A novel synthesis of multisubstituted pyrroles via trisubstituted olefins and tosmic derivatives

Article abstract of DOI:10.2174/157017812800233778

Abstract: A novel synthesis of multisubstituted pyrroles was developed where in trisubstituted olefins were reacted with p-toluenesulfonylmethyl isocyanide (TosMIC) derivatives. The entire process is operationally simplistic and utilizes mild reaction conditions. Additionally a possible mechanism is proposed.

Full text of DOI:10.2174/157017812800233778

Letters in Organic Chemistry, 2012, 9, 305-308
305
A Novel Synthesis of Multisubstituted Pyrroles via Trisubstituted Olefins
and TosMIC Derivatives
Fangli Qiua,b, Jianwei Wub, Yaohong Zhangb, Miao Hub, Feng Yuc, Guolin Zhangb and
Yongping Yu*,b
aCollege of pharmaceutical and chemical engineering, Taizhou University, Taizhou 317000, P.R. China
bCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
cZhejiang Chemical Industry Research Institute, Hangzhou 310058, P. R. China
Received October 22, 2011: Revised December 18, 2011: Accepted February 08, 2012
Abstract: A novel synthesis of multisubstituted pyrroles was developed where in trisubstituted olefins were reacted with
p-toluenesulfonylmethyl isocyanide (TosMIC) derivatives. The entire process is operationally simplistic and utilizes mild
reaction conditions. Additionally a possible mechanism is proposed.
Keywords: p-toluenesulfonylmethyl isocyanide(TosMIC), trisubstituted olefins, multisubstituted pyrrole, heterocycles,
derivatives.
INTRODUCTION
of the most important uses of TosMIC [14]. However,
TosMIC often reacts with alkenes to provide mono- and 1,2-
disubstituted pyrroles. Thus it remains highly desirable to
develop a facile and efficient procedure for the synthesis of
multisubstituted pyrroles and avoids the use of metal
catalysts.
The pyrrole ring is one of the most important
heterocycles. Substituted pyrroles are present in many
natural products [1] and pharmaceuticals [2], and are also
widely used in material science [3], bioorganic chemistry
[4], and supramolecular chemistry [5]. Additionally,
multisubstituted pyrroles exhibit a significant range of
biological and pharmacological activities (for example
antibacterial, antiviral, antiinflammatory, antitumour,
antioxidative) [6].
Therefore, we endeavored to develop a novel and simple
method for the synthesis of 3,4,5-trisubstituted pyrroles via
multisubstituted olefins and TosMIC derivatives. Initially,
we selected (Z)-ethyl 2-cyano-3-ethoxyacrylate and TosMIC
as the starting substrates (Scheme 1). We unexpectedly
found that unlike previous reports the ethoxy group was
In the past decades a variety of elegant methods for the
synthesis of pyrroles have been reported [7] such as the
H
N
CN
COOEt
solvent
+
EtO
Ts
N
C
CN
EtO
1a
2a
3a
Scheme 1. Reaction of (Z)-ethyl 2-cyano-3-ethoxyacrylate and TosMIC.
classic Knorr [8], Paal-Knorr [9], and Hantzsch reactions
[10], transition-metal catalyzed cyclizations [11], and
multicomponent coupling reactions [12] among others.
However, these methods are often limited due to high costs,
potential contamination of the products, and harsh reaction
conditions.
retained in the 4-position of the product pyrrole with
elimination of the p-toluenesulfonylmethyl group and ester
group.
We first examined the cycloaddition of (Z)-ethyl 2-
cyano-3-ethoxyacrylate (1a) with TosMIC (2a) under
varying reaction conditions in the presence of different
solvents (MeCN, CH2Cl2, THF, and 1, 4-dioxane) in Table 1.
