Silver-Catalyzed Cascade Reaction of β-Enaminones and Isocyanoacetates to Construct Functionalized Pyrroles

Article abstract of DOI:10.1021/acs.orglett.7b00201

An unexpected silver-catalyzed cascade reaction of β-enaminones and isocyanoacetates affording functionalized pyrrole derivatives is reported. In this reaction, tautomeric equilibria of β-enaminones are utilized to generate imine partners in situ. A hypothesized sequential Mannich addition/cyclization of imine tautomers and isocyanoacetates followed by an unprecedented ring-opening of the resultant 2-imidazolines and dehydration-condensation deliver the final 1,2,4,5-tetrasubstituted pyrrole products.

Full text of DOI:10.1021/acs.orglett.7b00201

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Cascade Reaction of β‑Enaminones and
Isocyanoacetates To Construct Functionalized Pyrroles
Guichun Fang,†,∥ Jianquan Liu,†,§,∥ Junkai Fu,*,† Qun Liu,† and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
§School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu
Normal University, Xuzhou 221116, China
S
* Supporting Information
ABSTRACT: An unexpected silver-catalyzed cascade reaction
of β-enaminones and isocyanoacetates affording functionalized
pyrrole derivatives is reported. In this reaction, tautomeric
equilibria of β-enaminones are utilized to generate imine
partners in situ. A hypothesized sequential Mannich addition/
cyclization of imine tautomers and isocyanoacetates followed by
an unprecedented ring-opening of the resultant 2-imidazolines
and dehydration−condensation deliver the final 1,2,4,5-tetrasub-
stituted pyrrole products.
automeric phenomena, in general, are of great importance
1
Tin many areas of chemistry and biochemistry. Different
isomers of a molecule usually have different molecular
characteristics, which provide an efficient entry to the access
of some thermodynamically unstable or not easily synthesized
compounds.
Base- or metal-promoted sequential Mannich-type addition/
cyclization of isocyanoacetates and imine electrophiles provides
a straightforward method to 2-imidazolines,2 versatile com-
pounds3 used as precursors to 2,3-diamino acids4,2c,d and N-
heterocyclic carbene ligands.5 However, this formal [3 + 2]
dipolar cycloaddition is restricted to the imines bearing
electron-deficient groups (eq 1 in Figure 1). Recently, Orru
et al. developed a flexible multicomponent reaction by mixing
aldehydes and amines to generate imines in situ (eq 2 in Figure
1).6 In spite of a comparatively long reaction time, this strategy
broadly extends the scope of the substrates. A large range of
aliphatic, aromatic, and olefinic substituents are allowed for
both aldehyde and amine components. In this case, searching
Figure 1. Cascade reaction of β-aminoenones and isocyanoacetates to
construct 1,2,4,5-tetrasubstituted pyrroles.
for some supplementary approaches to preform imines for this
formal [3 + 2] dipolar cycloaddition is of great value.
β-Enaminones are versatile, readily obtainable building
blocks and have received considerable attention in recent
years.7 One of the main characteristics of this chemistry is the
equivalent of imines, especially for the unstable aliphatic imines,
but also facilitates potential cascade reactions due to the
multifunctional groups on β-enaminones.
Highly focused on its versatile functionality, our group has
been making unremitting efforts on isocyanide chemistry.10,11
Herein, we report, for the first time, a silver-catalyzed11c cascade
tautomeric equilibrium of β-enaminone with β-ketoimine (eq 3
in Figure 1).8 Although the latter one is a minor tautomer, this
equilibrium could yet be considered as a potential supply of
imines.9 Therefore, we envisioned that β-enaminones might be
serviced as a valid source of imines to take part in the formal [3
+ 2] dipolar cycloaddition with isocyanoacetates. Compared to
the normal methods, this strategy not only features employ-
ment of stable and readily available β-enaminones as the
Received: January 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00201
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction of β-enaminones and isocyanoacetates to construct
functionalized pyrrole derivatives.12
Scheme 1. Construction of Pyrroles via Cascade Reaction of
β-Enaminones and Isocyanoacetates
a,b
Initially, the reaction of α-ester-β-enaminone (1a) and ethyl
isocyanoacetate (2a) in 1,4-dioxane at 80 °C was selected as a
model system (Table 1). Various metal salts that could
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Ag2O
temp (°C)
solvent
yield (%)
1
80
80
80
80
80
80
80
80
80
80
80
60
100
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
73
0
2
AgF
3
AgOAc
Ag2CO3
Pd(OAc)2
CuI
56
83
0
4
5
6
30
0
7
DBU
8
0
9
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
77
16
0
10
11
12
13
DCE
DMF
1,4-dioxane
1,4-dioxane
45
72
a
All reactions were carried out in 0.25 M solvent with 10 mol % of
b
catalyst under nitrogen atmosphere. Isolated yields.
a
All reactions were carried out in 0.25 M 1,4-dioxane with 10 mol % of
b
promote deprotonation of isocyanoacetate were evaluated.2c,d,f
Although the addition of AgF gave no desired product, other
silver salts have proven to be active species (entries 1−4).
