Synthesis of 3-(2-Nitroalkyl)pyrroles from sulfonylpyrroles and their conversion to 6-azaindole derivatives

Article abstract of DOI:10.1002/adsc.201300701

The reaction of sulfonylpyrroles with nitroalkanes in the presence of KF/alumina generates 3-(2-nitroalkyl)pyrroles in good yields. These compounds can be converted into trisubstituted 6-azaindoles by a sequence of reactions comprising reduction of the ni

Full text of DOI:10.1002/adsc.201300701

UPDATES
DOI: 10.1002/adsc.201300701
Synthesis of 3-(2-Nitroalkyl)pyrroles from Sulfonylpyrroles and
their Conversion to 6-Azaindole Derivatives
Stefano Lancianesi,a Alessandro Palmieri,a and Marino Petrinia,*
a
School of Science and Technology, Chemistry Division, Universitꢀ di Camerino, via S. Agostino 1, I-62032 Camerino, Italy
Fax : (+39)-0737-402-297; e-mail: marino.petrini@unicam.it
Received: August 3, 2013; Revised: September 3, 2013; Published online: November 11, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300701.
Abstract: The reaction of sulfonylpyrroles with ni-
troalkanes in the presence of KF/alumina generates
3-(2-nitroalkyl)pyrroles in good yields. These com-
pounds can be converted into trisubstituted 6-azain-
doles by a sequence of reactions comprising reduc-
tion of the nitro group, Pictet–Spengler cyclization
and final oxidative aromatization.
roles by reaction of pyrrole with nitrostyrenes in the
presence of Zn
(OAc)2.[5] However, when we repeated
that reaction with nitrostyrene, under the same condi-
tions, the exclusive formation of 2-(2-nitro-1-phenyl-
AHCTUNGTRENNUNG
AHCTUNGTREGeNNUN thyl)pyrrole was observed. Subsequently, a couple of
N-silylated pyrroles were used for the Friedel–Crafts
reaction with nitrostyrene in the presence of EtAlCl2
which among different Lewis acids tested was proved
to be the most effective one (Scheme 1).
The addition products 3 and 4 were obtained in sat-
isfactory yields at À308C regardless of the nature of
the silyl protecting group, but a complete lack of re-
gioselectivity was evidenced. Curiously, a better ratio
of regioisomers in favor of the wanted C-3 substituted
Keywords: azaindoles; electrophilic substitution;
heterogeneous catalysis; nitro compounds; pyrroles
The regioselective functionalization of pyrroles is gen- adduct 3 was observed at room temperature although
erally attained by exploiting a Friedel–Crafts reaction this improvement was obtained at the expense of the
using electrophilic reagents.[1] Like other five-mem- chemical yield. These results were rather discouraging
bered ring heterocycles, the obtained products of elec- and therefore we decided to exploit a different strat-
trophilic substitution are 2-functionalized pyrroles egy in the line of what we recently reported concern-
and this contrasts with the known preference dis- ing the utilization of 3-(1-arylsulfonylalkyl)pyrroles 5
played by indoles to afford C-3 substituted derivatives
in related processes. A cleaver strategy to address the
substitution at C-3 in pyrroles is to introduce suitable
functional groups in the ring and the particularly ef-
fective ones are usually located at the nitrogen
atom.[2] In this context, N-alkylated pyrroles have
been functionalized at C-3 using alkynes or ketones in
indium-catalyzed reactions.[3] A drawback often ob-
served using N-alkylpyrroles in these reactions is the
À
inherent difficulty in restoring the N H system by
cleavage of the nitrogen-carbon bond. For this reason
among the 1-substituted pyrroles, N-triisopropylsilyl-
pyrrole which is the most effective in leading to C-3
substitution is often used in Friedel–Crafts reactions.[4]
With the aim of preparing 3-(2-nitroalkyl)pyrroles to
be used as pivotal compounds for a new synthetic ap-
proach to 6-azaindoles, we undertook a study in order
to carry out a regioselective C-3 Friedel–Crafts addi-
tion of nitroalkenes to pyrrole derivatives. A litera-
ture survey revealed that a single paper is available in
which the authors claim to obtain 3-(2-nitroalkyl)pyr- sopropylsilylpyrrole.
Scheme 1. Friedel–Crafts addition of nitrostyrene to N-trii-
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Stefano Lancianesi et al.
Table 1. Synthesis of 3-(2-nitroalkyl)pyrroles 10.[a]
UPDATES
Scheme 2. General strategy for the preparation of function-
alized 3-substituted pyrroles.
for the synthesis of 3-functionalized pyrroles 8
(Scheme 2).[6] N-Protected sulfonylpyrroles 5 can be
prepared from N-triisopropylsilylpyrrole 1a in
a three-component coupling with an aldehyde and p-
toluenesulfinic acid in the presence of 30 mol% of p-
toluenesulfonic acid.
