Bifunctional cinchona alkaloid/thiourea catalyzes direct and enantioselective vinylogous Michael addition of 3-alkylidene oxindoles to nitroolefins

Article abstract of DOI:10.1002/anie.201202027

Vinylogy: Advances in asymmetric catalysis using the bifunctional cinchona alkaloid/thioureas enabled an umpolung of the classical C_β reactivity of 3-alkylidene oxindoles, thus allowing the development of the first and sole example of a direct, organocatalytic asymmetric vinylogous Michael (AVM) reaction with nitroolefins. Copyright

Full text of DOI:10.1002/anie.201202027

Angewandte
Chemie
DOI: 10.1002/anie.201202027
Organocatalysis
Bifunctional Cinchona Alkaloid/Thiourea Catalyzes Direct and
Enantioselective Vinylogous Michael Addition of 3-Alkylidene
Oxindoles to Nitroolefins**
Claudio Curti,* Gloria Rassu,* Vincenzo Zambrano, Luigi Pinna, Giorgio Pelosi,
Andrea Sartori, Lucia Battistini, Franca Zanardi, and Giovanni Casiraghi*
3-Alkylidene oxindoles (methyleneindolinones), be they
natural or man-made substances, occupy a preeminent posi-
tion among the various classes of chemically and medicinally
relevant small-molecule scaffolds.[1] Their plural functional
architecture featuring a lactam carbonyl flanked by a highly
substituted exocyclic double bond renders them enabling
intermediates to be elaborated into a myriad of useful
nitrogen heterocycles of varied complexity.[2] For example,
3-alkylidene oxindoles can be viewed as electrophilic Michael
acceptors, which react with carbon-centered anions to give b-
substituted oxindoles of type A (Scheme 1a). In addition,
they can act as electron-poor components in synchronous
(Scheme 1b) or stepwise (Scheme 1c) cycloadditive function-
alizations, thus opening the way to a wide range of highly
valuable 3,3-spirocyclic structures of type B or C. Whereas
these protocols have been largely pursued and formed the
basis of many synthetic achievements,[2] an “umpolung”
option could also be envisaged (Scheme 1d), and capitalizes
on the vinylogous pro-nucleophilic character of the alkyl
group attached at the b-position of the ylidene. By reacting
with the proper acceptors, these nucleophiles furnish olefinic
oxindoles of type D, which are functionalized at the most
distant point of the molecule (Cg). However, despite the
potential synthetic utility this method promises in terms of
product complexity and atom economy, this opportunity has
Scheme 1. Reactivity of 3-alkylidene oxindoles. a) Michael-type Cb func-
tionalization.[2d,e] b) A [3+2] trimethylenemethane (TMM) cycloadditio-
n.[2a,b] c) Michael/Michael/aldol annulation cascade.[2d,e] d) Vinylogous
Michael-type Cg functionalization (this work). PG=protecting group;
EWG=electron-withdrawing group.
[*] Dr. C. Curti, Dr. A. Sartori, Dr. L. Battistini, Prof. Dr. F. Zanardi,
Prof. Dr. G. Casiraghi
Dipartimento Farmaceutico, Universitꢀ degli Studi di Parma
Parco Area delle Scienze 27A, I-43124 Parma (Italy)
E-mail: claudio.curti@unipr.it
giovanni.casiraghi@unipr.it
Prof. Dr. G. Pelosi
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica,
Chimica Fisica, Universitꢀ degli Studi di Parma, Parma (Italy)
arguably been rather overlooked by the organic synthesis
community,[3] and only very recently has an inaugural
asymmetric vinylogous aldolization study been disclosed by
our own research group.[4] Continuing this program, we report
herein that a varied repertoire of g-substituted a-ylidene
oxindoles of type D can be assembled in high yield and
excellent enantioselectivity in the first example of a direct,
organocatalytic asymmetric vinylogous Michael (AVM) addi-
tion reaction of olefinic oxindoles to nitroolefins.[5,6] Reac-
tions were perfectly guided by the chiral cinchona alkaloid/
thiourea catalysts (Figure 1),[7] whose progeny was originally
conceived and exploited by the research groups of Chen,[8]
Soꢀs,[9] Connon,[10] and Dixon.[11]
Dr. G. Rassu, Dr. V. Zambrano
Istituto di Chimica Biomolecolare del CNR
Traversa La Crucca 3, I-07100 Li Punti, Sassari (Italy)
E-mail: gloria.rassu@icb.cnr.it
Dr. L. Pinna
Dipartimento di Chimica e Farmacia, Universitꢀ degli Studi di
Sassari, I-07100 Sassari (Italy)
[**] We thank the Universitꢀ degli Studi di Parma and the Regione
Autonoma della Sardegna (L.R. 07.08.2007, n.7) for funding. Thanks
are due to Centro Interdipartimentale Misure “G. Casnati” for
instrumental facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202027.
