Direct synthesis of pyrroles via 1,3-dipolar cycloaddition of azomethine ylides with ynones

Article abstract of DOI:10.1039/c3nj00067b

A direct and facile synthesis of multi-substituted pyrroles via AgOAc-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with ynones is developed, providing the corresponding adducts in moderate to high yields (up to 89%).

Full text of DOI:10.1039/c3nj00067b

NJC
View Article Online
View Journal
PAPER
Direct synthesis of pyrroles via 1,3-dipolar
cycloaddition of azomethine ylides with ynones†
Cite this: DOI: 10.1039/c3nj00067b
Zheng Wang,a Ying Shi,a Xiaoyan Luo,a De-Man Hanb and Wei-Ping Deng*ac
Received (in Montpellier, France)
16th January 2013,
Accepted 7th March 2013
A direct and facile synthesis of multi-substituted pyrroles via AgOAc-catalyzed 1,3-dipolar cycloaddition
of azomethine ylides with ynones is developed, providing the corresponding adducts in moderate to
high yields (up to 89%).
DOI: 10.1039/c3nj00067b
www.rsc.org/njc
Pyrroles are among the most common and important hetero-
aromatic compounds, and are found ubiquitously as essential
structural motifs in natural products, bioactive compounds, drug
molecules and materials.1,2 For example, Lipitor, as an HMG-CoA
reductase inhibitor used to lower LDL cholesterol levels, is the
best-selling drug in the past several years, which contains the
pyrrole as the core structural unit.3 The biological importance of
pyrroles prompted many research groups to develop new methods
for their preparation. The classic synthetic approaches to pyrrole
include the Knorr,4 Paal–Knorr,5 and Hantzsch6 syntheses, which
routinely involve multistep synthetic operations and suffer from
the substrate scope limitation. Recently, many efforts have been
devoted to develop novel and highly efficient synthetic protocols
for pyrrole synthesis, such as multi-component coupling reac-
tions,7 transition metal catalyzed cyclizations,8 cross-metatheses9
and [3+2] cycloadditions.10 With regard to the last approach, the
cycloaddition of azomethine ylides with both activated alkenes
and alkynes has undoubtedly provided the most powerful strate-
gies. Generally, these alkenes should be pre-functionalized with
potential leaving groups such as nitro, halogen, sulfone units,
which would undergo base-promoted elimination to form
pyrroles.11 As for the reaction with alkynes, in most cases,
in situ formed azomethine ylides were used for intramolecular
1,3-dipolar cycloaddition, and glycine-derived azomethine
ylides have rarely been employed for intermolecular 1,3-dipolar
cycloaddition to construct multisubstituted pyrroles.12
Scheme 1 AgOAc-catalyzed-1,3-dipolar cycloaddition of azomethine ylides
with ynones.
In this context, we would like to report an efficient AgOAc-
catalyzed intermolecular 1,3-dipolar cycloaddition of ynones 1
with glycine-derived azomethine ylides 2 to afford a variety of
2,3,5-trisubstituted pyrroles 3 in satisfactory yields (Scheme 1).
Initial study was performed with 1-phenylprop-2-yn-1-one 1a
and iminoester 2a in the presence of 10 mol% AgOAc in THF at
room temperature (Table 1). The reaction proceeded sluggishly
and the corresponding product 3aa was obtained in only 11%
yield after 24 h (Table 1, entry 1). The addition of TEA didn’t
improve the result. Interestingly, when 20 mol% PPh3 was
added as the ligand, the reaction proceeded much faster with
a better yield (Table 1, entry 3). The yield of 3aa was further
increased to 41% in the absence of TEA (Table 1, entry 4).
Screening both the amount and the ratio of AgOAc and PPh3
showed that 20 mol% AgOAc and 40 mol% PPh3 led to the
optimal result with 52% yield. It should be noted that the
independent use of 1 equivalent of TEA predominantly resulted
in the decomposition of 1a and afforded only trace amounts of
the product (Table 1, entry 10).
Next, the variation of crucial reaction parameters, such as
metal sources, ligands, solvent, reaction temperature and the
catalyst loading, was systematically investigated (Table 2).
