Iron-catalyzed tandem one-pot addition and cyclization of the blaise reaction intermediate and nitroolefins: Synthesis of substituted NH-pyrroles from nitriles

Article abstract of DOI:10.1002/adsc.201200673

The iron-catalyzed addition and cyclization of the Blaise reaction intermediate and nitroolefins to synthesize highly functionalized NH-pyrroles in a tandem one-pot manner from nitriles has been developed. This reaction shows good functional group tolerance and affords a broad spectrum of substituted NH-pyrroles in good yields. Copyright

Full text of DOI:10.1002/adsc.201200673

UPDATE
DOI: 10.1002/adsc.201200673
Iron-Catalyzed Tandem One-Pot Addition and Cyclization of
the Blaise Reaction Intermediate and Nitroolefins: Synthesis of
Substituted NH-Pyrroles from Nitriles
Mi-Na Zhao,a Hao Liang,a Zhi-Hui Ren,a and Zheng-Hui Guana,*
a
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of
Chemistry & Materials Science, Northwest University, Xi’an 710069, Peopleꢀs Republic of China
E-mail: guanzhh@nwu.edu.cn
Received: July 30, 2012; Revised: September 28, 2012; Published online: December 7, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200673.
Abstract: The iron-catalyzed addition and cycliza-
tion of the Blaise reaction intermediate and nitro-
ACHTUNGTRENNUNGolefins to synthesize highly functionalized NH-pyr-
roles in a tandem one-pot manner from nitriles has
been developed. This reaction shows good function-
al group tolerance and affords a broad spectrum of
substituted NH-pyrroles in good yields.
strong functional group tolerance and excellent effi-
ciency for the synthesis of fully substituted pyrroles.[11]
However, NH pyrroles,[12] which are an important
class of organic compounds, were not efficiently pre-
pared using this protocol. Our continuous interest in
addition and cyclization reactions prompted us to fur-
ther extend this methodology to synthesize substitut-
ed NH pyrroles. Zinc bromide complexes of b-enami-
no esters, known as Blaise reaction intermediates, are
powerful building blocks in organic synthesis.[13,14]
Using the Blaise reaction intermediate as an alterna-
tive enamino ester precursor would significantly
extend the scope of addition and cyclization reactions.
FeCl3-catalyzed addition and cyclization reactions
Keywords: addition and cyclization; iron catalysis;
nitroolefins; pyrroles; tandem reaction
Polysubstituted pyrroles are prevalent N-heterocyclic proceeded smoothly using the Blaise reaction inter-
compounds which are not only present in natural mediate and nitroolefins as substrates [Scheme 1, Eq.
products,[1] but are also widely used in materials sci- (2)]. In this paper we report the FeCl3-catalyzed
ence[2] and pharmaceuticals.[3] Accordingly, a number tandem one-pot addition and cyclization of the Blaise
of synthetic methods have been developed for the reaction intermediate and nitroolefins for the synthe-
construction of pyrrole rings. Classical methods, such sis of substituted NH pyrroles from nitriles.
as the Knorr reaction[4] and Paal–Knorr condensa-
The study began with the preparation of the Blaise
tion,[5] have been used frequently for the synthesis of reaction intermediate 2a, which could be formed by
functionalized pyrroles over the past few decades. Re- nucleophilic addition of an in situ generated Refor-
cently, elegant methods such as transition metal-cata- matsky reagent to benzonitrile 1a in THF.[13,14]
lyzed cyclizations[6] and multicomponent couplings[7]
have been developed for the synthesis of substituted
pyrroles.[8] Despite these advances, the development
of novel and efficient methodologies for the prepara-
tion of multisubstituted pyrroles using readily avail-
able starting materials under mild conditions is still
highly desirable.
Michael-type addition and cyclization of enamino
esters or enaminones to nitroolefins provides an effi-
cient approach to synthesize substituted pyrroles be-
cause the starting materials are readily available and
the reactions proceed under mild conditions.[9] Re-
cently, our group has improved this synthetic method
and developed a green protocol for the synthesis of
Scheme 1. Synthesis of substituted pyrroles by our addition
pyrroles [Scheme 1, Eq. (1)].[10] This method provided and cyclization reaction.
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Mi-Na Zhao et al.
UPDATE
Table 1. Optimization of reaction conditions for tandem re-
action of the Blaise reaction intermediate with nitroolefin
3a.[a]
ethane suggested that THF was still the most suitable
solvent for this reaction (Table 1, entries 10–12).
