3-alkenyl-2-silyloxyindoles: An enabling, yet understated progeny of vinylogous carbon nucleophiles

Article abstract of DOI:10.1002/ejoc.201101446

We introduce novel 3-alkenyl-2-silyloxyindole nucleophiles and demonstrate their utility by developing an unprecedented vinylogous Mukaiyama-type aldol reaction with aromatic aldehydes. This reaction displays excellent levels of γ-site selectivity and dia

Full text of DOI:10.1002/ejoc.201101446

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101446
3-Alkenyl-2-silyloxyindoles: An Enabling, Yet Understated Progeny of
Vinylogous Carbon Nucleophiles
Gloria Rassu,*[a] Vincenzo Zambrano,[a] Rossella Tanca,[a] Andrea Sartori,[b]
Lucia Battistini,[b] Franca Zanardi,[b] Claudio Curti,*[b] and Giovanni Casiraghi*[b]
Keywords: Aldol reactions / Asymmetric catalysis / Nitrogen heterocycles / Silicon / Nucleophiles
We introduce novel 3-alkenyl-2-silyloxyindole nucleophiles
and demonstrate their utility by developing an unprece-
hydroxylated oxindoles bearing
double bond at the C-3 position. A preliminary trial of an
a substituted exocyclic
dented vinylogous Mukaiyama-type aldol reaction with aro- asymmetric, catalytic version was conducted, and it showed
matic aldehydes. This reaction displays excellent levels of γ-
site selectivity and diastereoselectivity and delivers valuable
promising enantioselectivity for the desired vinylogous aldol
products.
functionalization of simple oxindole matrices is one of the
most suited protocols.[5] In spite of the efficiency of this
approach and the amount of literature data available, there
is no information on the use of 3-alkylidene oxindoles and
3-alkenyl-2-silyloxyindoles arising from them as the nucleo-
philic components in vinylogous aldolizations and related
processes,[6] a maneuver that would render a number of
structurally diverse hydroxylated oxoindolinylidene frame-
works expediently accessible.
Scheme 1 depicts a scenario where a “normal” Mukai-
yama-type aldol reaction (MAR) and a related vinylogous
variant (VMAR)[7] are confronted. Focusing on oxindole
products C and F, one can realize that extended 3-alkylid-
ene indolinones F, arising from vinyl-silyl ketene N,O-acet-
als D bearing an exocyclic double bond with two prochiral
carbon atoms, are structurally more adorned as compared
to carbinols C. This elects indolinones F as privileged struc-
tures that can be subjected to various synthetic manipula-
Introduction
The oxindole moiety is central in a number of natural
and man-made alkaloid products, many of which display
attractive profiles for biological and pharmaceutical appli-
cations.[1] A common feature of this complex compound
progeny is the substitution of the indole C-3 position, a
pattern present in several 3,3-spirofused and 3,4-bridged
oxindoles, such as marcfortine B,[2] welwitindolinone C,[3]
and gelsemine[4] core structures (Figure 1). These motives
can be realized in diverse synthetic ways, among which the
direct or indirect aldol-, Mannich-, and Michael-type C-3
Figure 1. Relevant naturally occurring members of the oxindole
alkaloid family.
[a] Istituto di Chimica Biomolecolare del CNR,
Traversa La Crucca 3, 07100 Li Punti, Sassari, Italy
Fax: +39-079-2841299
E-mail: gloria.rassu@icb.cnr.it
[b] Dipartimento Farmaceutico, Università degli Studi di Parma,
Parco Area delle Scienze 27A, 43124 Parma, Italy
Fax: +39-0521-905006
E-mail: claudio.curti@unipr.it
Scheme 1. Mukaiyama aldol reaction (MAR) and vinylogous Mu-
kaiyama aldol reaction (VMAR) involving 2-silyloxyindoles A and
D.
giovanni.casiraghi@unipr.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101446.
466
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 466–470

