Reaction of α-amido sulfones with functionalized nitrocompounds: A new two-step synthesis of N-alkoxycarbonyl-2,5-disubstituted pyrroles

Article abstract of DOI:10.1039/c4ra08112a

Reaction of α-amido sulfones with nitro ketals promoted by KF on alumina provides the corresponding adducts which, upon treatment with p-toluenesulfonic acid, generate the corresponding N-alkoxycarbonyl-2,5-disubstituted pyrroles. The latter transformation involves a cascade process including ketal cleavage, ring closure and final aromatization by nitrous acid elimination.

Full text of DOI:10.1039/c4ra08112a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Reaction of a-amido sulfones with functionalized
nitrocompounds: a new two-step synthesis of N-
alkoxycarbonyl-2,5-disubstituted pyrroles†
Cite this: RSC Adv., 2014, 4, 43258
Received 4th August 2014
Accepted 5th September 2014
*
*
Roberto Ballini, Serena Gabrielli, Alessandro Palmieri and Marino Petrini
DOI: 10.1039/c4ra08112a
www.rsc.org/advances
Reaction of a-amido sulfones with nitro ketals promoted by KF on
In a early work g-amino ketones I (Lg]OH) were obtained by
alumina provides the corresponding adducts which, upon treatment reductive cleavage of isoxazolines which upon reaction with
with p-toluenesulfonic acid, generate the corresponding N- acetic acid were converted into pyrroles III.14 Later on, a
alkoxycarbonyl-2,5-disubstituted pyrroles. The latter transformation procedure involving a Ti(IV) promoted Mukaiyama condensa-
involves a cascade process including ketal cleavage, ring closure and tion between silyl enol ethers and azido acetals was employed to
final aromatization by nitrous acid elimination.
prepare g-azido ketones that, under reductive conditions were
converted into polysubstituted pyrroles.15 More recently,
unsubstituted N-acylpyrroles have been prepared by acid
promoted ring closure of 4-amido-3-methoxy aldehyde dimethyl
acetals.16 Although quite efficient, the latter procedure is
affected by poor versatility since only the acyl moiety can be
changed in the target products. A common feature of the above
cited methods is the utilization of a hydroxy or a methoxy group
as leaving group used for the nal aromatization step. Knowing
the ability of the nitro system in acting as a good leaving group
in elimination reactions, we devised a new procedure for the
synthesis of N-alkoxycarbonyl-2,5-disubstituted pyrroles
exploiting a two step strategy as depicted in Scheme 2.17 a-
Amido sulfones 1 are well-known precursors of reactive N-acy-
limines which have been largely involved in nitro-Mannich
reactions promoted or catalyzed under basic conditions.18 For
our purpose, the N-acylimine is generated from 1 by base-
promoted elimination of p-toluenesulnc acid and then
attacked by the nitronate anion corresponding to nitro ketal 2
leading to the nitrocarbamate adduct 3.
The pyrrole ring occurs frequently in many natural products of
paramount importance for their notable bioactivity.1 Addition-
ally, this nitrogenated heterocyclic system is present in several
compounds of synthetic origin known for their antimycobacterial
activity and DNA cross-linking properties.2,3 Pyrrole-containing
macrocyclic derivatives are also involved in organic electronic
materials and neutral anion receptors.4,5 The ourishing chem-
istry associated with pyrrole synthesis has evidenced a plethora of
different procedures since the discovery of the Paal–Knorr and
Hantzsch reactions.6 Modern variants of these old-fashioned
methodologies involve multicomponent processes which are
particularly attractive for their efficiency and eco-sustainability.7
Several of these new synthetic procedures no longer entail the use
of dicarbonyl derivatives for the ring building but exploit other
functionalized backbones such as 1,4-dihalodienes,8 enamides,9
aminoketones,10 aminoalcohols11 and isonitriles.12
Intramolecular ring closure of amino derivatives I, bearing a
carbonyl function in a suitable position of the alkyl framework,
represents a viable process for the preparation of pyrrolines II
(Scheme 1).13 This strategy can also be settled for the synthesis
of pyrroles III but would require a tandem elimination process
aer the ring formation in order to provide the needed aromatic
system. To this goal, some synthetic protocols aimed to the
efficient preparation of precursors of type I have been devised.
In order to test the feasibility of this approach, a-amido
sulfone 1a was made to react with nitro ketal 2a under various
reaction conditions as summarized in Table 1.
`
School of Science and Technology, Chemistry Division, Universita di Camerino, via S.