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Table 1: Survey of catalysts and conditions for the direct AVM addition of
oxindole 1a to olefin 2a.[a]
Entry
Catalyst
Solvent
Yield [%][b]
d.r. [Z:E][c]
ee [%][d]
0
1
2
3
4
5
6
7
DABCO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
MeOH
toluene
toluene
toluene
toluene
toluene
16
60
0
5:1
10:1
–
10:1
10:1
10:1
10:1
10:1
12:1
9:1
20:1
20:1
>20:1
>20:1
>20:1
racemic
95
A
B
C
D
E
F
A
A
A
A
A
A
A
A
–
18
52
53
58
68[e]
42
24
85
76
90
98
73
À24
96
95
À96
97
8
9
94
77
98
98
>99
>99
>99
10[f]
11[f,g]
12[f,h]
13[f,h,i]
14[f,h,j]
[a] Unless otherwise stated, all AVM reactions were carried out on
a 0.2 mmol scale using 1:1 1a/2a molar ratio and 10 mol% of catalyst in
2 mL of solvent at RT for 30 h. [b] Yield of isolated product after column
chromatography. [c] Determined by 1H NMR analysis of the crude
reaction mixture. [d] Determined by chiral HPLC analysis. [e] 10% of an
over-reaction by-product was also obtained. [f] Reaction carried out at
À158C for 24 h followed by 12 h at RT. [g] 1a/2a molar ratio was 1:1.2.
[h] 1a/2a molar ratio was 1.2:1. [i] 5 mol% of A was used. [j] 1 mol% of A
was used in 72 h. DABCO=1,4-diazabicyclo[2.2.2]octane, THF=tetra-
hydrofuran.
Figure 1. Catalysts for the AVM addition of 3-alkylidene oxindoles to
nitroolefins.
Initiating our work, we investigated the possible carbon–
carbon bond-formation between readily available isopropy-
lidene oxindole 1a and trans-b-nitrostyrene (2a) in the
presence of the dihydroquinine-derived thiourea A at ambi-
ent temperature (Table 1, entry 1). It was pleasing that the
AVM reaction proceeded efficiently in CH2Cl2 with
a 10 mol% catalyst loading, and the expected Michael
adduct 3aa (> 99:1 g/a) was isolated in 60% yield after
30 hours. Notably, both diastereoselectivity and enantioselec-
tivity were good (10:1 Z/E d.r. and 95% ee). Although this
first result was rewarding insofar as the ee value was
concerned, a systematic catalyst screening and refinement
of the reaction parameters were performed to identify even
more productive and selective reaction conditions. To exclude
any uncertainty that the use of the cinchona/thiourea catalysts
might be decisive for positive reaction progress and an
efficient catalyst-to-product transfer of chirality, control
experiments were performed using the same reaction con-
ditions of entry 1 in Table 1, but switching catalyst A to
thiourea B and dihydroquinine C (Table 1, entries 2 and 3).
Similar to several precedents in this field, both experiments
failed, thus substantiating the principle that cooperativity
between the basic and acidic moieties within the catalyst is
indeed a stringent prerequisite for an effective asymmetric
induction and reactivity.
obtained with almost equal ease and only slightly reduced
yields upon isolation. As expected, quasienantiomers E and F
did produce compounds which were enantiomers at the newly
created stereocenters (entries 5 versus 6). Overall this trial
identifies catalyst A as the catalyst of choice to be advanced
for further optimization.
Of the solvents scrutinized, toluene was shown to be the
ideal candidate as 3aa was delivered in an improved 68%
yield with 10:1 Z/E d.r. and 97% ee (Table 1, entry 7). The
only cloud shadowing this notable result was the presence of
a marginal amount of an over-reaction by-product (ca. 10%
yield) arising from bilateral Michael addition at both the
methyl termini of the isopropylidene oxindole 1a.[12] Gratify-
ingly, by lowering the reaction temperature to À158C and
increasing the donor/acceptor molar ratio to as little as 1.2:1
at a 0.1m concentration (entry 12), the reaction returned 3aa
in 90% yield upon isolation, with virtually complete selectiv-
ity and little, if any, by-product generation. Conveniently, the
catalyst loading was reduced to 5 mol% with no erosion of
selectivity (entry 13). However, additional lowering to
1 mol% prolonged the reaction time, thus rendering this
option less practical (entry 14). Thus, by comprehensive
comparison, the optimal reaction conditions in view of
reactivity and global selectivity were those unveiled in
entry 13 of Table 1.