When Ag2CO3 was employed as the catalyst, to our delight, the
yield of pyrrole 3a was increased to 83%. Other types of metal
salts, such as Pd(OAc)2 and CuI, made no effect on the
reaction or resulted in a low yield (entries 5 and 6). Basic
conditions, which were general promotors in formal [3 + 2]
cycloaddition of imines and isocyanoacetates,2a were also
tested. However, in this case, only starting material was
recovered (entry 7). A control experiment in the absence of
silver salts gave no desired product, indicating that Ag2CO3
played an essential role in the reaction (entry 8). Further
screening of reaction solvents (entries 9−11) and reaction
temperatures (entries 12 and 13) showed that 1,4-dioxane and
80 °C were the best choices. In light of these results, the
optimized conditions for this reaction were Ag2CO3 (10 mol
%) in 1,4-dioxane at 80 °C for 6 h.
Ag2CO3 under a nitrogen atmosphere at 80 °C for 6−24 h. Isolated
yields. PMP = 4-MeOC6H4.
drawing groups (EWGs), including methyl and phenyl ketone
(3r,s) and a number of esters, such as methyl, benzyl, n-pentyl,
and propenyl esters (3n−q). Methyl isocyanoacetate 2b was
also a suitable partner to give pyrrole 3t. The aldimine part of
pyrrole products could be removed under basic conditions to
give corresponding 1H-pyrroles (for details, see the SI).
In an effort to better understand the reaction profile, control
experiments were carried out (Scheme 2). Deuterium-labeling
studies using 2.0 equiv of D2O resulted in the formation of
pyrrole 3m with deuterium on the imine carbon (30%), which
suggested that proton transfer occurred between the imine−
metal complex intermediate and D2O in the reaction cycle (see
Scheme 2. Mechanistic Investigations
With the optimized reaction conditions in hand, we
investigated the substrate scope, and the results are shown in
Scheme 1. First, we tested different β-enaminones 1. Various
substituted phenyl groups could be tolerated on the nitrogen
atom, including both electron-deficient I−, Br−, Cl−, F− and
CF3− (3b−g) and electron-rich MeO− and −OCH2O− (3h
and 3i). Other types of aryl rings, such as naphthalene- and
pyridine-derived β-enaminones, were also suitable partners for
the reaction to give the corresponding pyrroles 3j and 3k in
good yields. In addition, besides the methyl group, the R1
moiety could also be ethyl and n-propyl groups, and the
products 3l and 3m were obtained in 81% and 89% yields,
respectively. The structure of 3m was further confirmed by X-
ray crystallographic analysis.13 The R groups on the α-position
of β-enaminone were proven to be various electron-with-
B
DOI: 10.1021/acs.orglett.7b00201
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3). When 4-bromoaniline was added into the reaction
mixture in the presence of β-enaminone 1n and isocyanoacetate
Scheme 4. Formation of 1H-Pyrroles in the Presence of H2O
Scheme 3. Plausible Mechanism
In conclusion, we have developed a novel silver-catalyzed
cascade reaction of β-enaminones and isocyanoacetates to
construct 1,2,4,5-tetrasubstituted pyrrole derivatives. In this
reaction, stable and readily available β-enaminones are
employed as a valid source of imines through tautomeric
equilibria. An unprecedented ring-opening of 2-imidazoline
intermediate is reported for the first time and is attributed to
the existence of the EWGs on the α-position of β-enaminone. A
detailed study suggests that the reaction might process through
sequential Mannich addition/cyclization of imine tautomers
with isocyanoacetates, followed by a ring-opening of 2-
imidazolines and dehydration−condensation.
2a, no 4-bromoaniline-containing pyrrole derivative 4 was
detected, and the product 3n was obtained in 65% yield,
indicating the imine moiety of pyrrole product was not formed
through an intermolecular pathway.