CH2Cl2 proved ineffective, giving no desirable product after
24 hours at room temperature (entry 2), while CH3CN
proved to be the best choice (entry 1). In order to further
optimize the reaction conditions, the influence of the various
bases such as NaH, Cs2CO3, K2CO3, DBU and triethylamine
(TEA) were investigated (entries 1, 5, 6, 7 and 8). Poor
results were observed in reactions performed in TEA and
Toluenesulfonyl-methyl isocyanide (TosMIC) is
a
versatile synthon in organic chemistry and has been
extensively used for the synthesis of a wide variety of
heterocycles [13]. The construction of the pyrrole ring is one
*Address correspondence to this author at the College of Pharmaceutical
Sciences, Zhejiang University, Hangzhou 310058, P.R. China; Tel/Fax:
+86-571-88208452; E-mail: yyu@zju.edu.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

306 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Qiu et al.
Table 1. Optimization of Reaction Conditionsa
Entry
Solvent
base
time
Yield (%)b
1
2
MeCN
CH2Cl2
THF
NaH
NaH
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
5 h
12h
3h
87
no product
3
NaH
64
50
59
35
52
44
88
79
70c
4
1, 4- dioxane
MeCN
NaH Cs2CO3
K2CO3 DBU
TEA
5
6
MeCN
7
MeCN
NaH
8
MeCN
NaH
9
MeCN
NaH
10
11
MeCN
NaH
MeCN
NaH
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), Base (1.2mmol), solvent (10 mL), at r.t.. bThe yield of the isolated product. cThe reaction was done at 50 oC.
K2CO3 (entries 6 and 8). However we found that NaH was
the most effective base providing higher yield. The effect of
a further increase in the reaction time is small (entry 9 and
withdrawing groups (COOBu, COMe, CN, COOEt,
COOC(CH3)3) were present on the olefins included in this
study. When ketone and ester groups are both present on the
olefin at the same time, it is easier to eliminate the ketone
group than the ester group due to its higher reaction activity.
In regard to the steric effects, the steric hindrance of the tert-
Butyl ester group is harder to leave than the ethyl ester group
(3j-3l). The different TosMIC derivatives (TosMIC, Et-
TosMIC and Benzyl-TosMIC) were also tested under similar
conditions. It was clearly observed that Et-TosMIC and
Benzyl-TosMIC were much more reactive than TosMIC(3a-
3l). Benzyl-TosMIC (2c) gave the product (3c) in the best
o
10).ꢀ When increasing the reaction temperature to 50 C
decreased the yield (entry 11). Therefore the optimal reaction
condition was obtained with NaH in anhydrous acetonitrile
at room temperature under nitrogen for 3 h (entry 1).
We investigated the scope of the optimized reaction
conditions using various multisubstituted olefins and
TosMIC derivatives. As shown in Table 2, most substrates
examined provided moderate to excellent yields under the
optimized reaction conditions. Several different electron
Table 2. Synthesis of Trisubstituted Pyrrolesa
H
R1
N
R3
R3
NaH, r.t.
+
EtO
COR2
Ts
N
CH3CN
C
R1
EtO
1
2
3
Entry
R1
R2
R3
Yield (%)b
3a
3b
3c
3d
3e
3f
CN
CN
OEt
OEt
OEt
OEt
OEt
OEt
Me
H
87
90
92
73
78
91
76
83
86
56
87
88
Et
CN
C6H5CH2
COOEt
H
COOEt
Et
C6H5CH2
H
COOEt
3g
3h
3i
COOEt
COOEt
Me
Et
COOEt
Me
C6H5CH2
H
3j
COOC(CH3)3
COOC(CH3)3
COOC(CH3)3
OEt
OEt
OEt
3k
3l
Et
C6H5CH2
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), NaH (1.2mmol), solvent (10 mL), at r.t.. bThe yield of the isolated product.

A Novel Synthesis of Multisubstituted Pyrroles via Trisubstituted Olefins
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
307
R3
Ts
N
Ts
N
C
N
Ts
R3
2
R3
B
+
CH2OR2
EtO
R1
H
R1
EtO
COR2
R1
EtO
COR2
I
II
1
Ts
R3
N
N
N
R3
EtO
BH
-TsH
R3
Nu
O
COR2
R2
COR2
EtO
R1
EtO
R1
R1
Nu
IV
III
VI
H
N
R3
H
-NuCOR3
EtO
R1
3
Scheme 2. Possible formation mechanism of trisubstituted pyrroles.
yield under the conditions used. If we replaced the EtO
moiety of the olefins with aryl group, the target product
would not be obtained. NMR spectroscopic analysis of the
reaction product (3a) clearly indicated formation of the
Major Creation of New Drugs (No. 2009ZX09501-010) for
financial support.
