Catalytic asymmetric synthesis of 4-nitropyrazolidines: An access to optically active 1,2,3-triamines

Article abstract of DOI:10.1021/ja506694v

The first catalytic enantio- and diastereoselective synthesis of 4-nitropyrazolidines is presented. Asymmetric hydrogen-bonding activation of nitro-olefins facilitated the 1,3-dipolar cycloaddition with hydrazones, affording optically active 4-nitropyrazo

Full text of DOI:10.1021/ja506694v

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Synthesis of 4‑Nitropyrazolidines: An Access to
Optically Active 1,2,3-Triamines
Lennart Lykke, Bjørn Dreiø Carlsen, Raoní Scheibler Rambo, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
S
* Supporting Information
quence.5 Additionally, Gotor et al. have demonstrated a highly
ABSTRACT: The first catalytic enantio- and diastereose-
lective synthesis of 4-nitropyrazolidines is presented.
Asymmetric hydrogen-bonding activation of nitro-olefins
facilitated the 1,3-dipolar cycloaddition with hydrazones,
affording optically active 4-nitropyrazolidines containing
three continuous stereogenic centers as a single diaster-
eomer in up to 99% ee. Furthermore, it is demonstrated
that the optically active 4-nitropyrazolidines can be applied
as precursors for the synthesis of highly interesting 1,2,3-
triamines.
enantioselective chemoenzymatic desymmetrization of 2-N-
Boc-propane-1,2,3-triamine.6
The development of organocatalytic asymmetric methods for
the synthesis of vicinal diamines has attracted considerable
attention over the past decade.7 An access to this important
structural motif is the aza-Michael addition of ammonia
precursors to nitro-olefins, which, due to the diverse chemistry
of the nitro functionality, generates surrogates of 1,2-diamino
compounds.8 Along this line, we envisioned that catalytic
asymmetric 1,3-dipolar cycloaddition of hydrazones with nitro-
olefins would furnish 4-nitropyrazolidines which, upon
reduction of the nitro group and cleavage of the N−N
functionality, would afford 1,2,3-triamino compounds. In
previous reports, Deng et al. have demonstrated that
aldehyde-derived hydrazones efficiently react in a 1,3-dipolar
cycloaddition with nitro-olefins, forming racemic 4-nitro-
pyrazolidines, which readily undergo oxidation in air to afford
pyrazoles (Scheme 1).9 We speculated that employing ketone-
ue to the importance of amine-containing biologically
Dactive natural products and pharmaceutical compounds,
the development of methodologies giving access to stereo-
defined nitrogen-containing compounds is a cornerstone in
contemporary organic synthesis.1 Amino stereotriads, an array
of three continuous amine-bearing stereogenic carbons, are
essential parts of the scaffold of several bioactive compounds
(Figure 1).2 Given the biological importance of such nitrogen-
dense compounds, comprehensive multistep syntheses have
attracted considerable attention.3
Scheme 1. Strategy for the Synthesis of Optically Active 4-
Nitropyrazolidines and 1,2,3-Triamines
derived hydrazones would yield the desired 4-nitropyrazoli-
dines, which, due to the formed quaternary stereogenic center,
would be blocked from the oxidative formation of the
heteroaromatic compound.
Pyrazolidines are highly interesting heterocyclic structural
motifs found in numerous biologically relevant molecules;10
however, only a few protocols for the formation of 4-
nitropyrazolidines have been reported,11 and to the best of
our knowledge, no catalytic asymmetric route to this class of
compounds has been demonstrated.
Figure 1. Bioactive continuous triamine-containing compounds.