On this basis, we felt compelled to explore alternative
cinchona/thiourea catalysts D–F derived from quinine, cin-
chonidine, and quinidine, respectively (Table 1, entries 4–6).
With respect to the initial attempt with catalyst A, the data
did not show significant variation in the reaction outcome
and, in these cases, the vinylogous Michael adduct 3aa was
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At this point, with the optimal reaction conditions in
hand, the scope and limitations of this unprecedented, direct
AVM addition were surveyed with respect to both the indole
donor and the alkene acceptor components. The results are
summarized in Scheme 2. A number of indole nucleophiles
carrying diverse nitrogen protecting groups and substituents
at both the benzo and the olefin moieties were first studied.
Excellent results were achieved with carbamoyl oxindoles 1a
and 1b having methoxycarbonyl (Moc) and tert-butoxycar-
bonyl (Boc) substituents, thus leading to adducts 3aa and 3ba,
respectively, in very high yields and selectivities. In sharp
contrast, with protecting-group-free oxindoles and benzyl-
protected derivatives the reactions stalled; and this substan-
tiated that the presence of an electron-withdrawing group at
the indole nitrogen atom, capable of engaging in supplemen-
tary hydrogen-bonding interactions with the catalyst, is an
indispensable prerequisite for the reaction to occur efficiently
and selectively (see below).[13] Even indoles carrying electron-
releasing or electron-withdrawing substituents at the aro-
matic ring, such as the methoxy derivative 1c and chlorine
derivative 1d, nicely served as Michael donors, thus giving
rise to the corresponding vinylogous adducts 3ca and 3da,
respectively, in high yields and excellent levels of diastereo-
and enantioselectivity. Equally, benzylidene oxindole 1e,
carrying an aromatic ring at the Cb-position, was a competent
donor, and delivered E configured adduct 3ea solely in 93%
yield and 97% ee.[14,15]
A variety of nitroalkene acceptors were then investigated.
Irrespective of the electronic and steric demand of the
aromatic ring within styrenes 2b–e, all reactions went to
completion, and the respective adducts 3ab–3ae, as well as
3dc and 3ec, were isolated in good yields and very good
margins of diastereo- and enantioselectivities. Nitroalkenes
2 f and 2g bearing a heteroaromatic ring could also be used as
proper Michael acceptors, thus giving 3af and 3ag, respec-
tively, in excellent yields with diastereo- and enantioselecti-
vies close to 100%. Finally, to explore the substrate generality
further, AVM additions of 1a to nitroalkenes carrying
aliphatic side chains, such as b-cyclohexylnitroethene (2h)
and b-n-butylnitroethene (2i), were evaluated. To our delight,
with a 10 mol% catalyst loading at room temperature, the
same remarkable stereocontrol was attained, thereby afford-
ing products 3ah and 3ai, respectively with 10:1 d.r. and 97 to
greater than 99% ee, albeit in slightly lower yields (isolated)
because of decreased reactivity of these nitroolefins.
Based on the above results and several precedents with
these catalysts,[7] a possible model of dual activation of both
the nucleophile and the electrophile by means of catalyst A
was proposed (see Figure S5 in the Supporting Information).
A serves as the chiral bifunctional catalyst: the thiourea unit
activates the nitroalkene by double hydrogen bonding, while
the quinuclidine base deprotonates the oxindole to afford an
active dienolate species. An extra hydrogen bond between the
carbonyl of the indole N-protecting group and the protonated
quinuclidine base of the catalyst further contributes to
stabilization of the transition state, thus ensuring preferential
approach of the dienolate to the alkene Re face.[16,17] At the
same time, the favorable s-cis alignment of the indole
dienolates during the approach to the activated nitroolefins
Scheme 2. Generality of the direct AVM addition with respect to the donor
and acceptor components. Unless otherwise stated, all AVM reactions
were carried out on a 0.4 mmol scale using 1.2:1 1/2 molar ratio, and
5 mol% of catalyst in 4 mL of solvent at À158C for 24 h, followed by 12 h
at RT. The reported yields are those of the isolated products. The d.r. and
ee values were determined by 1H NMR spectroscopy and chiral HPLC
analysis, respectively. The origin of the adducts can be derived by the
formula abbreviation 3xy: the first letter identifies the oxindole donor,
while the second letter identifies the nitroolefin acceptor. [a] 10 mol%
catalyst was used, at RT for 72 h.