Deprotection of the pyrrole nitrogen atom with
TBAF generates sulfonylpyrrole 6 which upon elimi-
nation of p-toluenesulfinic acid under basic conditions
gives pyrrolenine 7. This vinylogous-like imino deriva-
tive is rather unstable but in the presence of a suitable
nucleophile can undergo an addition reaction leading
to the final product 8.[7] Using this strategy several
methylene active reactants (e.g., malonates, 1,3-dike-
tones, etc.) can be inserted onto the pyrrole side
chain leading to functionalized azole systems. The uti-
lization of nitroalkanes for such a purpose would be
particularly effective since the obtained products are
the same of type 3 as those arising from a regioselec-
tive Friedel–Crafts reaction of nitroalkenes with pyr-
roles.[8] By adjusting the conditions found for the reac-
tion of 5 with other methylene active compounds to
simple and functionalized nitroalkanes 9, different ad-
ducts 10 were obtained (Table 1). Cleavage of the N-
TIPS group was quantitatively achieved from com-
pounds 5 using TBAF supported on silica gel. The di-
chloromethane solution, obtained, after removal by
filtration of the fluoride promoter, was treated with
the appropriate nitroalkane 9 and KF on alumina at
room temperature leading to 3-(2-nitroalkyl)pyrroles
10. Reaction of sulfonylpyrrole 5a with nitromethane
(Table 1, entry 1), was less efficient when compared
with those achieved with other nitroalkanes. Howev-
er, the preparation of compound 10a allowed us to
demonstrate that, in the reaction of pyrrole with ni-
[a]
Reaction conditions: 1) sulfonylpyrrole 5 (1.0 mmol) in
CH2Cl2 (6 mL), TBAF/SiO2 (1.2 mmol), at room temper-
ature for 1 h. 2) KF/alumina (7.0 mmol) in CH2Cl2
(4 mL), nitrocompound 9 (1.5 mmol), at room tempera-
ture for 24 h.
trostyrene promoted by ZnACHTNUTRGNENG(U OAc)2, 2-(2-nitro-1-phe-
nylethyl)pyrrole 4 (R=H) was actually formed (see
the Supporting Information for details).[5] Primary ni-
troalkanes gave satisfactory yields of the correspond-
ing adducts 10 even when bearing typical functional
[b]
[c]
Yield of pure, isolated products.
Reaction time: 72 h
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Synthesis of 3-(2-Nitroalkyl)pyrroles from Sulfonylpyrroles
groups such as esters or ketal moieties (Table 1, en-
The regioselective preparation of nitropyrroles 10
tries 6–8). Compounds 10b–h were obtained as an that were never obtained in pure form through con-
equimolar mixture of two inseparable diastereoiso- ventional procedures, opens new scenarios in the gen-
mers, with the exception of compound 10g for which eral synthetic approaches to azole compounds. We
a separation was possible. The reactivity displayed by turned our attention to the utilization of compounds
secondary nitroalkanes 9g–i was also quite remark- 10 for an alternative synthesis of the 6-azaindole skel-
able allowing the preparation of adducts 10i and 10j eton which is included in many compounds endowed
featured by a tertiary nitro group (Table 1, entries 9– of important pharmacological profiles (Scheme 4).[10]
11).
The vast majority of available synthetic procedures
These derivatives would be absolutely unobtainable for the assembly of the 6-azaindole unit are currently
via a direct Friedel–Crafts reaction even if the regio- based on the implementation of pyridine systems
selectivity problems could be overcome. An interest- bearing a nitrogen atom linked at the 3 position.
ing behavior was displayed in the reaction of sulfonyl- Functionalized pyrroles are seldom used for the prep-
pyrrole 5d with 4-chloro-1-nitrobutane 9j which gave aration of azaindoles and even less examples are
functionalized pyrrole 11 carrying a cyclic nitronate available for the synthesis of 6-azaindoles.[11] A strat-
unit (Scheme 3). Formation of compound 11 can be egy for the synthesis of 6-azaindoles 14 starting from
rationalized by assuming a preliminary intermolecular nitropyrroles 10 was devised mimicking that em-
addition to the usual nitropyrrole 10l the nitronate of ployed for the preparation of b-carbolines from 3-(2-
which undergoes an intramolecular nucleophilic dis- nitroalkyl)indole derivatives (Table 2).[12] Reduction
placement to afford compound 11.[9]
of the nitropyrrole 10 with NaBH4/NiCl2·6H2O
proved to be much more effective than the classical
catalytic hydrogenation with Raney nickel in provid-
ing the corresponding primary amine 12. The subse-
quent Pictet–Spengler condensation was carried out
using an excess of aldehyde in the presence of TFA as
Scheme 4. Biologically active compounds featuring the 6-
azaindole system.
Scheme 3. Synthesis of cyclic nitronate 11.
Table 2. Synthesis of 6-azaindoles 14 by sequential reduction, cyclization and aromatization of nitropyrroles 10.
