Regioselective synthesis of 3-substituted pyrroles by nucleophilic addition of 3-(1-arylsulfonylalkyl) pyrroles activated under basic or acid conditions

Article abstract of DOI:10.1002/chem.201100434

Conditioned pyrroles! Sulfonyl pyrroles, obtained regioselectively from commercial N-triisopropylsilylpyrrole, undergo removal of the arylsulfonyl group under basic or acidic conditions to give vinylogous imino-like derivatives (see scheme; TIPS=triisopropylsilyl). These electrophilic intermediates react with nucleophilic reagents to give 3-functionalized pyrroles. Copyright

Full text of DOI:10.1002/chem.201100434

COMMUNICATION
DOI: 10.1002/chem.201100434
Regioselective Synthesis of 3-Substituted Pyrroles by Nucleophilic Addition
of 3-(1-Arylsulfonylalkyl) Pyrroles Activated under Basic or Acid Conditions
Fabio Martinelli, Alessandro Palmieri, and Marino Petrini*[a]
This paper is dedicated to Prof. Alfredo Ricci on the occasion of his retirement
Functionalization of heteroaromatic systems in a regiose-
lective fashion often represents a considerable challenge.
The insertion of a desired substituent at a specific position is
in fact thwarted by the intrinsic reactivity of the ring. Elec-
tron-rich five-membered-ring heterocycles are preferentially
attacked at C2 by electrophiles leading to the corresponding
substituted derivatives.[1] Even metalation by strongly basic
organometallic reagents occurs at the same position provid-
ing an electronically complementary way of functionaliza-
tion without altering the regioselectivity bias. In this context,
pyrrole rings exhibit the usual trend towards a preferential
C2 substitution, whereas it is widely known that indoles
have a tendency to afford 3-substituted derivatives.[2] The in-
terest in 3-functionalized pyrroles mainly stems from their
embedding in several compounds of natural as well as syn-
thetic origin, many of which display very interesting biologi-
cal activities.[3] In addition, polymers and other organic ma-
terials often include the 3-alkylpyrrole moiety as a key
structural motif.[4]
the considerable advantage to be easily introduced in the
pyrrole ring, but also to be very easily removed under mild
conditions.[7] On the other hand, N-alkyl pyrroles have re-
cently been involved in an interesting synthetic approach di-
rected to the preparation of 3-substituted pyrroles using al-
kynes, as well as carbonyl derivatives, under indium cataly-
sis.[8] Because of the involvement of bispyrrolyl intermedi-
ates in the reaction pathway, a threefold to fourfold excess
of pyrrole substrates had to be used to ensure an efficient
conversion. Recently, we reported an innovative procedure
for the preparation of 3-substituted indole derivatives 3
based on the utilization of 3-(1-arylsulfonylalkyl) indoles 1
as precursors of reactive alkylideneindolenines 2a
(Scheme 1).[9]
Scheme 1. General synthetic strategy for indole or pyrrole functionaliza-
tion. Ar=aryl; Nu=nucleophile.
It has been reported that N-substitution in pyrroles has a
significant effect in the orientation of the incoming electro-
phile during the corresponding aromatic substitution.[5] In-
creasing the bulkiness of the N-substituent, regardless of its
electronic properties, usually tends to shift the regioselectivi-
ty towards the 3-position.[6] The most pronounced shift is re-
ported using the N-triisopropylsilyl group. This moiety has
Upon removal of arylsulfinic acid under basic conditions,
sulfonyl indole 1 is converted into 2a, which effectively acts
as a vinylogous imino derivative in the reaction with a wide
range of nucleophilic reagents.[10] Acidic reagents (Lewis-
type) are also able to remove the arylsulfinic group from 1
leaving an iminium ion 2b, which can react with weak nucle-
ophiles thus generating the substituted products 3.[11] An
iminium ion structurally related to 2b is supposed to be
active in the indium-catalyzed procedure involving reaction
of N-alkyl pyrroles.[8] Therefore, we decided to test the feasi-
bility of our procedure effective on indoles for the prepara-
tion of sulfonyl pyrrole analogues.[12] Amongst the various
N-substituted pyrroles tested for this purpose, commercial
N-triisopropylsilyl pyrrole 4 proved to be the most effective
in giving the corresponding sulfonyl pyrroles 5 (Table 1).[13]
[a] F. Martinelli, Dr. A. Palmieri, Prof. M. Petrini
School of Science and Technology
Chemistry Division, Universitꢀ di Camerino
Via S. Agostino, 1, 62032 Camerino (Italy)
Fax : (+39)0737-402297
E-mail: marino.petrini@unicam.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100434.
