Direct and enantioselective vinylogous michael addition of α-alkylidenepyrazolinones to nitroolefins catalyzed by dual cinchona alkaloid thioureas

Article abstract of DOI:10.1002/adsc.201300964

While several protocols exist for the asymmetric functionalization of pyrazolinones at the α-position relying on nucleophilic addition or annulation procedures, use of α-alkylidene electron-rich analogues in asymmetric vinylogous coupling to carbon electrophiles is substantially an uncharted domain. We now report, for the first time, that alkylidenepyrazolinones carrying an enolizable carbon at the γ-position efficiently participate in direct and asymmetric, catalytic vinylogous Michael-type additions to nitroolefins providing the expected adducts in high yields, with complete γ-site selectivity and with extraordinary levels of enantio-, diastereo-, and geometrical selectivities. Both enantiomeric adducts were equally accessed by employing a quasi-enantiomeric quinine- or quinidine-based thiourea catalyst pair.

Full text of DOI:10.1002/adsc.201300964

UPDATES
DOI: 10.1002/adsc.201300964
Direct and Enantioselective Vinylogous Michael Addition of
a-Alkylidenepyrazolinones to Nitroolefins Catalyzed by Dual
Cinchona Alkaloid Thioureas
Gloria Rassu,a,* Vincenzo Zambrano,a Luigi Pinna,b Claudio Curti,c
Lucia Battistini,c Andrea Sartori,c Giorgio Pelosi,d Giovanni Casiraghi,c
and Franca Zanardic,*
a
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti Sassari, Italy
Fax : (+39)-079-284-1299; phone: (+39)-079-284-1226; e-mail: gloria.rassu@icb.cnr.it
Dipartimento di Chimica e Farmacia, Universitꢀ degli Studi di Sassari, Via Vienna 2, I-07100 Sassari, Italy
Dipartimento di Farmacia, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 27A, I-43124 Parma, Italy
b
c
Fax : (+39)-0521-905-006; phone: (+39)-0521-905-067; e-mail: franca.zanardi@unipr.it
Dipartimento di Chimica, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 17A, I-43124 Parma, Italy
d
Received: October 30, 2013; Revised: March 13, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300964.
Abstract: While several protocols exist for the
asymmetric functionalization of pyrazolinones at
the a-position relying on nucleophilic addition or
annulation procedures, use of a-alkylidene electron-
rich analogues in asymmetric vinylogous coupling
to carbon electrophiles is substantially an uncharted
domain. We now report, for the first time, that
sought after in the context of drug discovery and
agroscience.[1]
During our recent studies on the asymmetric vinyl-
ogous Michael-type reaction of a-alkylideneoxin-
doles,[2,3] we envisaged that the remote exocyclic g-
carbon of the substrates could be a suitable and exclu-
sive nucleophilic site for the conjugate addition to b-
nitroolefins by utilizing a dual Cinchona-based thiour-
ea organocatalyst and its chiral surrounding for syner-
gistic substrate activation and enantioinduction
[Scheme 1, Eq. (1)].[4]
In this way variously shaped oxindole nitroadducts
were assembled with extraordinary catalytic reactivity
and selectivity. As part of our ongoing program to-
wards the exploration of the vinylogous reactivity
space of nitrogen-embedding heterocycles in catalytic,
asymmetric carbon-carbon bond forming reactions,
we report here, for the first time, that olefinic pyrazo-
linones also engage in catalytic, direct and asymmetric
vinylogous Michael additions with a diverse range of
nitroalkenes to furnish the respective adducts with ad-
mirable levels of regio-, enantio-, diastereo-, and geo-
metrical selectivities [Scheme 1, Eq. (2)].[5,6]
alkylACHTUNGTRENNUNGidenepyrazolinones carrying an enolizable
carbon at the g-position efficiently participate in
direct and asymmetric, catalytic vinylogous Mi-
chael-type additions to nitroolefins providing the
expected adducts in high yields, with complete g-
site selectivity and with extraordinary levels of
enantio-, diastereo-, and geometrical selectivities.
Both enantiomeric adducts were equally accessed
by employing a quasi-enantiomeric quinine- or qui-
nidine-based thiourea catalyst pair.