3-Alkenyl-2-silyloxyindoles
tions en route to relevant indole and oxindole targets of pected products, which were obtained in a pure state and
varied origin and function.
good isolated yield after chromatography. Noteworthy, all
As part of our ongoing studies on vinylogous aldol and indole nucleophiles, be they solid or oily materials, showed
related reactions of heterocyclic 2-silyloxydienes,[7a–7c,8] remarkable stability in air, which allowed storage in a refrig-
herein we describe, for the first time, the preparation of erator for months under a nonprotected atmosphere, with
variously shaped 3-alkenyl-2-silyloxyindoles and their vali- no protodesilylation or decomposition.[11]
dation as the nucleophilic components of a remarkably se-
Of the compound repertoire in Scheme 2, acetone-de-
lective, vinylogous Mukaiyama aldol reaction with aromatic rived indole nucleophiles 2b, 2f, 2g, and 2h were selected as
aldehyde acceptors. This unprecedented method enables the test candidates in VMARs to aromatic aldehydes. As the
preparation of diverse hydroxylated indolinones bearing an opening move, we explored diverse Lewis acid catalysts in
exocyclic double bond at the indole C-3 position.
the VMAR between 2b and p-nitrobenzaldehyde (3a) in dif-
ferent solvents, with varied reaction temperatures. This
short trial delineated our best reaction conditions as 1:1
donor/acceptor molar ratio, 1.2 equiv. SiCl4, 40 mol-%
DMF, and 2.0 equiv. DIPEA in anhydrous CH2Cl2 at
–20 °C for 12 h. Under these conditions, a smooth addition
was observed and, upon aqueous NaHCO3 quenching, de-
sired adduct 4ba was obtained in a fair 59% isolated yield
after chromatography, with virtually complete γ-site selec-
tivity and 92:8 Z/E diastereoselectivity (Scheme 3).[12]
With these conditions elaborated, we next explored other
aldehyde acceptors, including benzaldehyde (3b), p-fluoro-
benzaldehyde (3c), and 1-naphthaldehyde (3d). Comparing
the results revealed that the ring substituents had only a
marginal impact on the VMAR performance, with all reac-
tions occurring with similar efficiency and selectivity, giving
the respective vinylogous aldols 4bb, 4bc, and 4bd in reason-
able isolated yields. Moc-substituted indoles 2f and 2g were
explored with p-nitrobenzaldehyde (3a). Equally, the ad-
ditions were productive and, regardless of the nature of the
nucleophile, Z adducts 4fa and 4ga were formed almost ex-
clusively with complete γ-site selectivity. N-Benzyl-pro-
tected indole 2h was also a pertinent substrate and reacted
with proper aldehydes to afford the expected aldol adducts
4hb, 4he, and 4hf in good yields and diastereoselectivities.
Of note, not only benzaldehyde (3b) was tolerated, but also
aldehydes with electron-donating groups in the aromatic
ring such as o-tolualdehyde (3e) and p-methoxybenzalde-
hyde (3f). Rather unexpectedly, substituted candidate 2e,
carrying a strong electron-withdrawing group at the indole
ring, proved recalcitrant to react with 3a, and only a minute
amount of the expected aldol product formed after 12 h at
room temperature.[13]
Results and Discussion
Our initial investigation focused on the assembly of sev-
eral methyl-substituted methylene indolinones 1, which
were quickly obtained from readily available oxindole or
isatin matrices by known standard procedures.[9,10] The sub-
sequent enol silylation stage was carried out by exposing
the corresponding 3-alkylidene oxindoles 1 to a 1:1.5 mix-
ture of the TBS-triflate/Et3N couple at room temperature
(Scheme 2). This simple protocol smoothly afforded the ex-
A final exploratory trial in an asymmetric, catalytic envi-
ronment was conducted by choosing Denmark’s highly per-
forming (R,R)-bisphosphoramide 5 in combination with
SiCl4 as the chiral catalyst, reasoning that this system could
here effect an efficient enantioface discrimination in the nu-
cleophilic attack at the aldehyde carbonyl, as was the case
for related asymmetric coupling reactions employing other
enoxysilane matrices.[8c,8h,8i]
As probes we evaluated N-Boc- and N-Moc indole nu-
cleophiles 2b, 2f, and 2g in reactions with p-nitrobenzalde-
hyde (3a). With the use of ligand 5 (3.0 mol-%), SiCl4
(1.1 equiv.), and DIPEA (10 mol-%) in CH2Cl2 at –78 °C,
we were delighted to see that the corresponding enantioen-
riched products (R)-4ba, (R)-4fa, and (R)-4ga were ob-
tained in acceptable yields of 37–45%, with 100% γ-site
Scheme 2. Preparation of 3-alkenyl-2-silyloxyindoles
2 from
indolinones 1. Reactions were carried out by using alkylidene ox-
indoles 1 (0.33 mmol), Et3N (2.0 equiv.), and TBSOTf (1.5 equiv.)
in anhydrous CH2Cl2 (0.1 m) at room temperature for 2 h. Yields
refer to pure, isolated products; see the Supporting Information for
details. TBS = tBuMe2Si; Boc = tBuOCO; Moc = MeOCO; Bn =
benzyl; PBB = p-bromobenzyl.
Eur. J. Org. Chem. 2012, 466–470
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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467