Chem. Eur. J. 2011, 17, 7183 – 7187
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7183

Table 1. Synthesis of 1-triisopropylsilyl-3-(1-tosylalkyl) pyrroles 5 by a
three-component reaction. TIPS=triisopropylsilyl.
during the desilylation of compound 5a was that the fluo-
ride anion was unable to achieve eliminative desulfonylation
to give intermediate 2a in the presence of diethyl malonate
7a. Potassium fluoride on basic alumina acted apparently as
a basic promoter, being ineffective in aiding the desilylation
of compounds 5.[14] Organic reactions on a solid support rep-
resent a crucial feature for the development of environmen-
tally friendly chemical processes. According to this principle,
a procedure involving a fully heterogeneous system for con-
version of derivatives 5 to functionalized pyrroles 8 was en-
visaged.[15] Silica-gel-supported TBAF[16] was demonstrated
to be effective for desilylation of derivatives 5 and therefore
synthesis of compounds 8 was attempted by simply mixing
sulfonyl pyrroles 5 and two solid promoters (TBAF/SiO2
and KF/basic Al2O3) in the presence of diethyl malonate 7a
(Scheme 3). To our delight, the two solid promoters worked
independently in a domino process. As soon as desilylated
pyrrole 6 was formed it reacted with the nucleophile
through the alkylidenepyrroline intermediate 2a leading to
the final functionalized pyrrole 8 (Scheme 3).
Entry
Product
R
Yield
[%][a]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
5g
5h
5i
Et
n-C5H11
n-C3H7CH=CH2
CH2CH2Ph
c-C6H11
77
69
75
58
78
55
60
57
64
56
C6H5
4-tBuC6H4
4-NO2C6H4
4-MeOC6H4
4-PhC6H4
10
5j
[a] Yield of pure isolated product.
The chemical yields for this process were far superior
compared to the two-step transformation as demonstrated
for the preparation of compound 8a (53 vs. 90% as reported
in Scheme 3). A large variety of methylene active reagents 7
were then reacted with sulfonyl pyrroles 5. Malonic acid die-
sters, 1,3-dicarbonyl derivatives, and b-keto esters were
equally effective in giving 3-functionalized pyrroles 8 in ex-
cellent yields (Scheme 3). In particular, 2-acetamido malo-
nate 7d was able to provide a rapid entry to pyrroles 8e and
8 f (Scheme 3), which can be considered as precursors of the
The triisopropylsilyl (TIPS) moiety was of crucial impor-
tance for the subsequent synthetic application of sulfonyl
pyrroles 5, as described later in this communication. A set
of aryl- as well as alkyl aldehydes, were found to be effec-
tive in producing the corresponding sulfonyl pyrroles 5. Be-
cause of the known sensitivity of the pyrrole ring towards
acidic environment, the experimental conditions had to be
carefully tuned. Relative to the original procedure opti-
mized for indoles, a decrease in the medium acidity of para-
toluenesulfonic acid and an increase of the amount of the al-
dehyde were mandatory to obtain satisfactory yields. Sulfo-
nyl pyrroles 5 have been subsequently tested in the reaction
with different active methylene compounds under basic con-
ditions. However, as already observed for the parent indole
derivatives, N-protected compounds 5 did not eliminate the
arylsulfinic moiety in the presence of a base. Formation of
the reactive alkylideneindolenine intermediate related to 2a
was not observed. It was thus necessary to remove the TIPS
group prior to the nucleophile addition using tetrabutylam-
monium fluoride (TBAF) under standard conditions
(Scheme 2). The unsubstituted compound 6a, resulting from
deprotection of 5a, reacted as expected with diethyl malo-
nate 7a in the presence of KF on basic alumina, leading to
the functionalized adduct 8a.
