Calcium(II)-Catalyzed Aza-Piancatelli Reaction

Article abstract of DOI:10.1021/ol5032987

The first examples of calcium-catalyzed aza-Piancatelli reactions between substituted 2-furylcarbinols and aniline derivatives are described. A variety of 4-aminocyclopentenones have been synthesized stereoselectively in high yields. The experimental proc

Full text of DOI:10.1021/ol5032987

Letter
pubs.acs.org/OrgLett
Calcium(II)-Catalyzed Aza-Piancatelli Reaction
David Lebœuf,†,‡ Emmanuelle Schulz,*,†,‡ and Vincent Gandon*,†
†Universite
France
́
Paris-Sud, Institut de Chimie Molec
́
ulaire et des Mater
́
iaux (UMR 8182), Equipe de Catalyse Molec
́
ulaire, 91405 Orsay,
‡CNRS, 91405 Orsay, France
S
* Supporting Information
ABSTRACT: The first examples of calcium-catalyzed aza-
Piancatelli reactions between substituted 2-furylcarbinols and
aniline derivatives are described. A variety of 4-aminocyclopente-
nones have been synthesized stereoselectively in high yields. The
experimental procedure utilizes simple salts and does not require
specific precautions.
(In).7 Interestingly, several reports showed that the reaction is
ecause of their multifunctional properties, cyclopente-
Bnones are very useful intermediates for the synthesis of not limited to the use of water as nucleophile but is also
natural products of therapeutic value. The Pauson−Khand1 and
compatible with amines, alcohols, or arenes. In the specific case
the Nazarov2 reactions are some of the most commonly used
of anilines, the Piancatelli reaction leads to 4-aminocyclopente-
nones.7a These compounds are highly desirable as they are
methods to generate such building blocks. Whereas the
potential intermediates to aminocyclopentitol frameworks,
which are present in a variety of bioactive molecules such as
peramivir,8 pactamycin,9 or trehazolin (Figure 1).10
Nazarov reaction and its variants have been extensively studied
by several groups,3 including ourselves,4 a related intriguing
transformation remained in its shadow for many years. In 1976,
Piancatelli et al. described the synthesis of 4-hydroxycyclo-
pentenones from 2-furylcarbinols and water in the presence of
strong Brønsted acids (Scheme 1).5 The common feature
between the Nazarov and the Piancatelli reactions is that their
stereoselectivity relies on the conrotatory 4π-electrocyclization
of a pentadienyl carbocation intermediate.6
The Piancatelli reaction has gained a renewed interest in the
past decade. This reaction can now be carried out by catalytic
systems based on lanthanides (La, Dy) or group 13 elements
Scheme 1. Mechanism of the Piancatelli Reaction
Figure 1. Natural products containing an aminocyclopentitol moiety.
In spite of the great synthetic interest of the aza-Piancatelli
reaction, some important issues remain to be addressed to
make this chemistry more appealing. First, an in-depth scope of
the reaction is necessary to fully demonstrate its usefulness in
organic synthesis. For instance, the influence of the substitution
of the furan ring has yet to be examined. Second, there is a
strong demand for a catalytic system that would be easier to
implement than those used so far in terms of price, toxicity, and
handling. In this context, group 1 and 2 metal salts look
particularly attractive, especially those based on calcium.11
Niggemann and others have demonstrated the high efficiency
of simple calcium salts such as Ca(NTf2)2, which combined
with a weakly coordinating anion source gives rise to exquisite
Received: November 13, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5032987 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Lewis acids in catalysis.12,13 In addition, such species are air-
and moisture-stable and do not require the use of distilled
solvents. The known lanthanide-like behavior of calcium
complexes could be used to mimic the reactivity observed
with lanthane- or dysprosium-based catalysts.11a Herein, we
show that simple calcium derivatives are efficient catalysts for
the aza-Piancatelli reaction. Polyfunctionalized 4-aminocyclo-
pentenones have been obtained in a highly selective fashion,
starting from various substituted furan derivatives.