REFERENCES AND NOTES
corresponding
ethyl
5-benzyl-4-ethoxy-1H-pyrrole-3-
carboxylate, corresponding observations were noted for the
other final products [15].
[1]
(a) Shafiee, A.; Kassaee, M. Z.; Bekhradnia, A. R. Synthesis of
novel 3,4-diaryl-1H-pyrroles. J. Heterocyclic Chem., 2007, 44,
471-474. (b) Sundburg, R. J.; In Comprehensive Heterocyclic
ChemistryII Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Bird,
C. W. Eds.; Pergamon Press: Oxford 1996, 2, 119. (c) Fan, H.;
Peng, J.; Hamann, M. T.; Hu, J. F. Lamellarins and Related
Pyrrole-Derived Alkaloids from Marine Organisms. Chem. Rev.,
2008, 108, 264-287.
Pinna, G. A.; Curzu, M. M.; Sechi, M.; Chelucci, G.; Maciocco, E.
Synthesis and dopamine D2-like receptor binding affinity of
substituted 5-phenyl-pyrrole-3-carboxamides. Farmaco, 1999, 54,
542-550.
(a) Novak, P.; Muller, K.; Santhanam, S. V.; Hass, O.
Electrochemically Active Polymers for Rechargeable Batteries.
Chem. Rev., 1997, 97, 207-282. (b) Nalwa, H. S. Advanced
Functional Molecules and Polymers: Electronic and Photonic
Properties, CRC Press: New York, 2001. (c) Groenendaal, L.;
Meijer, E. W.; Vekemans, J. A. J. M. In Electronic Materials: The
Oligomer Approach; Mullen, K.; Wegner, G. Eds.; Wiley-VCH:
Weinheim, 1997. (d) Gabriel, S.; Cecius, M.; Fleury-Frenette, K.;
Cossement, D.; Hecq, M.; Ruth, N.; Jerome, R.; Jerome, C.
Synthesis of Adherent Hydrophilic Polypyrrole Coatings onto
(Semi)conducting Surfaces. Chem. Mater., 2007, 19, 2364-2371.
(a) Furstner, A. Chemistry and Biology of Roseophilin and the
Prodigiosin Alkaloids: A Survey of the Last 2500 Years. Angew.
Chem. Int. Ed., 2003, 42, 3582-3603. (b) Rochais, C.; Lisowski, V.;
Dallemagne, P.; Rault, S. Synthesis and biological evaluation of
novel pyrrolopyrrolizinones as anticancer agents. Bioorg. Med.
Chem., 2006, 14, 8162-8175. (c) Zeng, L.; Miller, E. W.; Pralle,
A.;Isacoff, E. Y.; Chang, C. J. A Selective Turn-On Fluorescent
Sensor for Imaging Copper in Living Cells. J. Am. Chem. Soc.,
2006, 128, 10-11. (d) La Regina, G.; Silvestri, R.; Artico, M.;
Lavecchia, A.; Novellino, E.; Befani, O.; Turini, P.; Agostinelli, E.
New Pyrrole Inhibitors of Monoamine Oxidase:ꢀ Synthesis,
Biological Evaluation, and Structural Determinants of MAO-A and
MAO-B Selectivity. J. Med. Chem., 2007, 50, 922-931.
On the basis of these results, a possible mechanism for
the formation of trisubstituted pyrroles is proposed in
Scheme 2 [16]. First, in the presence of base the TosMIC(2)
reacts with the double-bond of the olefin(1) leading to the
intermediate(I).Then intermediate(I) occurs from an
intramolecular cycloaddition of the isocyano group to
[2]
[3]
produce the intermediate(III). Then elimination of
a
tosylsulphinic acid produces the intermediate (IV). Finally,
the ketone or ester group is eliminated with a nucleophilic
addition to obtain the product (3) [17].
