Phenyl α-bromovinyl sulfone in cycloadditions with azomethine ylides: An unexpected facile aromatization of the cycloadducts into pyrroles

Article abstract of DOI:10.1016/j.tetlet.2012.05.160

Phenyl α-bromovinyl sulfone reacts with glycine ester Schiff bases regioselectively in the presence of catalytic amounts of AgOAc and DBU yielding polysubstituted pyrrolidine cycloadducts. Utilization of excess DBU induces subsequent facile aromatization of the cycloadducts and affords 5-arylpyrrole-2-carboxylic acid esters in 39-85% yields in a single step.

Full text of DOI:10.1016/j.tetlet.2012.05.160

Tetrahedron Letters 53 (2012) 4300–4303
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Tetrahedron Letters
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Phenyl
a-bromovinyl sulfone in cycloadditions with azomethine ylides:
an unexpected facile aromatization of the cycloadducts into pyrroles
Konstantin V. Kudryavtsev a,b, , Polina M. Ivantcova a, Andrei V. Churakov c, Victor A. Vasin d
⇑
a Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Moscow Region, Russian Federation
c Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninskii prosp. 31, Moscow 119991, Russian Federation
d Ogarev Mordovian State University, ul. Bol’shevistskaya 68, Saransk 430005, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenyl a-bromovinyl sulfone reacts with glycine ester Schiff bases regioselectively in the presence of cat-
Received 23 March 2012
Revised 23 May 2012
Accepted 31 May 2012
Available online 9 June 2012
alytic amounts of AgOAc and DBU yielding polysubstituted pyrrolidine cycloadducts. Utilization of excess
DBU induces subsequent facile aromatization of the cycloadducts and affords 5-arylpyrrole-2-carboxylic
acid esters in 39–85% yields in a single step.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylide
1,3-Dipolar cycloaddition
Pyrrolidine
Vinyl sulfone
Pyrrole
Pyrroles and their hydrogenated analogs, pyrrolidines, occupy a
sizeable part of the drug-like chemical space represented by
numerous biologically1 and pharmaceutically2 active small mole-
cules derived from these five-membered nitrogen heterocyclic
scaffolds. Some recent developments of pyrrolidine and pyrrole
SO2
EWG
R
B
Br
EWG
R
compounds include ionotropic glutamate receptor antagonists,3
a
clinical anticoagulant candidate based on a factor Xa inhibitor,4
avian influenza neuraminidase inhibitors,5 a potential agent for
treatment of liver cirrhosis,6 antimycobacterials with high protec-
tion indices,7 and nanomolar selective b-secretase inhibitors.8
An efficient synthetic strategy for the construction of polysub-
stituted pyrrolidines C is 1,3-dipolar cycloaddition between azo-
methine ylides A and activated olefins B (Scheme 1).9 Modified
5-arylpyrrolidine-2-carboxylic acid derivatives generated by this
chemistry have been used for creating Staphylococcus aureus sor-
tase A inhibitors,10 antiplatelet agents11, and thrombin inhibi-
+
1
N
H
C
N+
A
C
R
COOMe
N
H
D
Scheme 1. Formation of a pyrrolidine ring by azomethine ylide cycloaddition.
Phenyl -bromovinyl sulfone (1) as a dipolarophile and conversion of C into D.
a
tors.12 Obviously, the structural variations of pyrrolidines
C
depend on both the nature of the azomethine and dipolarophile.13
Aiming to increase the available diversity of pyrrolidines prepared
via 1,3-dipolar cycloadditions, we have studied for the first time
cycloadducts into pyrroles D (R = Ar) which are suitable intermedi-
ates for the synthesis of biologically active compounds.14
Initial experiments were conducted with iminoesters 2a,b and
vinyl sulfone 1 using an equimolar ratio of the reagents (Table
1). Despite typical application of equimolar amounts of silver(I)
acetate and triethylamine as a system for the generation of azome-
thine ylides,9 we found that 20 mol % of both AgOAc and DBU were
appropriate for efficient cycloaddition.15 1H NMR spectroscopy of
the reaction mixture, in all cases, indicated two sets of signals cor-
responding to the products 3 and 4. The regioselectivity of the
the application of phenyl
a-bromovinyl sulfone (1) as a dipolaro-
phile in reactions with azomethine ylides (Scheme 1). We also dis-
covered
a convenient transformation of the corresponding
⇑
Corresponding author. Tel.: +7 495 939 3564; fax: +7 495 932 8846.