corresponding amino acid derivatives achievable by
a
common hydrolysis–decarboxylation procedure. A particular
behavior was observed using malononitrile 7h, which in the
reaction with sulfonyl pyrroles 5a and 5b afforded com-
pounds 9 deriving from a double attack (Scheme 4). This
result is consistent with the low steric hindrance of the ma-
lononitrile enolate, which allows multiple addition to
occur.[17]
Prior removal of the N-TIPS group from sulfonyl pyrroles
5 is required for every process carried out under basic con-
ditions. Conversely, generation of reactive iminium ions of
type 2b using Lewis acid promoters, may be done in the
presence of the N-protection, which often even facilitates its
formation.[8] Using AlEtCl2, a fast elimination of the arylsul-
fonyl anion on the sulfonyl pyrroles 5 was indeed observed
at moderately low temperature (À108C). The resulting imi-
nium ion intermediate promptly reacted with a series of nu-
cleophilic reagents 10 leading to the corresponding adducts
11 (Scheme 5).
The modest results recorded in the described two-step
process, prompted us to exploit an alternative procedure to
obtain adducts of type 8. A preliminary observation made
Silyl enol ethers and silyl ketene acetals 10a–f were effec-
tive in giving the corresponding adducts in good yields
(Scheme 5). Particularly, the utilization of silyl derivatives
10e and 10 f gave a ready entry to pyrrole derivatives 11 g
and 11h, which are hard to access through a conventional
Friedel–Crafts process. Similarly, a densely functionalized
pyrrole derivative 11i was prepared by reaction of sulfonyl
pyrrole 5a with 2-trimethylsilyloxy furan 10g (Scheme 5).
Scheme 2. Two-step synthesis of functionalized 3-substituted pyrroles 8.
pTol =p-tolyl.
7184
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7183 – 7187

Regioselective Synthesis of 3-Substituted Pyrroles
COMMUNICATION
and so it was therefore re-
tained in the final functional-
ized pyrroles 11. This feature
increases the versatility of our
procedure because unlike N-
alkyl pyrroles, the silyl protect-
ing group can be easily re-
moved under mild condi-
tions.[18]
In conclusion, a viable and
regioselective synthesis of 3-(1-
arylsulfonylalkyl) pyrroles
5
can be carried out starting
from commercially available
N-TIPS pyrrole 4. These sulfo-
nyl pyrrole derivatives under-
go N-deprotection, sulfinic
acid elimination, and nucleo-
philic addition by methylene-
active compounds 7 by using a
mixture of solid promoters
(TBAF/SiO2 and KF/Al2O3).
In a complementary way, re-
moval of the arylsulfinate
anion from sulfonyl pyrroles 5
by AlEtCl2 generates the imi-
nium species 2b, which reacts
with silyl enol ethers and relat-
ed weak nucleophiles 10 to
provide a different set of func-
tionalized pyrroles 11. These
results demonstrate that this
new procedure provides
a
viable access to 3-functional-
ized pyrroles, which are often
otherwise difficult to produce.
Applications in asymmetric
synthesis can be foreseen.
Scheme 3. Reaction of sulfonyl pyrroles 5 with methylene active compounds leading to 3-functionalized pyr-
role derivatives 8. Reaction conditions: sulfonyl pyrrole 5 (1.0 mmol), nucleophile 7 (1.5 mmol), tetrabutylam-
monium fluoride (TBAF)/SiO2 (1.2 g), and KF/Al2O3 (2.5 g) in dichloromethane (10 mL) at RT. Reaction
times are in parentheses. Product yields of compounds 8 are that of the pure isolated product.