In conclusion, we have developed a novel, effective and
simple route for the synthesis of multisubstituted pyrroles via
trisubstituted olefins and TosMIC derivatives. Moreover,
simple and readily available starting materials, good to
excellent yields of the products, mild reaction conditions are
the main advantages of this reaction.
[4]
DISCLOSURE
Part of information included in this article had been
previously published in Tetrahedron Letters [18].
CONFLICT OF INTEREST
Declared none.
[5]
(a) Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J. R. Handbook
of Conducting Polymers, 2nd ed.; Marcel Dekker: New York,
1998. (b) Chen, Y.; Zeng, D.; Xie, N.; Dang, Y. Study on
ACKNOWLEDGEMENT
We thank the National Natural Science Foundation of
China (No. 90813026) and National key Tech project for
Photochromism of Diarylethenes with
a 2,5-Dihydropyrrole

308 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Qiu et al.
Component Coupling Reaction of Aldehydes, Amines, and
Nitroalkanes. J. Org. Chem., 1998, 63, 6234-6238. (b) Bian, Y. J.;
Liu, X. Y.; Ji, K. G.; Shu, X. Z.; Guo, L. N.; Liang, Y. M. Efficient
synthesis of highly substituted pyrroles based on the tandem
Bridging Unit:ꢀ A Convenient Preparation of 3,4-Diarylpyrroles
from 3,4-Diaryl-2,5-dihydropyrroles. J. Org. Chem., 2005, 70,
5001-5005.
[6]
(a) Nogami, T.; Shigehara, Y.; Matsuda, N.; Takahashi, Y.;
Naganawa, H.; Nakamura, H.; Hamada, M.; Muraoka, Y.;Takita,
T.; Iitaka, T.; Takeuchi, T. Neopyrrolomycin, a new chlorinated
phenylpyrrole antibiotic. J. Antibiot., 1990, 43, 1192-1194. (b)
Jacobi, P. A.; Coults, L. D.; Guo, J. S.; Leung, S. I. New Strategies
for the Synthesis of Biologically Important Tetrapyrroles. The “B,C
+ D + A” Approach to Linear Tetrapyrroles. J. Org. Chem., 2000,
65, 205-213. (c) Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L.
Diradical Dications of m- and p-Phenylenebis[2,5-di(2-thienyl)-1-
pyrrole]:ꢀ Weakly Coupled Diradicals. J. Org. Chem., 2001, 66,
4058-4061. (d) Borzilleri, R. M.; Cai, Z. W.; Ellis, C.; Fargnoli, J.;
Fura, A.; Gerhardt, T.; Goyal, B.; Hunt, J. T. Synthesis and SAR of
reactions:intermolecular
amination
and
Pd(II)-catalyzed
intramolecular hydroamidation. Tetrahedron, 2009, 65, 1424-1429.
(c) Aponick, A.; Li, C. Y.; Malinge, J.; Marques, E. F. An
Extremely Facile Synthesis of Furans, Pyrroles, and Thiophenes by
the Dehydrative Cyclization of Propargyl Alcohols. Org. Lett.,
2009, 11, 4624-4627. (d) Dou, G.; Shi, C.; Shi, D. Highly
Regioselective Synthesis of Polysubstituted Pyrroles through
Three-Component Reaction Induced by Low-Valent Titanium
Reagent. J. Comb. Chem., 2008, 10, 810-813. (e) Lu, Y.; Fu, X.;
Chen, H.; Du, X.; Jia, X.; Liu, Y. An Efficient Domino Approach
for the Synthesis of Multisubstituted Pyrroles via Gold/Silver-
Catalyzed Amination/Cycloisomerization of (Z)-2-En-4-yn-1-ols.
Adv. Synth. Catal., 2009, 351, 129-134. (f) Lamande-Langle, S.;
Abarbri, M.; Thibonnet, J.; Duchene, A.; Parrain, J.-L. Domino
4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine
based
VEGFR-2 kinase inhibitors. Bioorg. Med. Chem., 2005, 15, 1429-
1433.