Agostino, 1, I-62032 Camerino, Italy. E-mail: serena.gabrielli@unicam.it; marino.
petrini@unicam.it; Fax: +39 0737 402297
† Electronic supplementary information (ESI) available: General procedures for
the preparation of compounds 3 and 4. Copies of the 1H NMR and 13C NMR
spectra for new compounds prepared. See DOI: 10.1039/c4ra08112a
Scheme 1 General strategy for the synthesis of substituted pyrroles.
43258 | RSC Adv., 2014, 4, 43258–43261
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Scheme 3 Proposed mechanism for the formation of pyrrole 4 from
nitro ketal 3.
Scheme 2 Synthetic plan for the two-step synthesis of 2,5-disubsti-
tuted pyrroles.
Because of the superior stability toward cleavage of cyclic
ketals over their open chain counterparts, the acidity level of the
reaction mixture must be carefully tuned and accounting for the
ability of macroreticular sulfonic resin Amberlyst 15 to carry out
related processes, this solid acid was initially checked for this
purpose (Table 2, entries 1–3).21
Table 1 Representative optimisation results for 3aa
Reaction of compound 3a with Amberlyst 15 was proved
ineffective in MeOH and only a modest yield of pyrrole 4a was
obtained increasing the solubility of the substrate by adding
CHCl3 to MeOH.
Other solid acids were tested for this conversion such as
Zeolite HSZ-320 and carbon-sulfonic acid,22 but only the latter
reagent provided encouraging results (Table 2, entries 4–5).
Finally, the utilization of p-toluenesulfonic acid gave a rather
satisfactory yield of pyrrole 4a when employed in equimolar
amount (Table 2, entry 6). Since a reduction of half the amount
of acid used resulted only in a negligible decrease in the yield of
the obtained pyrrole 4a, these conditions were selected for the
method development. N-Alkoxycarbonyl groups in a-amido
sulfones 1 other than N-ethoxy and N-methoxycarbonyl were
tested with the aim of providing a possible easier cleavage of the
carbamoyl moiety in the nal pyrrole 4. N-Benzyloxycarbonyl
sulfones 1 (R2 ¼ Bn) were less reactive than their methyl and
Entry
Base
Solvent
3a Yieldb [%]
1
2
3
4
5
NaH
NaH
NaH
Cs2CO3
KF/Al2O3
THF
THF
THF
CH2Cl2
EtOAc
50c
89
72d
83
86
a
Conditions: 1a (0.5 mmol), nitroalkane 2a (1.0 mmol), base (1.5
b
c
mmol), rt, 18 h. Yields of isolated products. 1 equiv. 2a (0.5 mmol)
was used. 2 equiv. of NaH were used.
d
Sodium hydride was the rst base used because of its known
efficiency in promoting the addition reaction of nitromethane
to a-amido sulfones.19 A preliminary trial using equimolar
amount of reactants and 3 equivalents of NaH gave a modest
result while a notable increase in the chemical yield was
observed doubling the amount of the nitrocompound 2a (Table
1, entries 1–2). In order to circumvent the problems associated
with the utilization of NaH as basic promoter (inammability,
dry conditions etc.), another couple of bases working under
heterogeneous conditions were tested for our process. Potas-
sium uoride on alumina and Cs2CO3 were proved to be effi-
cient promoters for this addition and aer a careful evaluation
we decided to employ the former base for all the next reac-
tions.20 The second step of our protocol for the preparation of
2,5-disubstituted pyrroles 4 entails an acid-promoted cascade
Table 2 Representative optimisation results for pyrrole 4aa
Entry
Acid (g)
Solventb
4a Yieldc [%]
1
2
3
4
5
6
7
Amb 15 (0.5)
Amb 15 (0.5)
Amb 15 (1.0)
HSZ-320 (1.0)
C-SO3H (1.0)
p-TSA (1.0)f
MeOH
Trace
23
CHCl3/MeOH
CHCl3/MeOH
CHCl3/MeOH
CHCl3/MeOH
CHCl3/MeOH
CHCl3/MeOH
process involving
a preliminary ketal protonation from
19
Traced
compound 3, followed by ring closure to the intermediate pyr-
rolidine and a nal aromatisation through nitrous acid and
ethylene glycol elimination (Scheme 3). An alternative pathway
involving direct formation of the carbonyl system, ring closure
to the parent 1-pyrroline followed by nitrous acid elimination
cannot obviously be ruled out.
56e
72
70
p-TSA (0.5)f
a
b
Conditions: 1a (0.5 mmol), acid, 60 ꢀC, 24 h. CHCl3/MeOH, 2 : 1.
Yields of isolated products.