Experimental Section
General procedure for the synthesis of compounds 5: The appropriate al-
dehyde (4 mmol) was added to a stirred solution of pyrrole 4 (2 mmol),
monohydrate para-toluenesulfonic acid (0.6 mmol), and para-toluenesul-
finic acid (2.4 mmol) in Et2O (1.5 mL). The resulting reaction mixture
was stirred at 308C for 2 h and, after cooling, was treated with saturated
NaHCO3 (7 mL). The aqueous layer was extracted with CH2Cl2 (3ꢂ
20 mL) and the combined organic extracts were dried over Na2SO4.
After filtration and removal of the solvent at reduced pressure, the ob-
tained crude product 5 was purified by flash chromatography (hexane/
ethyl acetate 8:2).
Scheme 4. Synthesis of bis-adducts 9 using manolonitrile as the nucleo-
phile.
Introduction of an allyl framework by electrophilic substitu-
tion is a common practice in synthesis because of the mani-
fold transformations pertaining to terminal double bonds.
Using our reaction conditions, allyltrimethylsilane was
poorly effective as an allylating agent, whereas better results
were obtained using the more nucleophilic allyltributyltin
10h, as evidenced in the formation of compound 11j
(Scheme 5). Interestingly, in all the reactions tested using
AlEtCl2, the Lewis acid did not affect the N-TIPS protection
General procedure for the synthesis of compounds 8: TBAF on silica
(1.2 mmol, 1.2 g) and KF on basic alumina (14 mmol, 2.5 g) were added
to a stirred solution of sulfonyl pyrrole 5 (1 mmol) and active methylene
compound 7 in CH2Cl2 (10 mL). The resulting heterogeneous mixture
was stirred at room temperature for the appropriate time (see Scheme 3),
then the solvent was removed at reduced pressure and the resulting solid
mixture was directly charged into
a flash chromatography column
(hexane/ethyl acetate, 8:2), giving pure product 8.
Chem. Eur. J. 2011, 17, 7183 – 7187
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7185

M. Petrini et al.
postgraduate fellowship. The authors
are greatly indebted to Dr. L. Bernar-
di for helpul discussions.
Keywords: carbonyl
compounds
imino
·
heterocycles
·
·
compounds
nucleophilic addition · pyrroles
[1] J. A. Joule, K. Mills, Heterocyclic
Chemistry, 5th ed., Wiley, New
York, 2010.
[2] a) G. Bartoli, G. Bencivenni, R.
Dalpozzo, Chem. Soc. Rev. 2010,
39, 4449–4465; b) M. Bandini,
A. Eichholzer, Angew. Chem.
2009, 121, 9786–9824; Angew.
Chem. Int. Ed. 2009, 48, 9608–
9644.
[3] a) H. Fan, J. Peng, M. T.
Hamman, J.-F. Hu, Chem. Rev.
2008, 108, 264–287; b) F. Belli-
na, R. Rossi, Tetrahedron 2006,
62, 7213–7256; c) S.-J. Tan, Y.-
M. Choo, N. F. Thomas, W. T.
Robinson, K. Komiyama, T.-S.
Kam, Tetrahedron 2010, 66,
7799–7806; d) A. Franks, C.
Tronrud, K. Kiakos, J. Kluza, M.
Munde, T. Brown, H. Mackay,
W. D. Wilson, D. Hochhauser,
J. A. Hartley, M. Lee, Bioorg.
Med. Chem. 2010, 18, 5553–
5561; e) C. S. Jacobs, P. B.
Dervan, J. Med. Chem. 2009, 52,
7380–7388; f) Y. Harrak, G.
Rosell, G. Daidone, S. Plescia,
D. Schillaci, M. D. Pujol, Bioorg.
Med. Chem. 2007, 15, 4876–
4890; g) A. Mai, S. Massa, I.
Cerbara, S. Valente, R. Ragno,
P. Bottoni, R. Scatena, P. Loidl,
G. Brosch, J. Med. Chem. 2004,
47, 1098–1109.