E-mail address: kudr@org.chem.msu.ru (K.V. Kudryavtsev).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.160

K. V. Kudryavtsev et al. / Tetrahedron Letters 53 (2012) 4300–4303
4301
Table 1
Phenylsulfonyl bromopyrrolidines 3 and 4 produced via cycloadditiona
O
Br
O
Br
i)
S
S
OMe
O
O
SO2
N
OMe
+
+
OMe
O
N
N
Br
R
H
R
H
R
O
O
2a R = H
2b R = Br
( )-3a,b
( )-4a,b
1
Entry
R
Solvent
Base (equiv)
AgOAc (equiv)
Conversion of 1 (%)
Ratio 3:4b
Yieldc (3 + 4) (%)
1
2
3
4
5
6
7
H
H
H
H
H
Br
Br
Toluene
Toluene
CH2Cl2
THF
CH3CN
Toluene
Toluene
Et3N (1.0)
DBU (0.2)
DBU (0.2)
DBU (0.2)
DBU (0.2)
Et3N (1.0)
DBU (0.2)
1.0
0.2
0.2
0.2
0.2
1.0
0.2
100
100
72
96
95
3:1
2:1
1:1
1:1
1:1.1
4:1
1:1
72
90
70
95
91
90
96
100
100
a
b
c
Reagents and conditions: (i) Vinyl sulfone 1 (5.9 mmol), iminoester 2 (5.9 mmol), AgOAc, base, solvent (25 ml), rt, 24 h under argon.
Determined from 1H NMR spectroscopy of the reaction mixture.
Isolated yield.
Figure 1. ORTEP drawing of molecule 3b. Displacement ellipsoids are shown at 50% probability level.
Ph
O
cycloaddition was determined based on the singlet resonances at
5.00 and 5.20 ppm consistent with the H-5 protons of 3 and 4,
respectively. This fact indicates that the phenylsulfonyl and bro-
mine substituents are located at C-4 of the pyrrolidine based on
the absence of H-5 spin interactions. Both isomers behave similarly
under different chromatographic conditions and were isolated as
mixtures (Table 1). Fractional crystallization of the 4-bromophenyl
cycloadducts led to isolation of the individual isomer 3b, which
was characterized by X-ray analysis (Fig. 1).16
With the aim to introduce an endocyclic double bond in cyc-
loadducts 3 and 4 we studied the reaction of these pyrrolidines
with bases. Treatment of compounds 3 and 4 with Et3N or DBU
at elevated temperatures in different solvents converted the start-
ing sulfonyl bromopyrrolidines into a certain extent (data not
shown), and in all cases pyrroles 5 were isolated from the reactions
(Scheme 2). A plausible mechanism for this transformation would
include E2-type elimination of HBr, double bond migration, and
phenylsulfinic acid elimination (Scheme 2). An analogous reaction
pathway can be proposed for the aromatization of the isomeric
S
Br
O
OMe
OMe
Ar
Ar
N
H
N
H
O
5
O
3
B:
- H+
- HBr
Ph
O
S
O
OMe
OMe
+
Ar
Ar
N
H
N
H
O
O
Ph
O
S
O
-
OMe
- PhSO2
Ar
N
H
O
Scheme 2. Aromatization of cycloadduct 3 under the influence of a base.

4302
K. V. Kudryavtsev et al. / Tetrahedron Letters 53 (2012) 4300–4303
Table 2
5-Arylpyrrole-2-carboxylic acid derivatives 5 produced via the one-pot cycloaddition-aromatization cascadea
i)
OMe
OMe
SO2
N
N
H
+
O
O
Br
R
R
2a-h
1
5a-h
Pyrrole
R
Yield (%)b
Mp (°C)
Mp (°C) (Lit.)