Entry
Nitropyrrole
10
Aminopyrrole
12
Yield[a]
[%]
Tetrahydro-
azaindole 13
R3
Yield[b]
[%]
Azaindole
14
Yield[c]
[%]
1
2
3
4
10d
10d
10b
10b
12a
12a
12b
12b
87
87
93
93
13a
13b
13c
13d
Ph
c-C6H11
Ph
63
81
65
73
14a
14b
14c
14d
73
70
68
71
c-C6H11
[a]
Reaction conditions: nitropyrrole (1.0 mmol), NiCl2·6H2O (1.0 mmol), NaBH4 (12.0 mmol) in MeOH (10 mL), at 08C.
Reaction conditions: aminopyrrole (0.8 mmol), MgSO4 (0.5 g), aldehyde (1.6 mmol), TFA (0.9 mmol) in CH2Cl2 (4 mL),
at room temperature.
[b]
[c]
Reaction conditions: tetrahydroindole (0.5 mmol), 10% Pd/C (0.10 g), O2 (balloon) in xylene (10 mL) at reflux.
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Stefano Lancianesi et al.
UPDATES
acidic promoter leading to tetrahydroazaindole 13.[13]
Aromatization of compounds 13 was realized by a de-
hydrogenative method using 10% Pd/C in xylene at
reflux under an oxygen atmosphere. This simple
three-step procedure was really effective in producing
4,5,7-trisubstituted-6-azaindoles 14 in satisfactory
yields, thus offering an alternative general procedure
to access this important class of indole derivatives.
Na2SO4 and then evaporated to afford the pure aminopyr-
role 12.
General Procedure for the Pictet–Spengler Cycli-
zation to Tetrahydoazaindoles 13
To a stirred solution of aminopyrrole 12 (0.8 mmol), in dry
CH2Cl2 (4 mL) were added MgSO4 (0.5 g), the appropriate
aldehyde (1.6 mmol) and CF3CO2H (0.9 mmol). The reac-
In conclusion, we have presented in this paper an tion was stirred under nitrogen atmosphere and monitored
by TLC (CH3Cl/MeOH/Et3N 9:0.95:0.05). After 4 h saturat-
ed NaHCO3 solution (4 mL) was slowly added and the re-
sulting mixture extracted with CH2Cl2 (3ꢂ15 mL). The re-
sulting organic layer was washed with brine, dried over
Na2SO4 and evaporated under reduced pressure. The result-
ing crude product was purified by column chromatography
(CH3Cl/MeOH/Et3N 9:0.95:0.05) to afford the desired tetra-
hydroazaindole 13.
unprecedented approach to the regioselective synthe-
sis of 3-(2-nitroalkyl)pyrroles and the utilization of
the obtained compound for the preparation of trisub-
stituted 6-azaindole derivatives. The strategy was
based on the utilization of regioselectively generated
sulfonylpyrroles 5 which upon N-desilylation and
treatment with a base gave reactive imino-like inter-
mediates 7 that were promptly attacked by alkylnitro-
nate anions. The nitropyrrole compounds 10 were
converted into 6-azaindoles by a reaction sequence in-
volving reduction of the nitro group, Pictet–Spengler
condensation with aldehydes and final dehydrogena-
tive aromatization.
General Procedure for the Preparation of 6-Aza-
indole Derivatives 14
To a stirred solution of compound 13 (0.5 mmol) in xylene
(10 mL) under an O2 atmosphere (balloon) was added 10%
Pd/C (0.10 g). The resulting mixture was stirred overnight at
reflux and then was cooled, diluted with CH2Cl2 (40 mL)
and filtered over a short pad of Celite to remove the cata-
lyst. The resulting solution was evaporated under reduced
pressure to remove the volatiles and the crude product con-
taining traces of xylene was purified by column chromatog-
raphy (hexanes/EtOAc 8:2) to afford pure 6-azaindole de-
rivative 14.
Experimental Section
General Procedure for the Preparation of Nitro-
pyrroles 10
To a stirred solution of sulfonylpyrrole 5 (1.0 mmol) in
CH2Cl2 (6 mL) was added TBAF/SiO2 (1.2 mmol) and the
reaction mixture was stirred for 1 h at room temperature.
The reaction mixture was then filtered to remove TBAF-PS
and the solid was rinsed with CH2Cl2 (3ꢂ5 mL). The major
part of CH2Cl2 containing the N-deprotected sulfonylpyrrole
was then evaporated off under reduced pressure to leave
a small volume (4 mL). To the solution was sequentially
added KF on alumina (7.0 mmol) and the corresponding
nitro compound (1.5 mmol). The reaction was monitored by
TLC (cyclohexane/EtOAc 7:3) and when complete the mix-
ture was diluted with EtOAc (50 mL), decanted and filtered
over a short pad of Florisil. After evaporation of the solvent
under reduced pressure the crude nitropyrrole was purified
by column chromatography over silica gel (hexanes/EtOAc
8:2) to afford the desired pure product 10.
Acknowledgements
We acknowledge financial support from University of Camer-
ino, and FIRB National Project ꢀMetodologie di nuova gener-
azione nella formazione di legami carbonio-carbonio e car-
bonio-eteroatomo in condizioni eco-sostenibili’.
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