(a) Fu, X.; Chen, J.; Li, G.; Liu, Y. Diverse Reactivity of
allylic
amination/Sonogashira/heterocyclisation
reactions:
[7]
palladium-catalysed three-component synthesis of pyrroles. Chem.
Commun., 2010, 46, 5157-5159.
Zirconacyclocumulenes
Derived
from
Coupling
of
Benzynezirconocenes with 1,3-Butadiynes Towards Acyl
Cyanides: Synthesis of Indeno[2,1-b]pyrroles or [3]Cumulenones.
Angew. Chem. Int. Ed., 2009, 48, 5500-5504. (b) Rueping, M.;
Parra, A. Related citations6.Fast, efficient, mild, and metal-free
synthesis of pyrroles by domino reactions in water. Org. Lett.,
2010, 11, 22, 5281-5283. (c) Misra, N. C.; Panda, K.; Ila, H.;
Junjappa, H. An Efficient Highly Regioselective Synthesis of 2,3,4-
Trisubstituted Pyrroles by Cycloaddition of Polarized Ketene S,S-
and N,S-Acetals with Activated Methylene Isocyanides. J. Org.
Chem., 2007, 72, 1246-1251. (d) Boger, D. L.; Boyce, C. W.;
Labroli, M. A.; Sehon, C. A. Total Syntheses of Ningalin A,
Lamellarin O, Lukianol A, and Permethyl Storniamide A Utilizing
Heterocyclic Azadiene Diels-Alder Reactions. J. Am. Chem. Soc.,
1999, 121, 54-62. (e) Larionov, O. V.; Meijere, A. D. Versatile
Direct Synthesis of Oligosubstituted Pyrroles by Cycloaddition of
alpha-Metallated Isocyanides to Acetylenes. Angew. Chem. Int.
Ed., 2005, 44, 5664-5667.
Shiner, C. M.; Lash, T. D. Porphyrins with exocyclic rings. Part 21:
Influence of pyrrolic and carbocyclic ring alkyl substituents on the
synthesis of porphyrins bearing six-membered exocyclic rings.
Tetrahedron, 2005, 61, 11628-11640.
(a) Chen, J.; Wu, H.; Zheng, Z.; Jin, C.; Zhang, X.; Su, W. An
approach to the Paal–Knorr pyrroles synthesis catalyzed by
Sc(OTf)3 under solvent-free conditions. Tetrahedron Lett., 2006,
47, 5383-5387. (b) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei,
[13]
(a) Van Leusen, A. M.; Boerma, G. J. M.; Helmholdt, R. B.;
Siderius, H.; Strating, J. Chemistry of sulfonylmethylisocyanides.
Simple synthetic approaches to a new versatile chemical building
block. Tetrahedron Lett., 1972, 13, 2367-2368. (b) Van Leusen, D.;
van Leusen, A. M. Synthetic uses of tosylmethyl isocyanide
(TosMIC). Org. React., 2001, 57, 417. (c) Tandon, V. K.; Rai, S. p-
Toluenesulfonylmethyl Isocyanide: A Versatile Synthon in Organic
Chemistry. Sulfur Rep., 2003, 24, 307-385.
[14]
[15]
Van Leusen, A. M.; Van Leusen, D. Encyclopedia for Organic
Synthesis, Vol. 7 (Ed.: L. A. Paquette), Wiley, New York, 1995,
4973.
General Procedure for the Synthesis of Compounds 3: A mixture of
1 (1.0mmol), 2 (1.0 mmol) and NaH (1.2mmol) was stirred in
anhydrous acetonitrile (10 mL) at room temperature under nitrogen
for 3 h. The reaction was terminated by the addition of an aqueous
saturated NH4Cl solution and adjusted the pH to 7-8. The mixtures
were extracted with CH2Cl2. The combined organic layers were
washed with a saturated Na2CO3 solution and brine. It was then
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography using petroleum
ether/ethyl acetate (5:1) as the eluent to afford the pure compound.