large scale, starting with 1 g of furan, albeit proceeding at a
slower rate (entry 9). The acceleration effect provided by n-
Bu4NPF6 was also observed with Mg(NTf2)2 and Ba(NTf2)2,
but the transformation remained slower compared to calcium
(entries 10 and 11). We examined also other additives with
Ca(NTf2)2, such as n-Bu4NBF4 or KPF6, which provided the
same activity as n-Bu4NPF6 (entries 12 and 13). A control
experiment using n-Bu4NPF6, in the absence of calcium, led to
the recovery of the starting material (entry 14). Of note, the
Lewis acids that have been previously used in Piancatelli
reaction (La(OTf)3, Dy(OTf)3, In(OTf)3), were proved as
active as the calcium catalyst in the formation of 3a, provided
nitromethane is employed as solvent. In acetonitrile, which is
the typical solvent for such transformations,7 the rate is lower,
especially with the lanthanide salts (see Table S1, Supporting
Information).
We started our investigation using 2-furyl(phenyl)methanol
1, p-iodoaniline 2a, and group 1 and 2 metal triflimidates as
catalysts (Table 1). In the case of LiNTf2, the reaction required
Table 1. Screening of Group 1 and 2 Lewis Acids in the
Catalytic Cyclization of 2-Furyl(phenyl)methanol 1 with p-
a
Iodoaniline 2a
We further explored the Ca(NTf2)2/n-Bu4NPF6 catalytic
system for the reaction of 2-furyl(phenyl)methanol with various
anilines (Table 2). A wide range of substituted anilines are
Table 2. Ca(II)-Catalyzed Cyclization of 2-
Furyl(phenyl)methanol 1 with Anilines 2b−k
a
entry
catalyst
LiNTf2
additive
solvent
time (min) yield (%)
1
MeNO2
MeNO2
MeNO2
MeNO2
DCE
120
45
45
80
60
10
60
30
90
20
60
10
10
60
82
81
90
84
86
92
91
91
87
90
85
86
91
2
Mg(NTf2)2
Ca(NTf2)2
Ba(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Mg(NTf2)2
Ba(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
3
4
5
entry
R1
R2
temp (°C) time (min) yield (%)
6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NPF6
n-Bu4NBF4
KPF6
MeNO2
DCE
1
2
H
C6H5
C6H5
C6H5
80
80
80
100
90
80
80
90
80
80
30
90
3b (90)
3c (82)
3d (76)
3e (81)
3f (75)
3g (91)
3h (74)
3i (92)
3j (92)
3k (62)
7
Me
Allyl
H
b
c
8
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
3
90
9
4
p-MeOC6H4
p-Tol
150
30
10
11
12
13
14
5
H
6
H
p-MeO2CC6H4
p-NCC6H4
m-AcC6H4
m-IC6H4
20
7
H
20
8
H
120
20
n-Bu4NPF6
9
H
a
Reaction conditions: 1 (1 equiv) and p-iodoaniline 2a (1.1 equiv) in
10
H
o-IC6H4
20
the indicated solvent (0.4 M) in the presence of catalyst (5 mol %)
a
b
Reaction conditions: 1 (1 equiv) and aniline 2b−k (1.1 equiv) in
MeNO2 (0.4 M) in the presence of Ca(NTf2)2 (5 mol %) and n-
Bu4NPF6 (5 mol %) at the indicated temperature.
with/or without additive (5 mol %) at 80 °C. 1 mol % of catalyst and
c
1 mol % of additive. On a gram scale of furan with 1 mol % of catalyst.
2 h to reach completion at 80 °C in MeNO2 (entry 1).
Gratifyingly, the expected product was isolated in 82% yield.
