Catalytic Enantioselective Addition of Pyrazol-5-ones to Trisubstituted Nitroalkenes with an N-Sulfinylurea Organocatalyst

Article abstract of DOI:10.1002/adsc.201600110

The first example of enantioselective nitronate protonation following Michael addition of a carbon nucleophile to an α,β,β-trisubstituted nitroalkene is reported. An N-sulfinylurea catalyst was employed to catalyze the addition of a variety of 3-substitut

Full text of DOI:10.1002/adsc.201600110

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DOI: 10.1002/adsc.201600110
Catalytic Enantioselective Addition of Pyrazol-5-ones to Trisub-
stituted Nitroalkenes with an N-Sulfinylurea Organocatalyst
James P. Phelana and Jonathan A. Ellmana,*
a
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520, USA
Fax: (+1)-203-432-6144; phone: (+1)-203-432-3915; e-mail: jonathan.ellman@yale.edu
Received: January 24, 2016; Revised: April 15, 2016; Published online: May 3, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600110.
Abstract: The first example of enantioselective ni-
tronate protonation following Michael addition of
a carbon nucleophile to an a,b,b-trisubstituted ni-
troalkene is reported. An N-sulfinylurea catalyst
was employed to catalyze the addition of a variety
of 3-substituted pyrazol-5-one nucleophiles to tri-
substituted nitroalkenes incorporating an oxetane
or azetidine ring at the b-position. The nitroalkane-
pyrazolone adducts were obtained with good yield
and enantioselectivity. Furthermore, the Michael
addition products can be reduced to the corre-
sponding enantioenriched amines with minimal loss
of enantiomeric purity.
A key challenge for additions to trisubstituted ni-
troalkenes followed by enantioselective protonation is
the inherent acidity of the new nitroalkane stereocen-
ter in the product,[7] which is susceptible to epimeriza-
tion by either the basic nucleophile or the tertiary
amine-substituted organocatalyst. Our group has
found that acidic nucleophiles buffer the reaction
mixture, preventing epimerization of the nitroalkane
stereocenter.[8,9]
The pyrazol-5-one is an acidic heterocycle because
it becomes aromatic upon deprotonation, and there-
fore should be appropriate for enantioselective nitro-
nate protonation. Numerous groups have investigated
the reactivity of pyrazolones.[10] One area of investiga-
tion has been hydrogen-bonding organocatalyzed pyr-
azolone additions, for which excellent enantioselectiv-
ities have been achieved using b-substituted nitroal-
kenes (Figure 2a).[11] However, only a single example
of pyrazolone nucleophile addition to an a-substitut-
ed nitroalkene has been reported (Figure 2b),[12] and
Keywords: asymmetric catalysis; Michael addition;
nitroalkenes; organic catalysis; protonation
The nitroalkene is a versatile electrophile that has here the high observed diastereoselectivity could be
been utilized in numerous catalytic enantioselective due to either diastereoselective protonation or epime-
conjugate addition reactions to access biologically rel- rization of the nitroalkane product.
evant compounds.[1] Previously, we reported the first
We began our investigation with reaction conditions
example of catalytic enantioselective additions of nu- that we previously used for the addition of thioacetic
cleophiles to a,b,b-trisubstituted nitroalkenes, which acid to trisubstituted nitroalkenes.[2] For our optimiza-
was accomplished by enantioselective protonation of tion studies, we chose to use oxetane nitroalkene 2a
the nitronate intermediate generated upon thioacid because the oxetane ring introduces ring strain to in-
addition (Figure 1a).[2] Very recently, Jørgensen and crease the reactivity of these fully substituted nitroal-
co-workers also employed trisubstituted nitroalkene kenes. Additionally, oxetanes are valued in medicinal
electrophiles to achieve intramolecular enantioselec- chemistry for their ability to modulate drug proper-
tive nitronate additions that proceeded by trienamine ties.[13] N-tert-Butylpyrazolone 1a was used because
catalysis (Figure 1b).[3] Here we report that enantiose- the tert-butyl group improved the solubility of the pyr-
lective nitronate protonation following catalytic nu- azolone nucleophile. N-H- and N-phenylpyrazolones
cleophile addition to trisubstituted nitroalkenes can were also investigated, but were found to be only
be extended to carbon nucleophiles with the addition sparingly soluble, leading to poor enantioselectivity.