Scheme 5. Reaction of sulfonyl pyrroles 5 with silyl enol ethers and related nucleophiles in the presence of
AlEtCl2. Reaction conditions: sulfonyl pyrrole (1.0 mmol), nucleophile 10 (1.5 mmol), and AlEtCl2
5
(2.0 mmol) in dichloromethane (10 mL) at À108C for 0.75 h. Product yields of compound 11 are that of the
[4] a) M. Krayer, M. Ptaszek, H.-J.
pure isolated product.
Kim, K. R. Meneely, D. Fan, K.
Secor, J. S. Lindsey, J. Org.
General procedure for the synthesis of compounds 11: The nucleophile
Chem. 2010, 75, 1016–1039;
10 (1.5 mmol) and AlEtCl2 (2 mmol) were added to a stirred solution of
the sulfonyl pyrrole 5 (1 mmol) in dry CH2Cl2 (12 mL) and kept under ni-
trogen atmosphere at À108C. After 0.75 h saturated NH4Cl (12 mL) was
added to the reaction mixture and the aqueous phase was extracted with
CH2Cl2 (3ꢂ10 mL). The organic phase was dried over Na2SO4 and after
evaporation of the solvent under reduced pressure, the crude product 11
was purified by flash chromatography (hexane/ethyl acetate 95:5).
b) A. Kaynak, R. C. Foitzik, F. M. Pfeffer, Mater. Chem. Phys. 2009,
113, 480–484; c) E. Unur, P. M. Beaujuge, S. Ellinger, J.-H. Jung,
J. R. Reynolds, Chem. Mater. 2009, 21, 5145–5153; d) R. C. Foitzik,
A. Kaynak, F. M. Pfeffer, Synth. Met. 2007, 157, 534–539.
[5] T. Tsuchimoto, Chem. Eur. J. 2011, 17, 4064–4075.
[6] a) G. Doddi, P. Mencarelli, A. Razzini, F. Stegel, J. Org. Chem.
1979, 44, 2321–2323; b) A. Zelikin, V. R. Shastri, R. Langer, J. Org.
Chem. 1999, 64, 3379–3380; c) J. M. Freitas, L. M. Abrante, T.
Darbre, Helv. Chim. Acta 2005, 88, 2470–2478.
[7] a) B. L. Bray, P. H. Mathies, R. Naef, D. R. Solas, T. T. Tidwell, D. R.
Artis, J. M. Muchowski, J. Org. Chem. 1990, 55, 6317–6328; for
more recent papers see: b) M. D. Morrison, J. J. Hanthorn, D. A.
Pratt, Org. Lett. 2009, 11, 1051–1054; c) C. Berini, N. Pelloux-Lꢃon,
F. Minassian, J.-N. Denis, Org. Biomol. Chem. 2009, 7, 4512–4516;
d) C. Berini, F. Minassian, N. Pelloux-Lꢃon, J.-N. Denis, Y. Vallꢃe,
C. Philouze, Org. Biomol. Chem. 2008, 6, 2574–2586; e) E. M. Beck,
R. Hatley, M. J. Gaunt, Angew. Chem. 2008, 120, 3046–3049;
Angew. Chem. Int. Ed. 2008, 47, 3004–3007; f) R. C. Foitzik, E. K.
Acknowledgements
We gratefully acknowledge financial support from the MIUR-Italy (Na-
tional Project “Sintesi organiche eco-sostenibili mediate da nuovi sistemi
catalitici” and FIRB National Project “Metodologie di nuova genera-
zione nella formazione di legami carbonio-carbonio e carbonio-eteroato-
mo in condizioni eco-sostenibili”). F.M. thanks C.I.N.M.P.I.S. (Bari) for a
7186
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7183 – 7187

Regioselective Synthesis of 3-Substituted Pyrroles
COMMUNICATION
Bowen, A. M. Taylor, F. M. Pfeffer, A. Kaynak, Synth. Met. 2007,
157, 924–929.