5a
5b
5c
5d
5e
5f
H
Br
70
62
75
52
39
85
60
65
145–147
182–183
110–112
105–107
189–191
106–107
197–198
177–179
145–14619
182–18319
—
3,4,5-(MeO)3
2-F
3,5-(Cl)2
Thienyl
4-CF3
—
—
105–10619
196–19719
177–17920
5g
5h
4-Cl
a
Reagents and conditions: (i) Vinyl sulfone 1 (0.81 mmol), iminoester 2 (0.81 mmol), THF (15 ml), AgOAc (0.16 mmol), DBU (2.03 mmol), rt, 24 h under argon, then 10 h at
reflux under argon.
b
Isolated yield.
Figure 2. ORTEP drawing of the crystal packing of 5c.
cycloadduct 4. It is worth noting that pyrrolines, as the products of
partial extrusion of HBr or PhSO2H, were never detected in the
reaction mixtures under various conditions.
Carretero et al. have disclosed an excellent strategy toward pyr-
roles via a one-pot 1,3-dipolar cycloaddition of azomethine ylides
with sulfonyl dipolarophiles.17 We decided to explore if we could
days at room temperature led to the formation of pyrrole 5b in
65% isolated yield.
THF was a superior solvent for pyrrole synthesis in contrast to
toluene, CH2Cl2, CH3CN, and DMF. To decrease the reaction time,
we also used heating of the reaction mixture. Extension of the opti-
mized reaction conditions18 to other glycine ester aromatic Schiff
bases 2, obtained from both electron-rich and electron-deficient
benzaldehydes, provided 5-arylpyrrole-2-carboxylic acid esters 5
in moderate to good yields (Table 2).
achieve the same goal using phenyl
a-bromovinyl sulfone (1) in
the one-pot cycloaddition-aromatization approach. We reasoned
to combine the requirements for cycloaddition and elimination
steps and applied a catalytic amount of AgOAc and 2.5 equiv of
DBU. At least 2 equiv of the base were needed to ensure both
HBr and PhSO2H elimination. Treatment of an equimolar mixture
of 1 and 2b in THF with the chosen catalytic system over seven
Compounds 5a,b,f–h have been synthesized previously19,20 and
demonstrate the same spectral and physico-chemical characteris-
tics as described in the corresponding references (Table 2). Novel
pyrroles 5c–e were fully characterized by elemental analysis and

K. V. Kudryavtsev et al. / Tetrahedron Letters 53 (2012) 4300–4303
4303
12. Kudryavtsev, K. V.; Shulga, D. A.; Chupakhin, V. I.; Churakov, A. V.; Datsuk, N.
G.; Zabolotnev, D. V.; Zefirov, N. S. Russ. Chem. Bull. 2011, 60, 685–693.
13. Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784–6794.
NMR (Supplementary data). Trimethoxy derivative 5c was ana-
lyzed by X-ray crystallography.16 Molecules of 5c form H-bond sta-
bilized chains in the crystal (Fig. 2). Each molecule of 5c forms two
H-bonds via the pyrrole N-hydrogen atom and ether oxygen atom.
In conclusion, the cycloaddition of the geminally-substituted
dipolarophile 1 and stabilized azomethine ylides has been studied
for the first time. The combination of ligand-free, 1,3-dipolar cyclo-
addition, and elimination stages during the reaction of glycine es-
14. (a) Pinna, G. A.; Loriga, G.; Murineddu, G.; Grella, G.; Mura, M.; Vargiu, L.;
Murgioni, C.; La Colla, P. Chem. Pharm. Bull. 2001, 49, 1406–1411; (b) Cara, L. C.
L.; Camacho, M. E.; Carrion, M. D.; Tapias, V.; Gallo, M. A.; Escames, G.; Acuna-
Castroviejo, D.; Espinosa, A.; Entrena, A. Eur. J. Med. Chem. 2009, 44, 2655–2666.