On the basis of the above experimental results, a plausible
mechanism is illustrated in Scheme 3. Initially, isocyanoacetate
2a with an acidic α-H atom is activated by silver salt to generate
α-metalated isocyanide A and its tautomer A′. In the meantime,
tautomerization of β-enaminone 1 could afford imine species B,
which would undergo a formal [3 + 2] dipolar cycloaddition
with α-metalated isocyanide A to deliver 2-imidazoline C.14 To
the best of our knowledge, there is no literature relating to the
ring-opening of 2-imidazoline and only limited examples about
the ring-opening of similar oxazolines under strong basic
conditions15 or in the presence of ruthenium complex16
affording α-formylaminoacrylates. However, in our case, due
to the existence of the electron-deficient ketone and EWG, the
Ha in 2-imidazoline C is very acidic. For example, when EWG is
ethyl ester group, pKa of Ha is approximately 11, while the pKa
of Hb is around 20.17 The enhancement of acidity of Ha makes
it possible to undergo a retro-hetero-Michael addition to
facilitate the unprecedented ring-opening of 2-imidazoline. The
resultant imidamide D would form alcohol E via a nucleophilic
addition pathway. Subsequent proton transfer between alcohol
E and isocyanoacetate 2a could regenerate α-metalated
isocyanide A and deliver intermediate F. Finally, intermediate
F undergoes dehydration and isomerization to give the pyrrole
product 3.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00201.
Experimental procedures and spectra copies (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: fujk109@nenu.edu.cn.
*E-mail: bixh507@nenu.edu.cn.
ORCID
Junkai Fu: 0000-0002-7714-8818
Author Contributions
∥G.F. and J.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Later, we found that when 5.0 equiv of H2O was added into
the reaction mixture, 1H-pyrroles 5a−e could be generated in
excellent yields (Scheme 4). The product 5a is proposed to be
formed through hydrolysis of imine tautomer F, followed by a
sequential reaction similar to that in Scheme 3 of the resultant
aldehyde G with isocyanoacetate 2a and final pyrrole-1-
carbaldehyde H hydrolysis.18 These reactions strongly support
our proposal for the formation of imine tautomer intermediate.
The structure of 5a was further confirmed by X-ray
crystallographic analysis.13
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21522202, 21502017,
21372038), the Ministry of Education of the People’s Republic
of China (NCET-13-0714), the Jilin Provincial Research
Foundation for Basic Research (20140519008JH), Fundamen-
tal Research Funds for Central Universities (2412015BJ005,
2412015KJ013, 2412016KJ040), and the Jilin Province Key
Laboratory of Organic Functional Molecular Design &
Synthesis (No. 130028658).
C
DOI: 10.1021/acs.orglett.7b00201
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) When β-enaminone 6 bearing a hydrogen atom on the α-
position was tested, no desired product was detected, suggesting the
positive impact of EWG for the reaction cycle.
REFERENCES
■
(1) For selected reviews, see: (a) Raczyn
Chem. Rev. 2005, 105, 3561. (b) Martin, Y. C. J. Comput.-Aided Mol.
ska, E. D.; Kosin
ska, W.
Des. 2009, 23, 693.
(2) (a) Meyer, R.; Schollkopf, U.; Bohme, P. Liebigs Ann. Chem.
̈
̈
1977, 1977, 1183. (b) van Leusen, A. M.; Wildeman, J.; Oldenziel, O.
H. J. Org. Chem. 1977, 42, 1153. (c) Hayashi, T.; Kishi, E.;
Soloshonok, V. A.; Uozumi, Y. Tetrahedron Lett. 1996, 37, 4969.
(d) Lin, Y.; Zhou, X.; Dai, L.; Sun, J. J. Org. Chem. 1997, 62, 1799.
(15) Panella, L.; Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.;
Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. J. Org. Chem. 2006, 71,
2026.
(16) Takaya, H.; Kojima, S.; Murahashi, S.-I. Org. Lett. 2001, 3, 421.
(17) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(18) Ag-mediated hydrolysis of imine after pyrrole formation to
generate formyl substituent can be ruled out on the basis of the
following reaction.
(e) Benito-Garagorri, D.; Bocokic,
2006, 47, 8641. (f) Aydin, J.; Kumar, K. S.; Eriksson, L.; Szabo,
́
V.; Kirchner, K. Tetrahedron Lett.
K. J.
́
Adv. Synth. Catal. 2007, 349, 2585. (g) Yue, T.; Wang, M.-X.; Wang,
D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717.