[12] a) While this work was in progress, a single example of preparation
of sulfonyl pyrrole from 2,5-dimethylpyrrole in low yield (30%) was
reported by using our procedure:[9b] M. C. Dobish, J. N. Johnston,
Org. Lett. 2010, 12, 5744–5747.
[13] Unclean reaction mixtures were indeed obtained by using N-benzyl,
N-Boc, and N-TBDMS pyrrole derivatives.
[14] It has been demonstrated that no free fluoride anions are present in
potassium fluoride on basic alumina: a) L. M. Weinstock, J. M. Ste-
venson, S. A. Tomellini, S.-H. Pan, T. Utne, R. B. Jobson, D. F. Rein-
hold, Tetrahedron Lett. 1986, 27, 3845–3848; for a review on syn-
thetic applications of potassium fluoride on alumina see: B. E. Blass,
Tetrahedron 2002, 58, 9301–9320.
[8] a) T. Tsuchimoto, M. Igarashi, K. Aoki, Chem. Eur. J. 2010, 16,
8975–8979; b) T. Tsuchimoto, T. Ainoya, K. Aoki, T. Wagatsuma,
E. Shirakawa, Eur. J. Org. Chem. 2009, 3437–2440; c) T. Tsuchimo-
to, T. Wagatsuma, K. Aoki, J. Shimotori, Org. Lett. 2009, 11, 2129–
2132.
[9] a) R. Ballini, A. Palmieri, M. Petrini, E. Torregiani, Org. Lett. 2006,
8, 4093–4096; b) A. Palmieri, M. Petrini, J. Org. Chem. 2007, 72,
1863–1866; c) R. Ballini, A. Palmieri, M. Petrini, R. R. Shaikh, Adv.
Synth. Catal. 2008, 350, 129–134; d) R. R. Shaikh, A. Mazzanti, M.
Petrini, G. Bartoli, P. Melchiorre, Angew. Chem. 2008, 120, 8835–
8838; Angew. Chem. Int. Ed. 2008, 47, 8707–8710; e) R. Ballini, S.
Gabrielli, A. Palmieri, M. Petrini, Adv. Synth. Catal. 2010, 352,
2459–2462; for a recent perspective on the utilization of alkylide-
neindolenine intermediates in synthesis, see: f) A. Palmieri, R. R.
Shaikh, M. Petrini, Org. Biomol. Chem. 2010, 8, 1259–1270.
[10] Very recently, stable alkylideneindolenine compounds have been
prepared by palladium-catalyzed reaction of alkynylimines with aryl
iodides: Z. Chen, J. Zhu, H. Xie, S. Li, Y. Wu, Y. Gong, Adv. Synth.
Catal. 2011, 353, 325–330. The 1,4-type regioselectivity and reactivi-
ty observed in nucleophilic additions to intermediate 2a probably
stems from the major contribution of the resonance structure 2a’’ in-
volving charge separation with aromatic character.
[15] G. Sartori, R. Ballini, F. Bigi, G. Bosica, R. Maggi, P. Righi, Chem.
Rev. 2004, 104, 199–250.
[16] J. H. Clark, J. Chem. Soc. Chem. Commun. 1978, 789–791.
[17] a) Y. I. Binev, J. A. Tsenov, I. N. Juchnovski, I. G. Binev, J. Mol.
Struct. 2003, 625, 207–214. For a recent double addition involving
malononitrile in a domino process, see: A. Carlone, S. Cabrera, M.
Marigo, K. A. Jørgensen, Angew. Chem. 2007, 119, 1119–1122;
Angew. Chem. Int. Ed. 2007, 46, 1101–1104.
[18] As a representative example, cleavage of compound 11b can be effi-
ciently carried out using TBAF/SiO2 leading to pyrrole 12 (see the
Supporting Information for details).
[11] L. Marsili, A. Palmieri, M. Petrini, Org. Biomol. Chem. 2010, 8,
Received: February 9, 2011
Published online: May 12, 2011
706–712.
Chem. Eur. J. 2011, 17, 7183 – 7187
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7187