15. General synthetic procedure for the cycloaddition of bromovinyl sulfone 1 and
azomethines 2: Et3N (0.597 g, 0.822 ml, 5.9 mmol) or DBU (0.183 g, 0.179 ml,
1.2 mmol) was added dropwise to a stirred solution of 1 (1.458 g, 5.9 mmol), 2
(5.9 mmol), and AgOAc (0.985 g, 5.9 mmol or 0.200 g, 1.2 mmol) in 25 ml of
solvent (Table 1) under argon. The suspension was stirred for 24 h at rt, filtered
through Celite and washed with H2O (2 Â 10 ml). The organic phase was dried
(Na2SO4), concentrated, and chromatographed on silica gel. Compound 3b: mp
160–162 °C. 1H NMR (400 MHz, CDCl3): d 2.77 (dd, J 15.2, 8.2 Hz, 1H, H-3), 3.26
(br s,1H, NH), 3.38 (dd, J 15.2, 8.2 Hz, 1H, H-3), 3.86 (s, 3H, OCH3), 4.21 (t, J
8.2 Hz, 1H, H-2), 4.93 (s, 1H, H-5), 7.38–7.44 (m, 6H, HAr), 7.57–7.64 (m, 3H,
ter Schiff bases and phenyl a-bromovinyl sulfone (1) represents a
simple pathway to 5-arylpyrrole-2-carboxylates.
Acknowledgments
H
Ar). 13C NMR (100 MHz, CDCl3): d 44.11, 52.83, 57.98, 74.71, 80.72, 122.96,
This study was supported by the Russian Foundation for Basic
Research (Project Nos. 11-03-00630-a and 11-03-91375-ST_a)
and the State Contract No. 11.519.11.2032.
128.51 (2C), 130.11 (2C), 131.01 (2C), 131.27 (2C), 133.60, 134.12, 136.00,
171.80. Anal. Calcd for C18H17Br2NO4S: C, 42.96; H, 3.41; N, 2.78. Found: C,
43.12; H, 3.45; N, 2.75.
16. Crystallographic data (excluding structure factors) for the structures reported
in this Letter have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication CCDC 832673 for compound 3b, and
CCDC 833574 for compound 5c. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44 (1223)336 033; e-mail: deposit@ccdc.cam.ac.uk].
17. (a) Lopez-Perez, A.; Robles-Machin, R.; Adrio, J.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2007, 46, 9261–9264; (b) Robles-Machin, R.; Lopez-Perez, A.; Gonzalez-
Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Eur. J. 2010, 16, 9864–9873.
18. General procedure for the synthesis of pyrroles 5 and spectral data for novel
Supplementary data
Supplementary data (NMR spectra of all synthesized com-
pounds and details of X-ray experiments) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.160.
compounds:
A solution of DBU (0.309 g, 0.304 ml, 2.03 mmol) and AgOAc
References and notes
(0.027 g, 0.16 mmol) in THF (1 ml) was added dropwise to a stirred solution of
1 (0.200 g, 0.81 mmol) and 2 (0.81 mmol) in 15 ml of THF under argon. The
suspension was stirred for 24 h at rt and for 10 h at reflux. The mixture was
diluted with 25 ml of CH2Cl2, washed with 5% HCl (2 Â 10 ml), and H2O
(2 Â 10 ml). The organic phase was dried (Na2SO4), concentrated, and
chromatographed on silica gel. Compound 5c: 1H NMR (400 MHz, CDCl3): d
3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.91 (s, 6H, OCH3), 6.46 (dd, J 3.7, 2.5 Hz,
1H, Hpyrrole), 6.75 (s, 2H, HAr), 6.94 (dd, J 3.7, 2.5 Hz, 1H, Hpyrrole), 9.42 (s, 1H,
NH). 13C NMR (100 MHz, CDCl3): d 51.64, 56.37 (3C), 61.05, 102.49 (2C),
108.02, 116.94, 122.90, 127.25, 137.17, 153.84 (2C), 161.86. Anal. Calcd for
1. Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–7256.
2. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011,
7, 442–495.
3. Larsen, A. M.; Venskutonite, R.; Valades, E. A.; Nielsen, B.; Pickering, D. S.;
Bunch, L. ACS Chem. Neurosci. 2011, 2, 107–114.