The product was characterized by LC–MS under ESI conditions, IR,
1H and 13C NMR. 4-ethoxy-1H-pyrrole-3-carbonitrile as
yellowish liquid(3a); IR(KBr):3318, 2982, 2223, 1651, 1525,
[8]
[9]
1
1360, 1188, 1074, 748, 592 cm-1. H NMR (500 MHz, CDCl3): δ
M.
Microwave-Assisted
Paal-Knorr
Reaction-Three-Step
8.52 (s, 1H), 7.06 (dd, J = 3.6, 2.3 Hz, 1H), 6.28 (t, J = 2.4 Hz,
1H), 3.97 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 148.80, 123.46, 115.73, 100.44, 83.85, 67.16,
14.75. MS (ESI): m/z ([M+ H])+: 137.
(a) Fornicola, R. S.; Oblinger, E.; Montgomery, J. A New
Synthesis of α -Amino Acid Derivatives Employing Methyl
Nitroacetate as a Versatile Glycine Template. J. Org. Chem., 1998,
63, 3528-3529. (b) Baxendale, I.R.; Buckle, C. D.; Ley, S. V.;
Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and
Thiophenes. Eur. J. Org. Chem., 2005, 24, 5277-5288.
Matiychuk, V. S.; Martyack, R. L.; Obushak, N. D.; Ostapiuk,Y.
V.; Pidlypnyi, N. I. 3-Aryl-2-chloropropanals in Hantzsch
Synthesis of Pyrroles. Chem. Heterocycl. Compd., 2004, 40, 1218-
1219.
[10]
[11]
[16]
(a) Sukhendu, M.; Srijit, B.; Umasish, J. Iron(III)-Catalyzed Four-
Component Coupling Reaction of 1,3-Dicarbonyl Compounds,
Tamborini, L.
A Base-Catalysed One-Pot Three-Component
Amines, Aldehydes, and Nitroalkanes:
A Simple and Direct
Coupling Reaction Leading to Nitrosubstituted Pyrroles. Synthesis,
2009, 9, 1485-1493.
Synthesis of Functionalized Pyrroles. J. Org. Chem., 2010, 75,
1674-1683. (b) Saito, A.; Konishi, T.; Hanzawa, Y. Synthesis of
pyrroles by gold(I)-catalyzed amino-claisen rearrangement of N-
propargyl enaminone derivatives. Org. Lett., 2010, 12, 372-374. (c)
Liu, W. B.; Jiang, H. F.; Huang, L. B. One-Pot Silver-Catalyzed
and PIDA-Mediated Sequential Reactions: Synthesis of
Polysubstituted Pyrroles Directly from Alkynoates and Amines.
Org. Lett., 2010, 12, 312-315. (d) Takahashi, A.; Kawai, S.;
Hachiya, I.; Shimizu, M. A New Method for the Synthesis of
Multisubstituted Pyrroles of Biological Interest by Double
Nucleophilic Addition to α,β-Unsaturated Imines. Eur. J. Org.
Chem., 2010, 1, 191-200.
[17]
[18]
(a) Van Leusen, D.; Flentge, E.; van Leusen, A. M. An efficient
synthesis of 3-nitropyrroles. Tetrahedron, 1991, 47, 4639-4644. (b)
Van Leusen, D.; van Echten, E.; van Leusen, A. M. Chemistry of
sulfonylmethyl isocyanides. 37. Synthesis of 3,4-disubstituted
pyrroles bearing substituents of electron-withdrawing and/or
electron-donating nature. J. Org. Chem., 1992, 57, 2245-2249.
Qiu F., Wu J., Zhang Y., Hu M., Yu Y. One-pot cascade approach
to 1,3’-bipyrrole derivatives from trisubstituted olefins with
tosylmethyl-isocyanide (TosMIC). Tetrahedron Lett., 2012, 53,
446-448.
[12]
(a) Shiraishi, H.; Nishitani, T.; Sakaguchi, S.; Ishii, Y. Preparation
of Substituted Alkylpyrroles via Samarium-Catalyzed Three-