Equivalents.
c
f
d
e
Zeolite. Carbon-sulfonic acid.22
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 43258–43261 | 43259

View Article Online
RSC Advances
Communication
Table 3 Synthesis of N-alkoxycarbonyl-2,5-disubstituted pyrroles 4
a-Amido
Sulfone 1
Nitro
ketal 2
Entry
R1
R2
R3
3 Yielda (%)
Pyrrole 4
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Me
2a
2b
2a
2c
2c
2d
2e
2a
2f
Me
4-MeOPh
Me
4-t-BuPh
4-t-BuPh
Ph(CH2)2
1-Hexyl
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
4a
4b
4c
4d
4e
4f
4g
4h
4i
70 (53)c
55
4-NO2Ph
4-NO2Ph
4-MeOPh
Ph
4-CNPh
2-FPh
1-Naphthyl
Et
65
63
80
99
97
99
67
90
95
88
72
84
55
75
79
53
74
9
Ph
Ph(Me)CH
Et
28
10
11
12
4-FPh
4-NO2Ph
Ph
2g
2h
2i
3j
3k
3l
4j
4k
4l
57d
73
1b
1d
4-MePh
54
a
Reaction conditions: a-amido sulfone (2.0 mmol), nitro ketal (4.0 mmol), KF/Al2O3 (6.0 mmol) in EtOAc (20 mL), at rt, 18 h. Yield of pure isolated
product. b Reaction conditions: nitrocarbamate (1.0 mmol), p-TSA (0.5 mmol), in CHCl3–MeOH (2 : 1, 9 mL) at 60 ꢀC, 24 h. Yield of pure isolated
product. Yield in parenthesis refers to the reaction carried out directly on crude 3a obtained aer ltration and evaporation of the solvent
calculated on compound 1a. Reaction time 48 h.
c
d
ethyl counterparts in the nitro-Mannich reaction, while nitro- value is close to that recorded (60%) for the whole process
carbamates 3 bearing the N-t-butoxycarbamoyl moiety (R2 ¼ t-Bu) carried out on puried 3a thus demonstrating that isolation of
gave disappointing results in the nal step probably because of the nitrocarbamates can be avoided with a minimum loss in the
acidic conditions affecting the t-butyl group.
overall yield of the target pyrroles 4.
The optimised conditions found for the two-step trans-
formation were applied to the reaction of different a-amido
sulfones 1 with nitro ketals 2 (Table 3). The addition reaction
generating the nitro carbamate 3 was quite efficient for most of
the combinations tested. The use of the solid base is instru-
mental in order to simplify the work up operations which
involve ltration of the solid base and evaporation of the
solvent. The excess of nitro ketal 2 employed, can be almost
completely recovered aer column chromatography together
with the wanted adduct 3. The subsequent cascade process
leading to the pyrrole derivative 4 was rather satisfactory for
most of the adducts 3 obtained. For unknown reasons
compound 3i obtained from a-amido sulfone 1h bearing an
alkyl framework gave disappointing results when converted into
the corresponding pyrrole (Table 3, entry 9). Conversely, the
nature of substituent R3 in adduct 3 did not affect the outcome
of the process so that alkyl or aryl groups can be inserted as
substituents in the pyrrole ring. Although isolation of nitro-
carbamates 3 is instrumental for the recovery of unreacted nitro
ketals 2, an attempt to use crude nitrocarbamates for the next
cyclization step has been pursued in order to evidence possible
advantages in the overall process. Crude compound 3a,
obtained by ltration of the basic promoter and evaporation of
the solvent, has been used for the next step leading to the
formation of pyrrole 4a in 53% yield based on substrate 1a. This
Conclusions
In conclusion, a novel procedure for the preparation of 2,5-
disubstituted pyrrole derivatives has been devised starting from
a-amido sulfones 1 which are made to react with nitro ketals 2
in a base promoted addition reaction. The obtained adducts 3
upon treatment with p-toluenesulfonic acid undergo to a
cascade reaction involving ketal cleavage, cyclization and nal
aromatization to the target substituted pyrrole. The overall
process is featured by a ready availability of the starting mate-
rials employed, inexpensive reactants and solvents used, mild
reaction conditions and molecular diversity of the substituted
pyrroles prepared. Further studies aimed at enlarging the
synthetic signicance of this procedure to other polysubstituted
pyrrole systems are currently underway in our laboratory.
Acknowledgements
We acknowledge nancial support from University of Camer-
ino, and FIRB National Project ‘Metodologie di nuova gen-
erazione nella formazione di legami carbonio-carbonio e
carbonio-eteroatomo in condizioni eco-sostenibili’.