Keywords: asymmetric catalysis; Cinchona alka-
loids; nitroolefins; organocatalysis; pyrazolinones;
vinylogous Michael addition
We began by investigating the vinylogous Michael
reaction of a-isopropylidenepyrazolinone 1a, which
Five-membered nitrogen heterocycles and compounds was quickly obtainable from 3-methyl-1-phenyl-2-pyr-
embedding these motifs have long been recognized as azolin-5-one (edaravone, also coded as MCI-186),
privileged structural frameworks for the development a free radical scavenger drug clinically used to reduce
of molecules with important biological and pharma- neuronal damage following cerebral ischemic stroke.[7]
ceutical properties. The pyrazole and pyrazolone Evaluation of the dihydroquinine-derived thiourea
nuclei subsets occupy a rewarding position in this catalyst I for the addition to trans-b-nitrostyrene (2a),
scaffold realm, and many representatives are highly using the conditions we previously reported for the
asymmetric Michael reaction of 3-alkylideneoxin-
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Table 1. Substrate scope: variation of the nitroolefin accept-
ors with pyrazole donor 1a, using catalysts I (normal entries)
or II (primed entries).[a–d]
Scheme 1. Direct, organocatalyzed asymmetric vinylogous
Michael reactions of nitrogen-embedding heterocycles. The
vinylogous reactivity space involves the remote exocyclic g-
carbon of the pronucleophilic substrates.
doles,[2] yielded an encouraging initial result. When
the reaction was conducted in toluene (0.2M) at am-
bient temperature, nearly full conversion of the start-
ing material was attained in less than 2 h, and adduct
3aa was obtained in 80% yield, exhibiting a 6:1 Z/E
isomeric ratio and a 97:3 er. To halt entirely the para-
site background reaction which could erode the reac-
tion selectivity, we lowered the temperature to À308C
and, as was our hope, the reaction selectivity marked-
ly improved, while maintaining high catalytic efficien-
cy, and 3aa was returned in a 93% isolated yield and
as just one enantiomer (>99:1 er) and one geometri-
cal isomer (>20:1 Z:E ratio) (Table 1, entry 1).
As expected, scrutinizing quinidine-based catalyst
II, a quasi-enantiomer of I, under standardized condi-
tions also underwent full substrate conversion, which
returned the enantiomer of 3aa (ent-3aa) in 89%
yield, with 17:1 Z:E ratio, and 94:6 er (Table 1,
entry 1’).
With these rewarding results established, we then
wished to evaluate the scope and limitation of this
process as regard to the nitroolefin acceptor. In addi-
tion to nitrostyrene 2a leading to 3aa and ent-3aa,
a variety of differently substituted nitroolefins was
first assayed in reactions with pyrazolinone 1a. Excel-
lent results were uniformly attained with aryl-substi-
tuted olefins and, whether they contain a neutral, an
[a]
Reactions were performed with 0.47 mmol of 1 and
0.47 mmol of 2 in toluene (0.2M) in the presence of cata-
lysts I or II (10 mol%) at À308C for 24 h.
[b]
Combined yield of isolated products.
[c]
Diastereomeric ratios (Z:E) were determined by
1H NMR spectroscopy.
[d]
Enantiomeric excesses of the major diastereoisomers
were analyzed by HPLC using a chiral stationary phase
column.
2
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Direct and Enantioselective Vinylogous Michael Addition
electron-withdrawing, or an electron-donating group, Z-configured adduct 3ha as the sole enantiomer and
the desired adducts 3ab–3ae were obtained in very diastereoisomer (>20:1 anti/syn, >99:1 er).[10] As for
good yields, almost complete geometrical selectivity the experiments grouped in Table 1, reactions were
in favor of the Z-configured isomers and with er run in parallel with quasi-enantiomeric catalyst II to
values of >99:1 (entries 2–5). Moreover, we conduct- enter the opposite enantiomeric adducts, and the re-
ed the reactions between 1a and heteroaromatic sults are displayed in the primed entries of Table 2.
olefin 2f leading to adduct 3af, and equally rewarding Invariably, reactions were high-performing, showing
results were obtained in terms of reactivity and selec- an excellent control of the product geometry and dia-
tivity (entry 6).