G. Rassu, C. Curti, G. Casiraghi et al.
SHORT COMMUNICATION
Scheme 4. Preliminary asymmetric VMAR trials of indole silyldi-
enolates 2b, 2f, and 2g catalyzed by the SiCl4·(R,R)-5 system. Yields
refer to isolated yields after chromatography (conversions in paren-
theses); dr determined by 1H NMR spectroscopic analysis of the
crude reaction mixtures; er determined by HPLC on chiral station-
ary phases.
way, with the nucleophile entering the Re face of the alde-
hyde carbonyl preferentially.[8c,8h,8i] This is expected to pro-
duce major 4ЈR-configured adducts, as shown in Scheme 4.
Conclusions
In summary, we present a series of novel 3-alkenyl-2-silyl-
oxyindole nucleophiles and validate their utility in the un-
precedented vinylogous Mukaiyama aldol addition to aro-
matic aldehydes. This route furnishes valuable hydroxylated
3-alkylidene oxindoles with virtually complete γ-site selec-
tivity and excellent levels of diastereoselectivity in favor of
the Z-configured adducts. A trial of an asymmetric, cata-
lytic variant showed promising enantioselectivity for the ex-
pected enantioenriched aldol products. Further investi-
gations to exploit these novel indole silicon dienolates in
vinylogous aldol and related vinylogous reactions, including
asymmetric catalysis, are currently underway in our labora-
tory.
Scheme 3. SiCl4-assisted vinylogous Mukaiyama aldol addition of
olefinic indole silyldienolates 2b, 2f, 2g, and 2h to aromatic alde-
hydes 3a–f. All reactions were carried out with silyloxyindoles 2
(0.26 mmol), aldehydes 3 (1.0 equiv.), SiCl4 (1.2 equiv.), DMF
(40 mol-%), diisopropylethylamine (2.0 equiv.) in anhydrous
CH2Cl2 (0.1 m) at –20 °C for 12 h. Yields refer to pure, isolated
products; α/γ ratio and dr were determined by H NMR spectro-
scopic analysis of the crude reaction mixtures; see the Supporting
Information for details.
1
selectivity, and Ͼ84:16dr in favor of the Z-configured iso-
mers,[14] with promising er values ranging from 93:7 to 95:5
(Scheme 4).
On the basis of several precedents on the use of catalyst
5·SiCl4 to assist vinylogous enantioselective Mukaiyama
aldol-type additions of enolsilanes to aromatic aldehydes,
we assume that the present aldolization involving indole nu-
Experimental Section
Preparation of Oxindole (؎)-(Z)-4ba as a Representative Procedure
cleophiles also proceeds through the same catalytic path- for the Diastereoselective SiCl4-Assisted VMAR: To a flame-dried,
468
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Eur. J. Org. Chem. 2012, 466–470