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controls the geometry of the newly formed double bond
within the oxindole products, as indicated.
The absolute configuration of brominated adduct 3ac, as
well as the geometry of the alkene subunit were firmly
established to be (3Z,4’R) by X-ray anomalous dispersion
analysis (see Figure S6 in the Supporting Information),[18] and
they are in accordance with those predicted by the proposed
catalytic models. The absolute configurations of the other
Michael adducts in Scheme 2 were assigned by analogy; their
Z/E geometry was established by 2D-NOESY NMR experi-
ments. In addition, the absolute configuration of Michael
adducts 3aa, ent-3aa, 3ea, 3ag, and 3ah was also determined
by OsO4/PhI(OAc)2-assisted oxidative fragmentation of the
exocyclic double bond to afford known nitroketones (see the
Supporting Information for details).
In conclusion, driven by lack of precedent for exploiting
a-ylidene oxindoles as vinylogous carbon nucleophiles, we
have realized the first and sole example of a direct, organo-
catalytic AVM addition of 3-alkylidene oxindoles to nitro-
olefins. The reactions were admirably orchestrated by the
bifunctional cinchona alkaloid/thiourea catalyst A, to deliver
almost enantiopure g-substituted 3-alkylidene oxindoles with
outstanding levels of regio-, diastereo-, and enantioselectivity.
Provided that N-carbamoyl-protected oxindoles were used,
the reaction scope and generality were substantial, regardless
of the presence of neutral, electron-withdrawing, or electron-
releasing substituents on the reaction components. Additional
investigations into the utility and scope of 3-alkylidene
oxindoles as electron-rich substrates in catalytic, asymmetric
vinylogous carbon–carbon and carbon–heteroatom bond
formations are currently underway.
Received: March 14, 2012
Published online: && &&, &&&&
Keywords: asymmetric synthesis · heterocycles ·
.
Michael reaction · organocatalysis · umpolung
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[12] Of note, only one stereoisomer of the bis(adduct) by-product
could be detected.
[13] In addition, the Moc/Boc protecting groups may enhance the
acidity of the g-methyl protons in 1, thereby allowing the
enolization of the substrates to be more facile.
[14] According to IUPAC nomenclature, adducts 3ea, as well as 3ec,
are indeed E configured, but the actual disposition of the
4
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double-bond substituents is the same as for all adducts portrayed
in Scheme 2.
cannot, in principle, be ruled out. See structure II in Figure S5
of the Supporting Information. See, for example: a) T. Okino, Y.
Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc.
2005, 127, 119 – 125; b) A. Hamza, G. Schubert, T. Soꢀs, I. Pꢁpai,
J. Am. Chem. Soc. 2006, 128, 13151 – 13160.
[15] Reactions performed with monosubstituted 3-ethylidene oxin-
2
=
dole (R H) failed because of extensive substrate decomposi-
tion under the scrutinized reaction conditions.
[16] The crucial role played by the indole carbamoyl protecting group
is additionally supported by the low enantiocontrol obtained
when a 3-ylidene benzofuranone analogue was utilized in lieu of
the present indole matrices.
[18] CCDC 870537 (3ac) 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.
[17] An alternative transition-state model involving electrophile
activation by the protonated amine group of the catalyst
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Communications
Organocatalysis
C. Curti,* G. Rassu,* V. Zambrano,
L. Pinna, G. Pelosi, A. Sartori, L. Battistini,
F. Zanardi, G. Casiraghi*
&&&& — &&&&
Bifunctional Cinchona Alkaloid/Thiourea
Catalyzes Direct and Enantioselective
Vinylogous Michael Addition of 3-
Alkylidene Oxindoles to Nitroolefins
Vinylogy: Advances in asymmetric catal-
ysis using the bifunctional cinchona
alkaloid/thioureas enabled an umpolung
of the classical Cb reactivity of 3-alkyli-
dene oxindoles, thus allowing the devel-
opment of the first and sole example of
a direct, organocatalytic asymmetric
vinylogous Michael (AVM) reaction with
nitroolefins.
6
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