43260 | RSC Adv., 2014, 4, 43258–43261
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
11 (a) S. Qu, Y. Dang, C. Song, M. Wen, K.-W. Huang and
Z.-X. Wang, J. Am. Chem. Soc., 2014, 136, 4974–4991; (b)
S. Michlik and R. Kempe, Nat. Chem., 2013, 5, 140–144; (c)
D. Srimani, Y. Ben-David and D. Milstein, Angew. Chem.,
Int. Ed., 2013, 52, 4012–4015.
12 (a) N. Ono and T. Okujima, Synthesis of Pyrroles and Their
Derivatives from Isocyanides, in Isocyanide Chemistry:
Applications in Synthesis and Material Science, ed. V. G.
Nenajdenko, Wiley-VCH, Weinheim, 2012, ch. 11, pp. 385–
430; (b) T. Wu, L. Pan, X. Xu and Q. Liu, Chem. Commun.,
2014, 50, 1797–1800; (c) I. Yavari and M. Nematpour, Helv.
Chim. Acta, 2013, 96, 2098–2102; (d) R. Sharma, K. Kumar,
M. Chouhan, V. Grover and V. A. Nair, RSC Adv., 2013, 3,
14521–14527; (e) M. Gao, C. He, H. Chen, R. Bai, B. Cheng
and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 6958–6961; (f)
S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem.
Soc., 2005, 127, 9260–9266.
Notes and references
1 (a) D. L. J. Clive and P. Cheng, Tetrahedron, 2013, 69, 5067–
5078; (b) I. S. Young, P. D. Thornton and A. Thompson,
Nat. Prod. Rep., 2010, 27, 1801–1839; (c) H. Fan, J. Peng,
M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264–
287; (d) C. T. Walsh, S. Garneau-Tsodikova and
A. R. Howard-Jones, Nat. Prod. Rep., 2006, 23, 517–531.
2 M. Biava, G. C. Porretta, G. Poce, C. Battilocchio, S. Alfonso,
A. de Logu, F. Manetti and M. Botta, ChemMedChem, 2011, 6,
593–599.
3 (a) T.-L. Su, T.-C. Lee and R. Kakadiya, Eur. J. Med. Chem.,
2013, 69, 609–621; (b) T. Vaijayanthi, T. Bando,
G. N. Pandian and H. Sugiyama, ChemBioChem, 2012, 13,
2170–2185.
4 S. C. Rasmussen and S. J. Everson, Prog. Polym. Sci., 2013, 38,
1773–1804.
13 (a) M. L. Wong, I. A. Guzei and L. L. Kiessling, Org. Lett., 2012,
14, 1378–1381; (b) T. J. Harrison and G. R. Dake, J. Org. Chem.,
2005, 70, 10872–10874; (c) J. R. Lennox, S. C. Turner and
H. Rappoport, J. Org. Chem., 2001, 66, 7078–7083.
14 (a) S. K. Mukerji, K. K. Sharma and K. G. B. Torssell,
Tetrahedron, 1983, 39, 2231–2235; (b) S. S. Ghabrial,
I. Thomsen and K. G. B. Torssell, Acta Chem. Scand., Ser. B,
1987, 41, 426–434.
5 P. Dydio, D. Lichosyt and J. Jurczak, Chem. Soc. Rev., 2011, 40,
2971–2985.
6 G. W. H. Cheeseman and C. W. Bird, in Comprehensive
Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees,
Pergamon Press, Oxford, 1984, vol. 4, pp. 89–147.
´
´
7 Reviews: (a) V. Estevez, M. Villacampa and J. C. Menendez,
´
Chem. Soc. Rev., 2014, 43, 4633–4657; (b) V. Estevez,
´
M. Villacampa and J. C. Menendez, Chem. Soc. Rev., 2010,
15 (a) H. Bertschy, A. Meunier and R. Neier, Angew. Chem., Int.
Ed. Engl., 1990, 29, 777–778; (b) E. Bellur, H. Gorls and
P. Langer, J. Org. Chem., 2005, 70, 4751–4761.
39, 4402–4421, for some recent examples see: (c)
M. Zhang, X. Fang, H. Neumann and M. Beller, J. Am.
Chem. Soc., 2013, 135, 11384–11388; (d) C. C. Silveira,
;
¨
16 (a) T. Maehara, R. Kanno, S. Yokoshima and T. Fukuyama,
Org. Lett., 2012, 14, 1946–1948; (b) R. A. W. Neves Filho,
S. Stark, M. C. Morejon, B. Westermann and
L. A. Wessjohann, Tetrahedron Lett., 2012, 53, 5360–5363.
17 (a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001; (b) R. Ballini, A. Palmieri and L. Barboni,
Chem. Commun., 2008, 2975–2985.