Despite being appealing structural motifs, only a few
asymmetric routes for the synthesis of 1,2,3-triamino
compounds have been reported.4 Trost et al. have established
a catalytic stereoselective transformation of allylic carbonates to
1,2,3-triamines employing sequential palladium-catalyzed allylic
amination/rhodium-catalyzed aziridination/azide addition se-
Received: July 3, 2014
Published: July 29, 2014
© 2014 American Chemical Society
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Asymmetric hydrogen-bonding-mediated catalysis has pro-
ven to be a reliable strategy for the enantioselective activation
of nitro-olefins,12 thus our studies were initiated by examining
the 1,3-dipolar cycloaddition of nitrostyrene 1a with ketone-
derived hydrazones 2 under hydrogen-bonding catalysis. Initial
attempts to employ N-tosyl or N-benzoyl hydrazones derived
from acetophenone were unsuccessful, thus we turned our
attention to the more electron-rich and hence more
nucleophilic N-methyl hydrazone. Due to its crystalline nature
and increased thermal stability N-methyl hydrazone derived
from 4′-chloroacetophenone 2a was employed as a model
substrate.
the generality of the reaction (Scheme 2). We were pleased to
find that the high efficiency demonstrated by catalyst 3c for the
Scheme 2. Nitro-olefin Scope for the Asymmetric Synthesis
a
of 4-Nitropyrazolidines 4
A survey of background reaction revealed that the 4-
nitropyrazolidine 4a was afforded as a single diastereoisomer
when the nitrostyrene 1a and hydrazone 2a were stirred in
chloroform at room temperature, while no conversion was
observed when the reaction was conducted in toluene at −30
°C (Table 1, entries 1 and 2). In a previous report, we
Table 1. Selected Screening Results for the Reaction
Conditions for Asymmetric Synthesis of 4-Nitropyrazolidine
4a
a
a
b
c
b
All reactions were performed on a 0.1 mmol scale using 1 (0.15
entry
catalyst
solvent
temp (°C) conv (%) ee (%)
dr
mmol), 2a (0.10 mmol), and 3c (0.005 mmol) in anhydrous toluene
(0.1 M) for 24 h at −30 °C. Isolated yields by FC. Diastereoselectivity
was determined by 1H NMR on the crude reaction mixture.
Enantioselectivity was determined by chiral ultraperformance con-
vergence chromatography (UPC2).
1
2
3
4
5
6
none
none
3a
CHCl3
toluene
toluene
toluene
toluene
toluene
rt
>95
nd
nd
99
98
99
88
>20:1
−30
−30
−30
−30
−30
>95
>95
>95
>95
>20:1
>20:1
>20:1
>20:1
3b
3c
3d
a
model reaction could be sustained for the 1,3-dipolar
cycloaddition of a broad range of nitro-olefins. Generally,
aromatic nitro-olefins having substituents in the ortho-, meta-,
and para-positions furnished the optically active 4-nitro-
pyrazolidine products in high to excellent yields as single
diastereomers with excellent enantioselectivities (products 4b−
g). Nitro-olefins in which the electronic nature of the aromatic
substituents varied from electron-donating to electron-with-
drawing participated successfully in the reaction. However,
when aromatic imines with electron-rich substituents, which are
able to conjugate a lone pair of electrons to the double bond,
were employed (e.g., p-MeO-C6H4 or 2-furanyl), no product
formations were observed. Interestingly, two nitro-olefins
bearing heteroaromatic substituents gave rise to the corre-
sponding 4-nitropyrazolidines 4h and 4i in good yields with
high to excellent enantioselectivities. The lower selectivity of
the 3-pyridyl-substituted substrate might be due to non-
constructive hydrogen bonding to the catalyst. Additionally,
two aliphatic nitro-olefins also participated in the reaction,
All reactions were performed on a 0.1 mmol scale using 1a (0.15
mmol), 2a (0.10 mmol), and 3 (0.005 mmol) in anhydrous solvent
b
1
(0.1 M) for 24 h. Determined by H NMR on the crude reaction
c
mixture. Determined by chiral ultraperformance convergence
chromatography (UPC2).
demonstrated that Jacobsen-type thiourea catalyst 3a is a
powerful activator of nitro-olefins,8c thus this catalyst was
subjected to the model system in toluene at −30 °C.
Delightfully, 4-nitropyrazolidine 4a was afforded in full
conversion with excellent enantioselectivity as a single
diastereoisomer (entry 3). Related catalysts 3b−d displayed
similar activity with regard to rate of the reaction, affording
enantioselectivities ranging from high to excellent (entries 4−
6). Catalysts 3a and 3c furnished the desired product in 99%
ee; however, it was later observed that catalyst 3c provided
better selectivity for more challenging substrates.