Screening of various metal salts revealed that AgOAc gave the
optimal results and other silver salts were found to be much less
active (Table 2, entries 2–4). Copper salts led to moderate to low
yield with a prolonged reaction time of 24 h (Table 2, entries 5–7).
Iron, zinc, and nickel were inactive under these conditions.
a School of Pharmacy and Shanghai Key Laboratory of Functional Materials Chemistry,
East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China. E-mail: weiping_deng@ecust.edu.cn
b Department of Chemistry, Taizhou University, 605 Dongfang Road, Linhai 317000,
China
c Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 LingLing Road,
Shanghai 200032, China
† Electronic supplementary information (ESI) available. CCDC 918358. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3nj00067b
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem.

View Article Online
Paper
NJC
Table 1 1,3-Dipolar cycloaddition of azomethine ylide 2a with ynone 1aa
The solvent effect was also investigated for this reaction, and THF
was found to be optimal for those tried (Table 2, entries 22–26).
Lowering the temperature to ꢀ20 1C had no positive effect on
yield albeit with prolonged reaction time. Pleasingly, when the
reaction was conducted at ꢀ40 1C, a remarkable improvement in
the yield of 3aa could be obtained (73% yield, Table 2, entry 28).
Further lowering the temperature to ꢀ78 1C led to lower yield.
The above optimization led to AgOAc (20 mol%)/PPh3 (40 mol%)/
THF/4 Å molecular sieve (MS)/ꢀ40 1C as the optimal reaction
conditions for this 1,3-dipolar cycloaddition reaction, and the
scope and generality of substrates were then examined. As shown
in Table 3, a wide array of ynones 1, bearing both electron-rich
and -deficient groups, reacted smoothly with iminoester 2a
affording the corresponding pyrrole adducts exclusively in good
yields (Table 3, entries 1–10). Notably, heteroaromatic substrate
1j was also tolerated in this reaction (Table 3, entry 11). Various
iminoesters were also evaluated as viable substrates for this
reaction. It appeared that the position and the electronic property
of the substituents on the aromatic rings of the iminoesters had a
very minor effect on the yields. What’s more, the variation in the
ester moiety of iminoesters from the methyl group to the ethyl or
the more hindered t-butyl group had no influence on the yield
(Table 3, entries 12 and 13). However, when the iminoester 2j
derived from aliphatic aldehyde was employed, the yield of the
corresponding product 3aj dropped dramatically to 31% (Table 3,
entry 23). It is noteworthy that comparable results were still
Entry Metal salt (mol%) Ligand (mol%) Base (mol%) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (15)
AgOAc (20)
—
—
—
—
TEA (20)
TEA (20)
—
—
—
—
—
11
9
PPh3 (20)
PPh3 (20)
PPh3 (10)
PPh3 (30)
PPh3 (40)
PPh3 (30)
PPh3 (40)
—
25
41
10
38
38
40
52
Trace
—
TEA (100)
a
All reactions were carried out with 0.30 mmol of 1a and 0.60 mmol of
b
2a in 2 mL of solvent at r.t. Isolated yield.
Table 2 Screening studies of the reactiona
Entry Metal salt
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
AgOAc
PPh3
PPh3
PPh3
PPh3
PPh3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
52
27
33
29
21
25
41
Trace
N.P.
Trace
N.P.