S. R. Mendes, G. M. Martins, S. C. Schlosser and
T. S. Kaufman, Tetrahedron, 2013, 69, 9076–9085; (e)
B.-L. Li, P.-H. Li, X.-N. Fang, C.-X. Li, J.-L. Sun, L.-P. Mo
and Z.-H. Zhang, Tetrahedron, 2013, 69, 7011–7018; (f)
X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou and S. J. Ji, Org.
Lett., 2013, 15, 4246–4249.
8 (a) M. Zhan, S. Zhang, W.-X. Zhang and Z. Xi, Org. Lett., 2013,
15, 4182–4185; (b) W. Geng, W.-X. Zhang, W. Hao and Z. Xi, J.
Am. Chem. Soc., 2012, 134, 20230–20233; (c) S. Li, Q. Liao,
F. Wang, C. Xi and L. Zhang, Eur. J. Org. Chem., 2010,
5426–5431.
9 (a) Y.-H. Xu, T. He, Q.-C. Zhang and T.-P. Loh, Chem.
Commun., 2014, 50, 2784–2786; (b) M.-N. Zhao, Z.-H. Ren,
Y.-Y. Wang and Z. H. Guan, Chem.–Eur. J., 2014, 20, 1839–
1842; (c) B. Li, N. Wang, Y. Liang, S. Xu and B. Wang, Org.
Lett., 2013, 15, 136–139; (d) M. Yamagishi, K. Nishigai,
T. Hata and H. Urabe, Org. Lett., 2011, 13, 4873–4875; (e)
A. Saito, O. Konishi and Y. Hanzawa, Org. Lett., 2010, 12,
372–374.
10 (a) R. Yan, X. Kang, X. Zhou, X. Li, X. Liu, L. Xiang, Y. Li and
G. Huang, J. Org. Chem., 2014, 79, 465–470; (b) M. Egorov,
B. Delpech, G. Aubert, T. Cresteil, M. C. Garcia-Alvarez,
P. Collin and C. Maranzano, Org. Biomol. Chem., 2014, 12,
1518–1524; (c) K. Ohta, F. Taguchi and Y. Endo,
Heterocycles, 2012, 86, 165–170; (d) A. Palmieri, S. Gabrielli,
C. Cimarelli and R. Ballini, Green Chem., 2011, 13, 3333–
3336; (e) Q. Li, A. Fan, Z. Lu, Y. Cui, W. Lin and X. Jia, Org.
Lett., 2010, 12, 4066–4069.
18 (a) M. Petrini, Chem. Rev., 2005, 105, 3949–3977; (b) A. Noble
and J. C. Anderson, Chem. Rev., 2013, 113, 2887–2939, For
ˇ
ˇ
some very recent examples see: ; (c) D. M. Barber, A. Duris,
A. L. Thompson, H. J. Sanganee and D. J. Dixon, ACS
Catal., 2014, 4, 634–638; (d) T. A. Davis, A. E. Vilgelm,
A. Richmond and J. N. Johnston, J. Org. Chem., 2013, 78,
10605–10616; (e) D. Cao, Z. Chai, J. Zhang, Z. Ye, H. Xiao,
H. Wang, J. Chen, X. Wu and G. Zhao, Chem. Commun.,
2013, 49, 5972–5974.
19 (a) R. Ballini and M. Petrini, Tetrahedron Lett., 1999, 40,
4449–4452; (b) E. Foresti, G. Palmieri, M. Petrini and
R. Profeta, Org. Biomol. Chem., 2003, 1, 4275–4281.
20 Reviews: (a) B. Basu and B. Mandal, Curr. Org. Chem., 2011,
15, 3870–3893; (b) B. E. Blass, Tetrahedron, 2002, 58, 9301–
9320.
21 (a) R. Ballini, S. Gabrielli, A. Palmieri and M. Petrini, Adv.
Synth. Catal., 2010, 352, 2459–2462; (b) A. Palmieri,
S. Gabrielli and R. Ballini, Chem. Commun., 2010, 46, 6165–
6167.
22 B. M. Rao, G. N. Reddy, T. V. Reddy, B. L. A. P. Devi,
R. B. N. Prasad, J. S. Yadav and B. V. S. Reddy, Tetrahedron
Lett., 2013, 54, 2466–2471.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 43258–43261 | 43261