Having established the optimized reaction condi-
tions, a series of nitriles was investigated for extend-
ing the substrate scope (Table 2). This transformation
displayed good functional group tolerance and proved
to be a general method for the preparation of multi-
substituted NH pyrroles. Various aromatic nitriles
bearing methyl, methoxy, amino, fluoro, chloro and
bromo substituents were transformed efficiently into
their corresponding pyrroles 4aa–4ja in good to excel-
lent yields through FeCl3-catalyzed tandem one-pot
addition and cyclization reactions (Table 2, entries 1–
10). The transformation was insensitive to electronic
effects of the aromatic nitriles, but steric effects had
a significant influence on the reaction. A longer reac-
tion time was generally required when o-MeO- or o-
Cl-substituted aromatic nitriles were used as the sub-
strates (Table 2, entries 5 and 9). Heteroaromatic ni-
trile 1k was tolerated and the corresponding pyrrole
4ka was achieved in 64% yield (Table 2, entry 11). It
was noteworthy that vinyl nitrile and aliphatic nitriles
exhibit similar reactivity with aromatic nitriles. They
were readily converted to the corresponding 2-vinyl-
pyrrole 4la and 2-alkylpyrroles 4ma–4oa in good
yields (Table 2, entries 12–15).
Next, the scope of the nitroolefins was surveyed
under the optimized reaction conditions. The results
are summarized in Table 3. Importantly, the para-,
meta- and ortho-substituted aromatic nitroolefins all
gave the desired polysubstituted NH pyrroles in good
yields (Table 3, entries 1–9). Nitroolefins with both
electron-donating and electron-withdrawing substitu-
ents on the aromatic rings displayed similar reactivi-
ties in the reaction. o-MeO- and o-Cl-substituted ni-
troolefins 3h–3j reacted smoothly to give the corre-
sponding pyrroles 4ah–4aj in good yields, indicating
Entry
Catalyst
Solvent
Time
[h]
Yield
[%][b]
1
2
3
4
5
6
7
8
–
THF
THF
THF
THF
THF
THF
THF
THF
20
20
20
20
10
10
10
10
10
10
12
8
40
44
87
trace
65
52
61
47
42
60
55
37
FeCl2
FeCl3
FeSO4
Fe
Fe(acac)3
ZnBr2
Cu(OTf)2
Yb(OTf)3
(acac)2
E
N
9
G
THF
10
11
12
FeCl3
FeCl3
FeCl3
toluene
1,4-dioxane
1,2-dimethoxy-
ethane
[a]
Reaction conditions: nitrile 1a (0.4 mmol), Zn (0.8 mmol)
and ethyl bromoacetate (0.6 mmol) in THF (1 mL) at
reflux. After 2 h of reflux, the catalyst (20 mol%), 3a
(0.2 mmol), and solvent (2 mL) were added with the re-
action mixture remaining at reflux.
[b]
Isolated yields.
After reaction with nitroolefin 3a, the desired pyr- that the transformation was insensitive to the steric
role 4aa was obtained in 40% yield (Table 1, entry 1). hindrance of the nitroolefins (Table 3, entries 7–9).
The conversion of the addition and cyclization of the When heterocyclic nitroolefins 3k and 3l were em-
Blaise reaction intermediate and nitroolefins could ployed as the substrates, the corresponding pyrroles
not be further improved, even by changing the sub- 4ak and 4al were obtained in good yields as well
strate ratios or by changing the reaction solvent and (Table 3, entries 10 and 11). Furthermore, a-ethyl- or
temperature. We hypothesized that a Lewis acid cata- phenyl-substituted nitroolefins 3m and 3n can be con-
lyzes this addition and cyclization reaction. Recently, verted into the corresponding NH pyrroles 4am and
iron salts have been extensively investigated as prom- 4an in 68% and 60% yields, respectively (Table 3, en-
ising catalysts for many organic transformations due tries 12 and 13). A trisubstituted pyrrole 4ao can also
to their low price and environmentally friendly be obtained using this reaction in 42% yield (Table 3,
nature.[15] Therefore, various iron catalysts such as entry 14).
