purification by
flash chromatography with a gradient Et O/EP (10/90 to 30/70) gave the
desired product (68mg, 44%) as a yellow oil. H-NMR (CDCl
5-(2-(tert-butylamino)-2-oxoethyl)-2-methyl-4-phenyl-1-
-1
(
CH
3
(
1
26 2 4
H N O
(
Methyl
5-(2-(tert-butylamino)-2-oxoethyl)-4-(4-methoxyphenyl)-2-
2
1
methyl-1-phenyl-1H-pyrrole-3-carboxylate (3c): Compound 3c was
3
, 400 MHz)
prepared according general procedure C starting from 100mg (0.33mmol,
(δ, ppm) 7.36 (t, J = 7.2 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 7.25 - 7.20 (m,
3H), 6.94 (dd, J = 5.1, 3.5 Hz, 1H), 6.81 - 6.73 (m, 1H), 5.40 (s, 2H), 5.01
1
equiv) of 1c and 1equiv (0.33mmol) of 2a. Purification by flash
chromatography with a gradient Et O/EP (10/90 to 30/70) gave the
desired product (86mg, 60%) as a yellow oil. H-NMR (CDCl
13
2
(s, 1H), 3.57 (s, 3H), 3.30 (s, 2H), 2.61 (s, 3H), 1.17 (s, 9H) ; C-NMR
(CDCl , 100.6 MHz) (δ, ppm) 168.79 (Cq), 165.98 (Cq), 139.80 (Cq),
1
3
, 400 MHz)
δ, ppm) 7.45 - 7.39 (m, 3H), 7.19 - 7.15 (m, 4H), 6.87 - 6.82 (m, 1H),
3
(
136.23 (Cq), 135.94 (Cq), 130.24 (2CH), 128.77 (Cq), 127.89 (2CH),
127.14 (CH), 126.71 (CH), 125.21 (CH), 125.04 (CH), 124.15 (Cq),
5
9
1
1
1
.02 (s, 1H), 3.77 (s, 3H), 3.57 (s, 3H), 3.07 (s, 2H), 2.25 (s, 3H), 1.10 (s,
13
H) ; C-NMR (CDCl
3
, 100.6 MHz) (δ, ppm) 168.41 (Cq), 166.15 (Cq),
111.29 (Cq), 51.25 (Cq), 50.56 (CH ), 43.19 (CH
3
2 2
), 34.05 (CH ), 28.54
-
1
58.41 (Cq), 137.15 (Cq), 136.99 (Cq), 131.14 (2CH), 129.60 (2CH),
29.15 (CH), 128.51 (2CH), 127.68 (Cq), 125.06 (Cq), 124.63 (Cq),
(3CH ), 11.83 (CH ) ; IR (ν, cm ) 3341, 2963, 1655, 1526, 1449, 1408,
3
3
28 2 3
1364, 1194, 1070 ; HRMS (EI) Calcd. for C24H N O S : 424.1821 found :
13.38 (2CH), 111.31 (Cq), 55.27 (CH
), 28.56 (3CH ), 12.95 (CH ) ; IR (ν, cm ) 3331, 3061, 2963, 1656,
439, 1392, 1363, 1288, 1241, 1160, 1082, 1029 ; HRMS (EI) Calcd. for
3
), 51.05 (Cq), 50.65 (CH
3
), 34.11
424,1824
-
1
(
CH
2
3
3
1
2-(4-acetyl-5-methyl-1,3-diphenyl-1H-pyrrol-2-yl)-N-(tert-
C
26
H
30
2
N O
4
: 434.2206 found : 434,2195
butyl)acetamide (3h): Compound 3h was prepared according general
procedure C starting from 100mg (0.36mmol, 1 equiv) of 1a and 1equiv
(0.36mmol) of 2d. Purification by flash chromatography with a gradient
Methyl
5-(2-((4-methoxybenzyl)amino)-2-oxoethyl)-2-methyl-1,4-
diphenyl-1H-pyrrole-3-carboxylate (3d): Compound 3d was prepared
according general procedure C starting from 100mg (0.29mmol, 1 equiv)
of 1d and 1equiv (0.29mmol) of 2a. Purification by flash chromatography
Et
yellow oil. H-NMR (CDCl
7.37 - 7.25 (m, 6H), 7.19 (d, J = 6.2 Hz, 2H), 4.96 (s, 1H), 3.03 (s, 2H),
2
O/EP (10/90 to 30/70) gave the desired product (27mg, 20%) as
1
3
, 400 MHz) (δ, ppm) 7.42 (d, J = 6.3 Hz, 2H),
13
with a gradient AcOEt/EP (10/90 to 20/80) gave the desired product
1
66mg, 48%) as a yellow oil. H-NMR (CDCl
3
2.22 (s, 3H), 1.86 (s, 3H), 1.10 (s, 9H) ; C-NMR (CDCl , 100.6 MHz) (δ,
ppm) 197.35 (Cq), 168.33 (Cq), 136.79 (Cq), 136.38 (Cq), 135.99 (Cq),
(
3
, 400 MHz) (δ, ppm) 7.37 (d,
J = 6.2 Hz, 2H), 7.27 - 7.15 (m, 6H), 7.07 (d, J = 7.4 Hz, 2H), 6.97 (d, J =
130.32 (2CH), 129.63 (2CH), 129.18 (CH), 128.62 (2CH), 128.44 (2CH),
7
2
.2 Hz, 2H), 6.77 (d, J = 7.0 Hz, 2H), 5.53 (s, 1H), 4.12 (d, J = 5.5 Hz,
127.31 (CH), 124.79 (Cq), 124.61 (Cq), 122.04 (Cq), 51.13 (Cq), 34.01
-1
13
H), 3.74 (s, 3H), 3.53 (s, 3H), 3.19 (s, 2H), 2.21 (s, 3H) ; C-NMR
, 100.6 MHz) (δ, ppm) 169.13 (Cq), 166.00 (Cq), 159.08 (Cq),
(CH
2
), 31.05 (CH ), 28.56 (3CH
3
3
), 13.11 (CH
3
) ; IR (ν, cm ) 3315, 3060,
(
CDCl
3
2963, 2925, 1650, 1496, 1362, 1224, 1157, 1028, 954 ; HRMS (EI) Calcd.
for C25 : 388.2151 found : 388,2139
1
1
1
5
37.50 (Cq), 136.76 (Cq), 135.20 (Cq), 129.99 (2CH), 129.70 (2CH),
29.36 (2CH), 129.23 (Cq), 128.40 (2CH), 127.91 (2CH), 126.73 (CH),
25.42 (Cq), 124.33 (CH), 114.12 (Cq), 114.01 (2CH), 111.40 (Cq),
28 2 2
H N O
3 3 2 2 3
5.38 (CH ), 50.67 (CH ), 43.12 (CH ), 33.08 (CH ), 12.83 (CH ) ; IR (ν,
Acknowledgements
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700653
COMMUNICATION
We thank ENSTA ParisTech and the Direction Générale de
l’Armement for financial support.
We thank Dina Boyarskaya et Paula Martin Moyano for their
help during an internship in our group.
Keywords: pyrrole • Passerini • Tsuji-Trost • enamine •
multicomponent
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European Journal of Organic Chemistry
10.1002/ejoc.201700653
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Multicomponent reactions
Laurent El Kaim, Noisette Narboni
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Passerini/Tsuji-Trost strategy
towards pyrroles derivatives
New Tsuji-Trost coupling between Passerini adducts and enamines:
multicomponent access to pyrroles presenting five points of variation.
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