Trace
35
24
34
47
46
AgClO4ꢁH2O
Table 3 Substrate scope of 1,3-dipolar cycloaddition of various azomethine
ylides 2 with ynones 1aa
AgOTf
AgBF4
CuBr
Cu(ClO4)2ꢁ6H2O PPh3
Cu(acac)2
CuCl2ꢁH2O
FeCl3
PPh3
PPh3
PPh3
9
10
11
12
13
14
15
16c
17c
18c
19c
20c
21
22
23
24
25
26
27d
28d,g
Zn(ClO4)2ꢁ6H2O PPh3
Zn(OAc)2ꢁ2H2O
Ni(OAc)2ꢁ2H2O
AgOAc
PPh3
PPh3
P(o-Tol)3
PCy3
P(t-Bu)3
dppb
Entry
R1
R2/R3
Yieldb (%)
t (h)
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
1
2
3
4
5
6
7
8
C6H5 (1a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Me (2a)
4-ClC6H4/Et (2b)
4-ClC6H4/t-Bu (2c)
C6H5/Me (2d)
73
63
71
69
67
62
53
80
51
65
68
69
69
82
61
79
89
79
72
76
82
63
31
30
20
20
20
20
48
48
48
48
48
20
12
12
20
20
20
20
20
20
30
30
30
30
4-ClC6H4 (1b)
4-NO2C6H4 (1c)
3-BrC6H4 (1d)
2-FC6H4 (1e)
2-MeC6H4 (1f)
2,4-MeC6H3 (1g)
4-MeOC6H4 (1h)
4-MeOC6H4 (1h)
4-MeC6H4 (1i)
2-Furyl (1j)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
dppf
2,20-bpye
1,10-phenf
30
14
39
35
(S,S)-iPr-phosferrox THF
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
CH3CN
Toluene 30
CH2Cl2
Et2O
DMF
EtOAc
THF
9c
10
11
12
13
14
15c
16
17
18c
19
20
21
22c
23
17
44
10
27
73
47
THF
C6H5/Me (2d)
4-BrC6H4/Me (2e)
2-ClC6H4/Me (2f)
2-ClC6H4/Me (2f)
3-BrC6H4/Me (2g)
4-MeC6H4/Me (2h)
2-MeC6H4/Me (2i)
2-MeC6H4/Me (2i)
Cy/Me (2j)
a
b
See Table 1. Isolated yields, N.P. means no product observed (TLC
c
d
analysis). 20 mol% ligand is added. The reaction was carried out at
e
f
ꢀ40 1C. 2,20-bpy = 2,20-bipyridine. 1,10-phen = 1,10-phenathroline.
g
10 mol% AgOAc and 20 mol% PPh3 were used.
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
Other ligands, including monophosphine ligands, bisphosphine
ligands, diamine ligands and N,P-ligands, were found to be inferior
to PPh3 in terms of the yield of 3aa (Table 2, entries 13–20).
a
Conditions: AgOAc (20 mol%), PPh3 (40 mol%), THF, 4 Å MS, ꢀ40 1C.
b
c
Isolated yields. 10 mol% AgOAc and 20 mol% PPh3 were used.
c
New J. Chem.
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013

View Article Online
NJC
Paper
Tetrahedron, 2006, 62, 7213; (c) B. A. Trofimov,
A. I. Mikhaleva, E. Yu. Schmidt and L. N. Sobenina, Adv.
Heterocycl. Chem., 2010, 99, 209; (d) other reviews please see
ref. 6a, 7b and 8.
2 For selected examples: (a) D. P. O’Malley, K. Li, M. Maue,
A. L. Zografos and P. S. Baran, J. Am. Chem. Soc., 2007,
129, 4762; (b) C. C. Hughes, A. Prieto-Davo, P. R. Jensen and
W. Fenical, Org. Lett., 2008, 10, 629; (c) C. Teixeira,
F. Barbault, J. Rebehmed, K. Liu, L. Xie, H. Lu, S. Jiang,
B. Fan and F. Maurel, Bioinorg. Med. Chem., 2008, 16, 3039;
(d) M. Biava, G. C. Porretta, D. Deidda, R. Pompei, A. Tafi
and F. Manetti, Bioinorg. Med. Chem., 2004, 12, 1453;
(e) B. Forte, B. Malgesini, C. Piutti, F. Quartieri, A. Scolaro
and G. Papeo, Mar. Drugs, 2009, 7, 705; ( f ) A. Hall,
S. Atkinson, S. H. Brown, I. P. Chessell, A. Chowdhury,
G. M. P. Giblin, P. Goldsmith, M. P. Healy, K. S. Jandu,
M. R. Johnson, A. D. Michel, A. Naylor and J. A. Sweeting,
Bioorg. Med. Chem. Lett., 2007, 17, 1200; (g) A. Loudet and
K. Burgess, Chem. Rev., 2007, 107, 4891; (h) V. M. Domingo,
Scheme 2 A plausible mechanism of the synthesis of pyrroles via 1,3-dipolar
cycloaddition of azomethine ylides with ynones.
achieved for some substrates when the catalyst loading was
decreased to 10 mol% (Table 3, entries 9, 15, 18, and 22).