FeCl2, FeCl3, FeSO4, Fe
G
G
A tentative mechanism for this reaction is proposed
screened to improve the efficiency of the reaction in Scheme 2. The first step involves a Michael-type
(Table 1, entries 2–6). Importantly, an 87% isolated addition of the Blaise reaction intermediate 2 to ni-
yield of pyrrole 4aa was obtained in the presence of troolefin 3 to form an intermediate A,[10,13,14] followed
FeCl3 as catalyst (Table 1, entry 3). Other Lewis acids, by tautomerization and coordination to FeCl3 to give
(OTf)3, were inferior intermediate B.[16] Then, intermediate B undergoes an
such as ZnBr2, CuACHTUNTGRNENUG(OTf)2 and YbACHTUTGNRENNUGN
to FeCl3 (Table 1, entries 7–9). Further modification intramolecular nucleophilic cyclization and elimina-
of the solvent to toluene, 1,4-dioxane and dimethoxy- tion reaction to give the desired pyrrole 4.[7b,10,16]
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Iron-Catalyzed Tandem One-Pot Addition and Cyclization of the Blaise Reaction Intermediate and Nitroolefins
Table 2. Tandem one-pot synthesis of substituted pyrroles from various nitriles.[a]
Entry
Nitrile 1
Product 4
R1
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
H (4aa)
87
80
79
74
54
65
76
78
36
81
4-CH3 (4ba)
3-CH3 (4ca)
4-OMe (4da)
2-OMe (4ea)
4-NMe2 (4fa)
4-F (4ga)
4-Cl (4ha)
2-Cl (4ia)
4-Br (4ja)
11
4ka
64
12
13
4la
56
72
4ma
14
4na
4oa
63
40
15
[a]
Reaction conditions: nitrile 1 (0.6 mmol), Zn (1.2 mmol) and ethyl bromoacetate (0.9 mmol) in THF (1 mL) at reflux.
After the appropriate time, the FeCl3 (20 mol%), 3a (0.3 mmol), THF (2 mL) were added with the reaction mixture re-
maining at reflux.
Isolated yields.
[b]
In summary, we have developed an efficient Experimental Section
tandem one-pot protocol for the synthesis of highly
functionalized NH pyrroles based on FeCl3-catalyzed General Information
addition and cyclization of Blaise reaction intermedi-
Column chromatography was carried out on silica gel.
ates and nitroolefins. The reaction shows good func-
tional group tolerance and affords a series of substi-
tuted NH pyrroles in good yields. The diverse and
readily available nitriles and nitroolefins make this
method versatile and powerful.
1H NMR spectra were recorded at 400 MHz in CDCl3 and
13C NMR spectra were recorded at 100 MHz in CDCl3. The
following abbreviations were used to explain multiplicities:
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet.
All new products were further characterized by HR-MS
(Bruker, TOF-Q). Unless otherwise stated, all reagents and
solvents were purchased from commercial suppliers and
used without further purification.
Adv. Synth. Catal. 2013, 355, 221 – 226
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Mi-Na Zhao et al.
UPDATE
Table 3. Tandem one-pot synthesis of substituted pyrroles with various nitroolefins.[a]
Entry
Nitroolefin 3
Product 4
R
Yield [%][b]
1
2
3
4
5
6
7
8
4-CH3 (4ab)
4-OMe (4ac)
4-F (4ad)
4-Cl (4ae)
4-Br (4af)
3-CH3 (4ag)
2-OMe (4ah)
2-Cl (4ai)
70
66
71
73
66
77
65
60
9
4aj
61
10
11
4ak
4al
64
56
12
13
4am
4an
4ao
68
60
42
14
[a]
Reaction conditions: nitrile 1a (0.6 mmol), Zn (1.2 mmol) and ethyl bromoacetate (0.9 mmol) in THF (1 mL) at reflux.
After 2 h of reflux, the FeCl3 (20 mol%), 3 (0.3 mmol), THF (2 mL) were added with the reaction mixture remaining at
reflux.
Isolated yields.
[b]
General Procedure for the Tandem One-Pot
Synthesis of Substituted NH-Pyrroles
were added successively to the flask. The mixture was re-
fluxed for 2–12 h, then, FeCl3 (20 mol%, 9.7 mg), nitroolefin
3 (0.3 mmol), and THF (2 mL) were added to the reaction,
and heating under reflux was cointinued until the comple-
tion of the reaction (detected by TLC). The mixture was
cooled to room temperature, quenched with saturated aque-
ous NH4Cl (20 mL) and extracted with ethyl acetate
In a 25-mL round-bottom flask, a solution of methanesul-
fonic acid (5 mol%) in anhydrous THF (1 mL) was added to
the stirred suspension of commercial zinc dust (1.2 mmol,
0.0785 g). After refluxing for 10 min (908C oil bath), nitrile
1 (0.6 mmol) and ethyl bromoacetate (0.9 mmol, 0.1503 g)
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Iron-Catalyzed Tandem One-Pot Addition and Cyclization of the Blaise Reaction Intermediate and Nitroolefins
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