On the other hand, with Mg(NTf2)2 and Ca(NTf2)2, full
conversion was reached in 45 min and 3a was isolated in 81%
and 90% yield, respectively (entries 2 and 3). With Ba(NTf2)2,
the product was obtained after 80 min in 84% yield (entry 4).
1,2-Dichloroethane (DCE) also proved to be a compatible
solvent for the calcium-catalyzed reaction (entry 5), although
the rate was lower. Interestingly, the use of the Ca(NTf2)2/n-
Bu4NPF6 catalytic system in MeNO2 resulted in a strong
acceleration of the reaction and provided the desired product in
only 10 min and 92% yield, best yield of the series (entry 6).
The ammonium salt can actually promote an anion metathesis
to form the heteroleptic complex Ca(NTf2)(PF6), which, as
shown recently,13f is more Lewis acidic than Ca(NTf2)2. This
increase of the reaction rate was not observed in DCE, but the
yield was also excellent (entry 7). While the aforementioned
tests involved a 5 mol % loading of each catalytic component, it
is worthy of note that the reaction is still very efficient with just
1 mol % (entry 8). In addition, the reaction can be run on a
compatible with these conditions and afford the corresponding
4-aminocyclopentenones in high yields (up to 92%). Ortho,
meta, and para substitution did not affect the reactivity (entries
4−10). The reaction is markedly slower with secondary anilines
(entries 2 and 3). Anilines bearing an electron-donating group
at the para position required temperatures higher than 80 °C to
provide the corresponding 4-aminocyclopentenones (entries 4
and 5).
We then turned our attention to the substitution at the α
position of the 2-furylcarbinols (Table 3). The reaction is not
limited to an aryl substitution such as PMP (p-methoxyphenyl)
(entry 1) but can be also carried out in the presence of an alkyl
group (entry 2). Furthermore, in the presence of an allyl or a
benzyl substituent, which have already been proven compatible
with the Piancantelli reaction,7i,14 the expected 4-amino-
cyclopentenones were obtained as sole products in good yields
(entries 3 and 4). Higher temperatures were required with the
more sterically demanding substrates (entries 4 and 5).
B
dx.doi.org/10.1021/ol5032987 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
polyfunctionalized 4-aminocyclopentenones, which may serve
as a platform for the synthesis of natural products such as those
mentioned above has been developed.
Table 3. Ca(II)-Catalyzed Cyclization of 2-Furylcarbinols
3a−e with p-Iodoaniline 2a
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
■
S
C
NMR spectra for all new 4-aminocyclopentenones. This
material is available free of charge via the Internet at http://
pubs.acs.org.
entry
R
temp (°C)
time (min)
yield (%)
1
2
3
4
5
PMP
Me
40
80
10
60
30
60
20
5a (81)
5b (80)
5c (86)
5d (75)
5e (58)
AUTHOR INFORMATION
Corresponding Authors
■
allyl
80
benzyl
100
100
* E-mail: emmanuelle.schulz@u-psud.fr.
* E-mail: vincent.gandon@u-psud.fr.
Notes
CH2OTBDPS
a
Reaction conditions: 4a−e (1 equiv) and aniline 2a (1.1 equiv) in
MeNO2 (0.4 M) in the presence of Ca(NTf2)2 (5 mol %) and n-
Bu4NPF6 (5 mol %) at the indicated temperature.
The authors declare no competing financial interest.
In the next set of experiments, we focused on the reactivity of
2-furyl(phenyl)methanol substituted at the furan ring (Table
4). In most cases, we noticed that the introduction of a
ACKNOWLEDGMENTS
We thank the CNRS, IUF, the Minister
■
̀
e de l’Enseignement
Super
support of this work.
́
ieur et de la Recherche, and the LabEx CharM3At for
Table 4. Ca(II)-Catalyzed Cyclization of Substituted 2-
a
Furyl(phenyl)methanol 6a−g with p-Iodoaniline 2a
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R2
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temp (°C)
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yield (%)
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2
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Me
Ph
Br
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