Encouraged by the screening results, we tested a
representative selection of nitro-olefins in order to investigate
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affording 4-nitropyrazolidines 4j and 4k in high to excellent
yields with high enantioselectivities.
Subsequently, we turned our attention toward the scope of
the hydrazone 1,3-dipoles (Scheme 3). Generally, benzophe-
reductive approach was undertaken. In attempts to reduce the
nitro group selectively, either no conversion or decomposition
of 4-nitropyrazolidine 4a was observed when subjected to
various hydrogenative conditions. We circumvented this
challenge by employing the methodology developed by
Anderson,14 in which mercury-coated alumina strips success-
fully reduced the nitro group to the hydroxylamine, which
subsequently could be turned in the 4-aminopyrazolidine 5 in
67% yield over two steps (Scheme 4). Sequential Cbz
Scheme 3. Hydrazone Scope for the Asymmetric Synthesis of
a
4-Nitropyrazolidines 4
Scheme 4. Synthesis of Triamine 7 from 4-Nitropyrazolidine
a
4a
a
See Supporting Information for experimental details.
a
All reactions were performed on a 0.1 mmol scale using 1a (0.15
mmol), 2 (0.10 mmol), and 3c (0.005 mmol) in anhydrous toluene
(0.1 M) for 24 h at −30 °C. Isolated yields by FC. Diastereoselectivity
was determined by 1H NMR on the crude reaction mixture.
Enantioselectivity was determined by chiral ultraperformance con-
protection of the exocyclic primary amine followed by
trifluoroacetyl protection of the unsubstituted pyrazolidine
nitrogen afforded 6 in 84% yield over two steps. Finally,
samariumdiiodide-mediated reduction furnished the desired
triamine product 7.15
b
vergence chromatography (UPC2). Performed using catalyst 3d at
−78 °C.
In conclusion, this work constitutes the first example of
catalytic asymmetric synthesis of 4-nitropyrazolidines. The
developed methodology takes advantage of a hydrogen-
bonding-catalyzed 1,3-dipolar cycloaddition of aromatic and
aliphatic nitro-olefins with ketone-derived hydrazones to afford
4-nitropyrazolidines in good to excellent yields (up to 97%)
with high to excellent stereocontrol (up to 99% ee and >20:1
dr). The utility of the developed protocol was highlighted by
demonstrating that optically active 4-nitropyrazolidines can be
employed as precursors for 1,2,3-triamines.
none-derived hydrazones bearing substituents of a broad
electronegativity range afforded similar excellent selectivity,
although slightly lower yields were observed in some cases
(products 4n−r). The decreased diastereoselectivity observed
for product 4p is attributed to the corresponding E/Z ratio of
starting material 4′-chloropropiophenone-derived hydrazone.
Interestingly, hydrazones rising from 3-methylbutan-2-one and
cyclohexanone also gave rise to the desired 4-nitropyrazolidines
4q and 4r when catalyst 3d was employed and the temperature
decreased to −78 °C, affording the products in good yields and
high enantioselectivities.
Determination of the absolute configuration of the optically
active 4-nitropyrazolidines was carried out by X-ray analysis of
4c, which proved to be the (3R,4R,5R)-3,5-diaryl-1,3-dimethyl-
4-nitropyrazolidine as shown in Figure 2.13 Hence, the
remaining 4-nitropyrazolidines 4 were assigned by analogy
assuming a common reaction pathway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Finally, we set out to investigate the transformation of the
optically active 4-nitropyrazolidines into their corresponding
1,2,3-triamines. After several unsuccessful attempts to reduce
the nitro and hydrazine functionalities directly, a sequential
■
Corresponding Author
kaj@chem.au.dk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Aarhus University,
Carlsberg Foundation, and FNU. R.S.R. thanks the CNPq/CsF
for the fellowship. Esben Eikeland is gratefully acknowledged
for performing X-ray analysis.
Figure 2. Single-crystal X-ray structure of 4c.
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