of pyrazolones, a class of nitrogen heterocycles found At room temperature in cyclopentyl methyl ether
in various biologically active molecules and dyes (Fig- (CPME), a solvent that we have often found to be op-
ure 1c).[4,5] For this transformation, an N-sulfinylurea timal for hydrogen-bonding organocatalysis,[6a–d] the
catalyst provided the highest enantioselectivity.[6]
reaction proceeded with high conversion but low
enantioselectivity for 3,5-bistrifluoromethylphenyl-
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Figure 1. Enantioselective transformations of a,b,b-trisubstituted nitroalkenes.
containing catalysts 4 and 5 (Table 1, entries 1 and
2).[14,15]
To improve the enantioselectivity of the transfor-
mation, we evaluated catalysts that combined a chiral
N-sulfinyl motif with the chiral N,N-dimethylcyclo-
hexane-1,2-diamine motif.[6b–d] Catalysts
6 and 7
showed a modest increase in enantioselectivity, with
the all (S)-diastereomer providing superior enantiose-
lectivity and conversion (entries 3 and 4). Increasing
the steric bulk of the pendant tertiary amine by using
piperidine catalysts 8 and 9 further improved the
enantioselectivity for both catalyst diastereomers and
also established that the diamine is the most signifi-
cant contributor to the control of stereochemistry (en-
tries 5 and 6).
Because bulkier amines improved the enantioselec-
tivity, we explored other sterically encumbered chiral
diamines (Figure 3). Combining the N-sulfinylurea
motif with 9-amino(9-deoxy)epiquinine furnished cat-
alyst 10, which retained the enantioselectivity of the
reaction, but at lower conversion (entry 7). However,
when using catalyst 11, the all (S)-diastereomer of 10,
Figure 2. Reported catalytic enantioselective Michael addi-
tions of pyrazolones to nitroalkenes.
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Table 1. Optimization of the reaction conditions.[a]
for the Michael addition, 3aa was obtained in good
conversion and enantioselectivity (entry 8). Using di-
oxane, a solvent in which the pyrazolone nucleophile
was more soluble, and adding 3Š molecular sieves as
a desiccant further improved the enantioselectivity of
the reaction to a 91:9 er (entries 9 and 10). A number
of other solvents was also investigated, including di-
chloromethane, diethyl ether, THF, and toluene, but
all gave lower enantioselectivities (data not shown).
Increasing the catalyst loading to 10 mol% and ex-
tending the reaction time to two days provided 3aa in
93% conversion and 91:9 er (entry 11). Acid additives
were also investigated. The addition of 10 mol% of
acetic acid improved the reaction conversion, but
a lower enantioselectivity was observed (entry 12).
Entry Catalyst (X mol%) Solvent Conversion[b] er[c]
1
2
3
4
5
6
7
8
4 (5)
5 (5)
6 (5)
7 (5)
8 (5)
9 (5)
10 (5)
11 (5)
11 (5)
11 (5)
CPME 87%
CPME 83%
CPME 29%
CPME 62%
CPME 40%
CPME 33%
CPME 22%
CPME 60%
CPME 46%
dioxane 44%
dioxane 90%
dioxane 98%
dioxane 93%
33:67
60:40
69:31
75:25
73:27
16:84
81:19
80:20 While the addition of 10 mol% of benzoic acid did
9[d]
10[d]
86:14
91:9
91:9
85:15
not adversely impact our model system (entry 13), it
was not beneficial when used with poorer performing
substrates.
With a set of optimized conditions, we explored the
scope of the transformation, focusing first on the pyr-
11[d,e] 11 (10)
12[d,e,f] 11 (10)
13[d,e,g] 11 (10)
91:9
[a]
azolone nucleophile 1 (Table 2). N-tert-Butylpyrazo-
lones with methyl (1a), ethyl (1b), and isopropyl (1c)
R2 substituents all gave products with good enantiose-
lectivity (3aa, 3ba and 3ca); however, as illustrated by
3aa versus 3ca, increasing steric bulk at R2 resulted in
lower yields due to reduced conversion. Some varia-
bility in the enantioselectivity of the reaction to form
3aa was observed, with enantioselectivity ranging
from 93:7 to 90:10 er. Substitution at R2 was not limit-
ed to simple alkyl chains. When R2 was phenyl,
adduct 3da was obtained in good yield and 82:18 er.