(h) Zhang, Z.-W.; Lu, G.; Chen, M.-M.; Lin, N.; Li, Y.-B.; Hayashi, T.;
Chan, A. S. C. Tetrahedron: Asymmetry 2010, 21, 1715. (i) Nakamura,
S.; Maeno, Y.; Ohara, M.; Yamamura, A.; Funahashi, Y.; Shibata, N.
Org. Lett. 2012, 14, 2960. (j) Ortín, I.; Dixon, D. J. Angew. Chem., Int.
Ed. 2014, 53, 3462. (k) Shao, P.-L.; Liao, J.-Y.; Ho, Y. A.; Zhao, Y.
Angew. Chem., Int. Ed. 2014, 53, 5435. (l) Hayashi, M.; Iwanaga, M.;
Shiomi, N.; Nakane, D.; Masuda, H.; Nakamura, S. Angew. Chem., Int.
Ed. 2014, 53, 8411. (m) Zhao, M.-X.; Bi, H.-L.; Jiang, R.-H.; Xu, X.-
W.; Shi, M. Org. Lett. 2014, 16, 4566.
(3) Liu, H.; Du, D.-M. Adv. Synth. Catal. 2009, 351, 489.
(4) Viso, A.; Fernan
Flores, A. Chem. Rev. 2011, 111, PR1.
́
dez de la Pradilla, R.; Tortosa, M.; García, A.;
(5) (a) Herrmann, W. A.; Weskamp, T.; Bohm, V. P. W. Adv.
̈
Organomet. Chem. 2001, 48, 1. (d) Herrmann, W. A. Angew. Chem., Int.
Ed. 2002, 41, 1290.
(6) (a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de Kanter,
F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Lett. 2003, 5, 3759.
(b) Bon, R. S.; van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; de
Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen,
M. B.; Orru, R. V. A. J. Org. Chem. 2005, 70, 3542. (c) Elders, N.;
Schmitz, R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V.
A. J. Org. Chem. 2007, 72, 6135. (d) Elders, N.; van der Born, D.;
Hendrickx, L. J. D.; Timmer, B. J. J.; Krause, A.; Janssen, E.; de Kanter,
F. J. J.; Ruijter, E.; Orru, R. V. A. Angew. Chem., Int. Ed. 2009, 48, 5856.
(7) For selected reviews, see: (a) Greenhill, J. V. Chem. Soc. Rev.
1977, 6, 277. (b) Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003,
59, 8463. (c) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
(d) Wan, J.-P.; Gao, Y. Chem. Rec. 2016, 16, 1164.
(8) (a) Nagy, P. I.; Fabian, W. M. F. J. Phys. Chem. B 2006, 110,
25026. (b) Ruiz, D. L.; Spaltro, A.; Caputo, M.; Iglesias, D. A.;
Allegretti, P. E. Int. J. Mass Spectrom. 2015, 379, 87.
(9) Zhao, J.-J.; Zhang, Y.-C.; Xu, M.-M.; Tang, M.; Shi, F. J. Org.
Chem. 2015, 80, 10016.
(10) For selected recent reviews on isocyanide chemistry, see:
(a) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G.
Chem. Rev. 2010, 110, 5235. (b) Lygin, A. V.; de Meijere, A. Angew.
Chem., Int. Ed. 2010, 49, 9094. (c) van Berkel, S. S.; Bogels, B. G. M.;
̈
Wijdeven, M. A.; Westermann, B.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
2012, 2012, 3543. (d) Boyarskiy, V. P.; Bokach, N. A.; Luzyanin, K. V.;
Kukushkin, V. Y. Chem. Rev. 2015, 115, 2698. (e) Giustiniano, M.;
Basso, A.; Mercalli, V.; Massarotti, A.; Novellino, E.; Tron, G. C.; Zhu,
J. Chem. Soc. Rev. 2017, DOI: 10.1039/C6CS00444J.
(11) (a) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int.
Ed. 2013, 52, 6953. (b) Liu, J.; Liu, Z.; Liao, P.; Zhang, L.; Tu, T.; Bi,
X. Angew. Chem., Int. Ed. 2015, 54, 10618. (c) Wang, Y.; Kumar, R. K.;
Bi, X. Tetrahedron Lett. 2016, 57, 5730.
(12) For selected reviews, see: (a) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (b) Estev
́
ez,
V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633.
́
(c) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC
Adv. 2015, 5, 15233.
(13) CCDC 1528464 (3m) and CCDC 1528376 (5a) contain the
supplementary crystallographic data. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk.
D
DOI: 10.1021/acs.orglett.7b00201
Org. Lett. XXXX, XXX, XXX−XXX