Due to the fact that silver mirror was found after the
completion of the reaction, we speculate the possible pathway
for this transformation although we failed to isolate the key
intermediate dihydropyrrole A. The dihydropyrrole molecules A
were formed first via AgOAc-catalyzed 1,3-dipolar cycloaddition
followed by a fast silver-catalyzed dehydrogenation process to
afford the corresponding pyrrole products (Scheme 2).12,13
´
Conclusions
C. Aleman, E. Brillas and L. Julia, J. Org. Chem., 2001,
66, 4058.
In summary, we have developed an efficient protocol for the
synthesis of 2,3,5-trisubstituted pyrroles via AgOAc-catalyzed
1,3-dipolar cycloaddition of azomethine ylides with ynones in
good yields (up to 89%). A possible reaction pathway for this
one-pot pyrroles preparation was proposed. Further application
of this novel method is still ongoing in our laboratory.
3 R. B. Thompson, FASEB J., 2001, 15, 1671.
4 For selected examples of the Knorr synthesis: (a) A. Alberola,
´
˜
A. G. Ortega, M. L. Sadaba and C. Sanudo, Tetrahedron,
1999, 55, 6555; (b) C. M. Shiner and T. D. Lash, Tetrahedron,
2005, 61, 11628.
5 For recent examples of the Paal–Knorr synthesis:
(a) A. Rahmatpour, J. Organomet. Chem., 2012, 712, 15;
(b) K. Aghapoor, L. Ebadi-Nia, F. Mohsenzadeh,
M. M. Morad, Y. Balavar and H. R. Darabi, J. Organomet.
Chem., 2012, 708–709, 25; (c) G. Minetto, L. F. Raveglia,
A. Sega and M. Taddei, Eur. J. Org. Chem., 2005, 5277;
(d) N. Azizi, A. Khajeh-Amiri, H. Ghafuri, M. Bolourtchian
and M. R. Saidi, Synlett, 2009, 2245.
General procedure for AgOAc catalyzed
1,3-dipolar cycloaddition of azomethine
ylides with ynones
Under a N2 atmosphere, AgOAc (10 mg, 0.06 mmol), PPh3
(31.5 mg, 0.12 mmol) and activated 4 Å MS were dissolved in
2 mL anhydrous THF and stirred at room temperature for about
1 h. Iminoesters 2 (0.6 mmol) were added and after the reaction
temperature was reduced to ꢀ40 1C, ynones 1 (0.3 mmol) were
added. Once starting material was consumed (monitored by
TLC), the mixture was concentrated to dryness and then the
residue was purified by column chromatography to give the
corresponding products 3.
6 (a) A. W. Trautwein, R. D. Su¨ßmuth and G. Jung, Bioorg.
Med. Chem. Lett., 1998, 8, 2381; (b) A. Herath and N. D. P.
Cosford, Org. Lett., 2010, 12, 5182.
´
7 For review: (a) V. Estevez, M. Villacampa and
´
J. C. Menendez, Chem. Soc. Rev., 2010, 39, 4402. For recent
examples: (b) D. Hong, Y. Zhu, Y. Li, X. Lin, P. Lu and
Y. Wang, Org. Lett., 2011, 13, 4668; (c) O. A. Attanasi, G. Favi,
F. Mantellini, G. Moscatelli and S. Santeusanio, J. Org.
Chem., 2011, 76, 2860; (d) C. V. Galliford and K. A.