stereoselectivity, albeit suffering, in some instances,
Reactions were duplicated with catalyst II to access from a minute drop in enantioselectivity.
the opposite enantiomeric series (Table 1, primed en-
The relative configuration of 3ha, carrying two con-
tries). In all cases, reactions performed well with re- secutive stereogenic centers, was unambiguously de-
spect to both the regio- and diastereocontrol, albeit termined as (Z)-3’,4’-anti via single crystal X-ray dif-
they displayed slightly reduced enantioselectivities; fraction analysis (Figure 1).[11] The absolute configura-
and this reflects the diastereomeric nature of the two tion of products 3 was tentatively assumed (R-config-
Cinchona alkaloid-based catalysts employed, not ex- ured from I, S-configured from II)[12] by analogy to
actly an enantiomeric pair.[8]
the previous work on nucleophilic vinylogous addition
The addition to b-alkyl-substituted nitroalkenes as to nitroolefins catalyzed by I and II.[2] However, an
well as the use of congested b,b-disubstituted conge- indirect, though reliable assignment of the 3aa struc-
ners were also evaluated. We found that these sub- ture was carried out via OsO4/PhIACHTNUTRGNENG(U OAc)2-assisted oxi-
strates, which are known to be less prone to nucleo- dative fission of the exocyclic double bond to give
philic addition reactions,[9] were significantly less reac- a known nitroketone product, as detailed in the Sup-
tive than the (hetero)aryl-substituted nitroalkenes in porting Information. The Z/E geometry of products 3
our processes and, under the conditions shown in was also corroborated by proton nuclear Overhauser
Table 1, no reaction was observed using b-cyclohexyl- effect spectroscopy measurements.
and b-n-butyl-substituted nitroalkenes as well as a-
Based on the observed stereochemistry of the Mi-
methyl-b-nitrostyrene even after extended reaction chael adducts and capitalizing on previous studies on
times or raising the reaction temperature and catalyst closely related organocatalytic transformations,[2,4]
loading. Importantly, we carried out the reactions to- a plausible mechanistic itinerary for the present con-
wards 3aa on a 1.0 mmol scale, and found that the re- jugate addition was proposed (Figure 2). We postulat-
activity and geometry control, as well as the site selec- ed that the pendent tertiary amine of the bifunctional
tivity and enantioselectivity, remained excellent.
catalyst I (or II) first deprotonates the alkylidenepyra-
The applicability of the reaction with different yli- zolones at the g-position, and that the protonated cat-
denepyrazolinones was next explored under the alyst then brings the dienolate nucleophile and the
above established conditions, using either unsubstitut- alkene electrophile together to give a tight H-bonded
ed styrene 2a or the brominated counterpart 2b. Sub- ternary complex with the right alignment of the reac-
strates with substituents on the pyrazole N-phenyl tants to ensure a precise control during the key
group invariably gave good yields ranging from 80% carbon-carbon bond formation.
to 91% (Table 2, entries 1–6), irrespective of their
Specifically, linking the nitroolefin to the two NH
electronic nature. No significant influence was ob- groups of the thiourea moiety and the pyrazole dieno-
served on the enantio- and geometrical selectivities, late to the quinuclidinium portion of the catalyst pro-
whose levels remained rewarding in all cases. Chang- duces a stereo-determining transition state which re-
ing the methyl substituent at the pyrazole C-3 posi- sults in the formation of the g-alkylated products pre-
tion to n-propyl or phenyl groups was also tolerated, dominantly, via preferential acceptor Re-face addition
allowing access to Z-configured nitroadducts 3ea and trajectory (catalyst I), consistent with the experimen-
3fa in 71–75% yields and with exceptional margins of tal observations. We rationalize that the s-cis confor-
enantio- and geometrical selectivities (entries 7 and mational preference of the transient dienolate con-
8). Use of prochiral symmetrical diethyl-substituted trols the double bond geometry of the adducts, while
ylidene substrate 1g and unsymmetrical methyl-ethyl the prevalence for g- over a-alkylation might likely
substituted analogue 1h, where two adjacent stereo- be the result of stereoelectronic influences.