A pendent methyl ether could also be incorporated to
provide 3ea in moderate yield and good enantioselec-
tivity. Different substituents at the R1 position of the
pyrazolone were also investigated. While pyrazolones
where R1 was H or phenyl were not tolerated due to
poor solubility under the reaction conditions, other R1
substituents were compatible. N-Cyclohexylpyrazo-
lone 1f reacted to give 3fa in good yield and 83:17 er.
An aromatic R1 group containing 2,6-disubstitution
was also compatible, N-2,6-dimethylphenylpyrazolone
1g reacted with nitroalkene 2a to give 3ga in moder-
ate yield and diminished enantioselectivity.
Reaction conditions: 1a (0.10 mmol), 2a (0.05 mmol) in
0.5 mL of solvent (0.1M).
[b]
[c]
Determined by 1H NMR.
Enantiomeric ratios were determined by HPLC analysis
of the crude reaction mixture on a chiral stationary
phase.
[d]
[e]
[f]
Added 3Š MS (250 mgmmolÀ1).
2 days.
Added 10 mol% of acetic acid.
Added 10 mol% of benzoic acid.
[g]
Variation of the R3 substituent on nitroalkene 2
was also tolerated; adduct 3bb from nitroalkene 2b
(R3 =Me) was isolated in acceptable yield and 90:10
er. Nitroalkene 2c (R3 =benzyl) also reacted with pyr-
azolones 1b and 1c to give 3bc and 3cc, respectively.
Additionally, a pendent ester could be incorporated
at R3 to provide product 3ad, although a decrease in
enantioselectivity was observed.
The transformation is not limited to oxetane nitro-
alkenes, but also proceeds in good yields and enantio-
selectivity for azetidine nitroalkenes (Table 3). Multi-
ple nitrogen protecting groups were tolerated on the
azetidine nitroalkenes. Pyrazolone 1a added to N-Boc
Figure 3. Bifunctional (thio)urea organocatalysts.
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Table 2. Oxetane substrate scope.[a]
[a]
Reaction conditions: 1 (2 equiv.), 2 (1 equiv.), 11 (10 mol%), 3Š MS (250 mgmmolÀ1) in dioxane (0.1M). Yields are of
isolated product after chromatography. Enantiomeric ratios of isolated products were determined using HPLC analysis
on a chiral stationary phase.
(2e), N-Cbz (2f), and N-Ts (2g) azetidine nitroalkenes acid (TFA) buffered column, amine 4 was isolated as
with good enantioselectivity. Additionally, N-Boc and the TFA salt in 61% yield with minimal reduction of
N-Cbz products (3ae and 3af) were isolated in good enantiopurity (Scheme 1). To determine the sense of
yields. Methylpyrazolone 1a also added to N-Boc-aze-
tidine nitroalkene 2h (R3 =Bn) to give 3ah in good
yield and enantioselectivity. Upon decreasing the
steric bulk of R2 from methyl to H, an expected in-
crease in yield was observed, although the enantiose-
lectivity of the reaction was also diminished (3he). Ni-
troalkenes lacking ring strain at the b-position were
also explored, but were found to be unreactive.
To demonstrate the ability to access chiral amines
from the addition products, we explored selective re-
duction of the nitro group in 3aa. Using Pd/C and hy-
drogen at atmospheric pressure, the nitroalkane was
selectively reduced in the presence of the pyrazol-5-ol
heterocycle. After purification using a trifluoroacetic Scheme 1. Reduction of enantioenriched 3a.
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Table 3. Azetidine substrate scope.[a]
[a]
Reaction conditions: 1 (2 equiv.), 2 (1 equiv.), 11 (10 mol%), 3Š MS (250 mgmmolÀ1) in dioxane (0.1M). Yields are of
isolated product after chromatography. Enantiomeric ratios of isolated products were determined using HPLC analysis
on a chiral stationary phase.
induction, we performed Mosher amide analysis on 4 Acknowledgements
and have tentatively assigned the stereochemistry to
be (S).[16,17]
We gratefully acknowledge the National Science Foundation
(CHE-1464129) for support of this work. We thank AstaTech
for supplying the 2,4,6-triisoproplybenzenesulfinamide.
In conclusion, we have developed a catalytic enan-
tioselective addition of pyrazolones to trisubstituted
nitroalkenes using a bifunctional N-sulfinylurea orga-
nocatalyst. This transformation is the first example of
a Michael addition of a carbon nucleophile to a trisub-
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