Acknowledgements
´
Scheidt, J. Org. Chem., 2007, 72, 1811; (e) S. Lamande-
ˆ
Langle, M. Abarbri, J. Thibonnet, A. Duchene and
J. Parrain, Chem. Commun., 2010, 46, 5157.
This work was financially supported by the Fundamental
Research Funds for the Central Universities, the Shanghai
Committee of Science and Technology (No. 11DZ2260600),
the ‘‘Shu Guang’’ project of Shanghai Education Development
Foundation (No. 09SG28) and Natural Science Foundation of
China (No. 21172068).
¨
8 (a) I. Bauer and H. Knolker, Top. Curr. Chem., 2012, 309, 203
and references therein; (b) V. Cadierno and P. Crochet, Curr.
Org. Synth., 2008, 5, 343; (c) W. Liu, H. Jiang and L. Huang,
Org. Lett., 2010, 12, 312.
9 T. J. Donohoe, J. F. Bower and L. K. M. Chan, Org. Biomol.
Chem., 2012, 10, 1322.
10 (a) A. Padwa and W. H. Pearson, in The Chemistry of
Heterocyclic Compounds, ed. E. C. Taylor and P. Wipf, John
Wiley & Sons, Inc., New York, 2002, vol. 59; (b) O. V.
Larionov and A. D. Meijere, Angew. Chem., Int. Ed., 2005,
Notes and references
1 For reviews: (a) V. F. Ferreira, M.C B.V. de Souza,
A. C. Cunha, L. O. R. Pereira and M. L. G. Ferreira, Org.
Prep. Proced. Int., 2001, 33, 411; (b) F. Bellina and R. Rossi,
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
New J. Chem.

View Article Online
Paper
44, 5664; (c) S. Kamijo, C. Kanazawa and Y. Yamamoto,
NJC
2010, 16, 9864; (b) Y. Xin, J. Zhao, J. Han and S. Zhu,
J. Fluorine Chem., 2010, 131, 642; (c) A. Arrieta, D. Otaegui,
A. Zubia, F. P. Cossıo, A. Dıaz-Ortiz, A. D. L. Hoz,
M. A. Herrero, P. Prieto, C. Foces-Foces, J. L. Pizarro and
M. I. Arriortua, J. Org. Chem., 2007, 72, 4313.
J. Am. Chem. Soc., 2005, 127, 9260; (d) F. M. R. Laia and
T. M. V. D. Pinho e Melo, Tetrahedron Lett., 2009, 50,
6180; (e) N. C. Misra, K. Panda, H. Ila and H. Junjappa,
J. Org. Chem., 2007, 72, 1246; ( f ) F. Shi, S.-W. Luo, Z.-L.
´
´
Tao, L. He, J. Yu, S.-J. Tu and L.-Z. Gong, Org. Lett., 12 (a) W. R. Dolbier Jr. and Z. Zheng, J. Fluorine Chem., 2011,
2011, 13, 4680; (g) D. J. St-Cyr, M. S. T. Morin,
132, 389; (b) W. R. Dolbier Jr. and Z. Zheng, J. Org. Chem.,
2009, 74, 5626; (c) G. Bashiardes, I. Safir, F. Barbot and
J. Laduranty, Tetrahedron Lett., 2003, 44, 8417;
(d) G. Bashiardes, I. Safir and F. Barbot, Synlett, 2007,
1707; (e) P. Armstrong, R. Grigg, M. W. Jordan and
J. F. Malone, Tetrahedron, 1985, 41, 3547.
´
´
F. Belanger-Gariepy, B. A. Arndtsen, E. H. Krenske and
K. N. Houk, J. Org. Chem., 2010, 75, 4261; (h) M. S. T.
Morin, D. J. St-Cyr and B. A. Arndtsen, Org. Lett., 2010,
12, 4916; (i) C. V. Galliford and K. A. Scheidt, J. Org. Chem.,
2007, 72, 1811.
´
´
´
´
11 (a) R. Robles-Machın, A. Lopez-Perez, M. Gonzalez- 13 M. Montazerozohori, B. Karami, M. Nasr-Esfahani and
Esguevillas, J. Adrio and J. C. Carretero, Chem.–Eur. J.,
S. A. Musavi, Heterocycl. Commun., 2007, 13, 289.
c
New J. Chem.
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013