centers were installed simultaneously, was also suited
Moreover, our model to explain the reaction diaste-
to this reaction, which afforded the corresponding ad- reoselectivity using prochiral ylidene substrates (anti
ducts 3ga and 3ha in excellent yields and selectivities vs. syn) is consistent with the observation that, in the
(entries 9 and 10). The result with precursor 1h is par- stereo-determining step, the active dienolate species
ticularly impressive: of the two different enolizable assumes a favorable Z-geometry, which translates
g,g’-carbon sites (CH3 and C2H5) only the ethylene completely into the anti configuration in the addition
group participated in the addition, giving rise to the products.[13]
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Table 2. Substrate scope: variation of pyrazole donors with olefins 2a or 2b as acceptors, using catalysts I (normal entries) or
II (primed entries).[a]
[a]
For conditions and measurements, see footnotes in Table 1.
A salient feature of the present asymmetric vinylo- be cis via 2D-NOESY experiments, as detailed in the
gous Michael addition is that it provides products in Supporting Information.
which the exocyclic unsaturation of the initial pyrazo-
In summary, we have developed the first highly
linone substrate is preserved. This olefinic function enantioselective, diastereoselective, and geometry-se-
could in turn be used to further manipulate the lective direct vinylogous Michael addition between a-
system, thus increasing the molecular complexity of alkylidenepyrazolinones and nitroalkenes catalyzed
the pyrazole products. As an example (Scheme 2), by readily available Cinchona alkaloid-based bifunc-
enantiomerically pure pyrazolinone 3ha was stereose- tional thioureas. Under our optimized reaction condi-
lectively elaborated into a rare oxopyrazoline spiroox- tions, site-specific functionalization at the remote g-
irane 4, as a single isomer, by subjecting the olefin to carbon of the pyrazole scaffold was realized to pro-
nucleophilic H2O2 epoxidation,[14] a manoeuver that vide a range of structurally diverse Z-configured Mi-
completes the installation of four consecutive stereo- chael adducts with extraordinary levels of selectivity
genic carbon centers, two of which are quaternary. for both the enantiomers. Further investigations,
The stereochemistry of oxirane 4 was determined to which involve the use of diverse nucleophilic and pro-
4
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Direct and Enantioselective Vinylogous Michael Addition
Experimental Section
Representative Procedure for the Synthesis of 3aa
To a solution of pyrazolinone 1a (100 mg, 0.47 mmol,
1.0 equiv.) and nitrostyrene 2a (70 mg, 0.47 mmol, 1.0 equiv.)
in toluene (2.35 mL), cooled at À308C, was added thiourea-
catalyst I (28 mg, 0.047 mmol, 0.1 equiv.). The reaction was
kept under vigorous stirring at À308C for 24 h. After warm-
ing to room temperature, the reaction solution was passed
through a celite pad, concentrated under vacuum, and the
crude product was purified by silica gel flash chromatogra-
phy (80:20 hexane/EtOAc) to yield pure (R,Z)-3aa as an
orange solid; yield: 159 mg (93%). The dr (Z:E) of the
1
product was determined to be >20:1 by H NMR analysis
of the crude reaction mixture; mp 118–1228C; [a]2D0: À33.6
(c 1.4, chloroform); Rf =0.38 (80:20 hexane/EtOAc). Chiral
HPLC (Chiracel OD-H, hexane/ethanol 90:10, 1.0 mLminÀ1,
254 nm): Rt 17.79 min (major), 21.86 min (minor) (99.7:0.3
er). 1H NMR (400 MHz, CDCl3): d=7.90 (m, 2H, arom),
7.13–7.45 (m, 8H, arom), 4.76 (dd, 1H, J=12.9, 8.7 Hz, H-
5’a), 4.71 (dd, 1H, J=12.9, 6.5 Hz, H-5’b), 4.00 (dd, 1H, J=
12.0, 7.4 Hz, H-3’a), 3.86 (dddd, 1H, J=8.7, 8.1, 7.4, 6.5 Hz,
H-4’), 3.06 (dd, 1H, J=12.0, 8.1 Hz, H-3’b), 2.36 (s, 3H, C3-
Me), 2.18 (s, 3H, C1’-Me); 13C NMR (100 MHz, CDCl3): d=
164.8 (Cq), 163.0 (Cq), 148.0 (Cq), 138.7 (Cq), 137.9 (Cq),
129.0 (2C, CH), 128.8 (2C, CH), 128.7 (Cq), 128.1 (CH),
127.5 (2C, CH), 125.1 (CH), 119.2 (2C, CH), 79.6 (CH2),
43.2 (CH), 38.4 (CH2), 23.0 (Me), 19.0 (Me); HR-MS (ESI):
m/z=364.1669, calcd. for C21H22N3O3 [M+H]+: 364.1661.