4. Anselm, L.; Banner, D. W.; Benz, J.; Zbinden, K. G.; Himber, J.; Hilpert, H.; Huber,
W.; Kuhn, W.; Mary, J.-L.; Otteneder, M. B.; Panday, N.; Ricklin, F.; Stahl, M.;
Thomi, S.; Haap, W. Bioorg. Med. Chem. Lett. 2010, 20, 5313–5319.
5. Rungrotmongkol, T.; Udommaneethanakit, T.; Frecer, V.; Miertus, S. Comb.
Chem. High Throughput Screening 2010, 13, 268–277.
C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.98; H, 5.92; N, 4.81.
Compound 5d: 1H NMR (400 MHz, CDCl3): d 3.90 (s, 3H, OCH3), 6.67–6.69 (m,
1H, Hpyrrole), 6.99–7.01 (m, 1H, Hpyrrole), 7.14–7.23 (m, 2H, HAr), 7.25–7.30 (m,
1H, HAr), 7.67 (td, J 7.8, 1.7 Hz, 1H, HAr), 9.75 (s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d 51.61, 109.71, 116.14, 116.51 (d, J 22.3 Hz), 119.02 (d, J 11.3 Hz),
123.37, 124.82, 127.44, 128.92 (d, J 8.4 Hz), 131.29, 158.86 (d, J 247.0 Hz),
161.42. Anal. Calcd for C12H10FNO2: C, 65.75; H, 4.60; N, 6.39. Found: C, 65.68;
H, 4.75; N, 6.20. Compound 5e: 1H NMR (400 MHz, DMSO-d6): d 3.77 (s, 3H,
OCH3), 6.48 (dd, J 3.8, 2.5 Hz, 1H, Hpyrrole), 6.79 (dd, J 3.8, 2.5 Hz, 1H, Hpyrrole),
7.12 (t, J 1.8 Hz, 1H, HAr), 7.69 (d, J 1.8 Hz, 2H, HAr), 11.90 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d 51.28, 109.77, 116.57, 123.37 (2C), 124.24, 126.18 (2C),
133.82, 134.57 (2C), 160.55. Anal. Calcd for C12H9Cl2NO2: C, 53.36; H, 3.36; N,
5.19. Found: C, 53.25; H, 3.40; N, 5.02.
6. Wang, X.; Gao, Z.; Xue, X.; Cheng, Y.; Yue, P.; Fang, X.; Qu, X. Toxicol. In Vitro
2011, 25, 897–904.
7. Biava, M.; Porretta, G. C.; Poce, G.; Battilocchio, C.; Alfonso, S.; De Logu, A.;
Serra, N.; Manetti, F.; Botta, M. Bioorg. Med. Chem. 2010, 18, 8076–8084.
8. Malamas, M. S.; Barnes, K.; Hui, Y.; Johnson, M.; Lovering, F.; Condon, J.; Fobare,
W.; Solvibile, W.; Turner, J.; Hu, Y.; Manas, E. S.; Fan, K.; Olland, A.; Chopra, R.;
Bard, J.; Pangalos, M. N.; Reinhart, P.; Robichaud, A. J. Bioorg. Med. Chem. Lett.
2010, 20, 2068–2073.
9. (a) Grigg, R. Chem. Soc. Rev. 1987, 16, 89–121; (b) Tsuge, O.; Kanemasa, S. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: San
Diego, 1989; Vol. 45, pp 231–349.
10. Kudryavtsev, K. V.; Bentley, M. L.; McCafferty, D. G. Bioorg. Med. Chem. 2009, 17,
2886–2893.
11. Kudryavtsev, K. V.; Podoplelova, N. A.; Novikova, A. F.; Panteleev, M. A.;
Zabolotnev, D. V.; Zefirov, N. S. Russ. Chem. Bull. 2011, 60, 679–684.
19. Dong, H.; Shen, M.; Redford, J. E.; Stokes, B. J.; Pumphrey, A. L.; Driver, T. G. Org.
Lett. 2007, 9, 5191–5194.
20. Barnes, K. D.; Kamhi, V. M.; Diehl, R. E. U.S. Patent 5306,827; 1994; Chem. Abstr.
1993, 119, 225812.