Figure 1. ORTEP drawing of compound 3ha as determined
by single crystal X-ray analysis.
Supporting Information
Experimental procedures, characterization, spectroscopic
data, X-ray crystal structure of 3ha, HPLC profiles, and
1
copies of H and 13C NMR spectra are available in the Sup-
porting Information.
Figure 2. Proposed organocatalytic cycle for the vinylogous
1,4-addition of olefinic pyrazolinones to nitroolefins. The Z-
geometry of the prochiral dienolate translates into the anti
configuration of the product. The s-cis conformation of the
pyrazole dienolate results in a Z-configured double bond in
the adduct.
Acknowledgements
We thank the Universitꢀ degli Studi di Parma for funding.
Thanks are due to Centro Interdipartimentale Misure “G.
Casnati” (University of Parma) for instrumental facilities.
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[10] Actually, 1h was a 80:20 mixture of Z and E isomers,
however the result proved independent of the starting
olefin geometry. Equal results were obtained using
a 50:50 Z/E mixture.
[11] Lacking heavy atoms, the assignment of the absolute
configuration of 3ha could not be exactly determined
[Flack parameter for the (R,R)-isomer was 0.102ACHTUNGTRENNUNG(602)].
CCDC 986579 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
6
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These are not the final page numbers!

UPDATES
Direct and Enantioselective Vinylogous Michael Addition
[or from the Cambridge Crystallographic Data Centre
12, Union Road, Cambridge CB2 1EZ, U.K.; fax: (+
44)-1223-336-033; or deposit@ccdc.cam.ac.uk].
thiourea group of the catalyst, while the protonated
quinuclidine nitrogen engenders a bifurcate H-bonding
with the nitroolefin. See: a) A. Hamza, G. Schubert, T.
Soꢈs, I. Pꢄpai, J. Am. Chem. Soc. 2006, 128, 13151–
13160; b) B. Tan, Y. Lu, X. Zeng, P. J. Chua, G. Zhong,
Org. Lett. 2010, 12, 2682–2685.
[12] Assuming that the olefin facial selectivity imparted by
the catalyst was the same for all the reactions (Re-face
from I; Si-face from II), the absolute configuration of
the products 3 is 4R while that of products ent-3 is 4S.
However, due to IUPAC substituent priority rules,
adduct 3af is S-configured; ent-3af is R-configured.
[13] An alternative dual activation channel cannot in princi-
ple be excluded. According to the proposals of Pꢄpai
and Zhong, the nucleophile could be activated by the
˘
[14] a) S. N. Ege, A. D. Adams, E. J. Gess, K. S. Ragone,
B. J. Kober, M. B. Lampert, P. Umrigar, D. C. Lankin,
G. W. Griffin, J. Chem. Soc. Perkin Trans. 1 1983, 325–
331; b) K. Kirschke, E. Schmitz, J. Prakt. Chem. 1985,
327, 35–44.
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
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These are not the final page numbers!

UPDATES
8 Direct and Enantioselective Vinylogous Michael Addition
of a-Alkylidenepyrazolinones to Nitroolefins Catalyzed by
Dual Cinchona Alkaloid Thioureas
Adv. Synth. Catal. 2014, 356, 1 – 8
Gloria Rassu,* Vincenzo Zambrano, Luigi Pinna,
Claudio Curti, Lucia Battistini, Andrea Sartori,
Giorgio Pelosi, Giovanni Casiraghi, Franca Zanardi*
8
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!