3-Alkenyl-2-silyloxyindoles
10-mL round-bottomed flask containing a portion of diisopropyl-
ethylamine (90 μL, 0.52 mmol, 2.0 equiv.) cooled to –20 °C was se-
quentially added SiCl4 (1 m in CH2Cl2, 310 μL, 0.31 mmol,
1.2 equiv.), DMF (8 μL, 0.10 mmol, 0.4 equiv.), a solution of 4-
nitrobenzaldehyde (3a; 39 mg, 0.26 mmol, 1.0 equiv.) in anhydrous
CH2Cl2 (1.0 mL), and a solution of silyloxyindole 2b (100 mg,
0.26 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (1.0 mL). The re-
sulting mixture was stirred at –20 °C for 12 h, whereupon a satu-
rated aqueous solution of NaHCO3 (3.0 mL) was added allowing
the temperature of the mixture to reach room temperature. The two
phases were separated, and the aqueous phase was washed with
CH2Cl2 (3ϫ 3 mL) and EtOAc (1ϫ 3 mL). The organic layers were
collected, dried with MgSO4, and filtered, and the filtrate was con-
centrated in vacuo. The diastereomeric ratio (Z/E) of the addition
products was determined to be 92:8 by 1H NMR spectroscopic
analysis of the crude reaction mixture. The crude residue was puri-
fied by silica gel flash chromatography (petroleum ether/EtOAc,
75:25) to give (Ϯ)-(Z)-4ba (65 mg, 59%) as white crystals (CH2Cl2/
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, copies of the 1H NMR and
13C NMR spectra, and chiral HPLC traces.
Acknowledgments
We gratefully acknowledge the Regione Autonoma della Sardegna
(L.R. 07.08.2007, n.7) and Università degli Studi di Parma for fin-
ancial support. R.T. thanks the Regione Autonoma della Sardegna
for a M&B fellowship. We thank the Centro Interdipartimentale
Misure “G. Casnati” (Università degli Studi di Parma) for instru-
mental facilities. We also thank Eugenia Accorsi Buttini (Uni-
versità degli Studi di Parma) for preliminary experiments.
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1
hexane). M.p. 130–132 °C. H NMR (400 MHz, CDCl3): δ = 8.20
(d, J = 8.8 Hz, 2 H, Ar), 7.80 (d, J = 7.8 Hz, 1 H, H7), 7.69 (d, J
= 8.6 Hz, 2 H, Ar), 7.59 (d, J = 7.6 Hz, 1 H, H4), 7.32 (ddd, J =
7.6, 7.6, 1.1 Hz, 1 H, H6), 7.19 (ddd, J = 7.7, 7.7, 1.0 Hz, 1 H, H5),
5.20 (ddd, J = 9.2, 5.3, 3.8 Hz, 1 H, H4Ј), 3.57 (d, J = 5.3 Hz, 1
H, OH), 3.45 (dd, J = 12.4, 9.1 Hz, 1 H, H3Јa), 3.32 (dd, J = 12.4,
3.8 Hz, 1 H, H3Јb), 2.37 (s, 3 H, H1Ј), 1.68 (s, 9 H, tBu, Boc) ppm.
13C NMR (100 MHz, CDCl3): δ = 167.4 (Cq), 155.8 (Cq), 152.0
(Cq), 148.9 (Cq), 147.2 (Cq), 138.1 (Cq), 128.5 (CH), 126.4 (2 C,
CH), 124.5 (Cq), 124.1 (CH), 123.8 (CH), 123.7 (2 C, CH), 123.5
(Cq), 114.7 (CH), 84.7 (Cq), 73.6 (CH), 46.9 (CH2), 28.1 (3 C,
CH3), 25.8 (CH3) ppm. MS (ESI, 50 eV): m/z = 447.1 [M + Na]+.
C23H24N2O6 (424.45): calcd. C 65.08, H 5.70, N 6.60; found C
65.01, H 5.78, N 6.52.
Preparation of Oxindole (R,Z)-4ba as a Representative Procedure
for the Catalytic, Asymmetric SiCl4-Assisted VMAR: Diisopropyl-
ethylamine (4.5 μL, 0.025 mmol, 0.1 equiv.) was added by syringe
to a flame-dried, 20-mL, two-necked round-bottomed flask con-
taining
a
solution of bisphosphoramide (R,R)-5 (6.5 mg,
0.007 mmol, 0.03 equiv.) in anhydrous CH2Cl2 (1.2 mL) under an
argon atmosphere. The resulting solution was cooled to –78 °C
(bath temperature) over 15 min, then SiCl4 (1 m in CH2Cl2, 284 μL,
0.28 mmol, 1.1 equiv.) was added in one portion. After 10 min, 4-
nitrobenzaldehyde (3a; 43 mg, 0.28 mmol, 1.1 equiv.) was added in
one portion followed by the slow dropwise addition (over 5 min)
of a solution of silyloxyindole 2b (100 mg, 0.26 mmol, 1.0 equiv.)
in anhydrous CH2Cl2 (1.0 mL). The resulting mixture was stirred at
–78 °C for 8 h, whereupon a solution NaHCO3 (43 mg, 0.50 mmol,
2.0 equiv.) in H2O (1.5 mL) was added, and the temperature was
allowed to reach room temperature. This biphasic mixture was
promptly separated, and the aqueous phase was washed with
EtOAc (3ϫ5 mL). The organic layers were collected, dried with
MgSO4, and filtered, and the filtrate was concentrated. The dia-
stereomeric ratio of the addition products was determined to be
1
84:16 (68% conversion) by H NMR spectroscopic analysis of the
crude reaction mixture. The crude residue, dissolved in EtOAc, was
purified by silica gel flash chromatography (petroleum ether/
EtOAc, 85:15) to yield (R,Z)-4ba (41 mg, 37%) as colorless crystals.
M.p. 143–144 °C (CH2Cl2/hexane). [α]2D0 = –28.8 (c = 0.6, CHCl3).
1H and 13C NMR spectroscopic data as for the corresponding race-
mic compound (vide supra). HPLC [Regis (S,S)-Whelk-O 1, 20 °C,
hexane/EtOH = 70:30, 0.6 mL/min, 254 nm): tR = 12.63 (minor),
13.42 min (major); er = 95:5. Bisphosphoramide (R,R)-5 was al-
most quantitatively recovered by washing the silica chromatog-
raphy pad with a EtOAc/NH3-saturated MeOH (90:10).
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469

G. Rassu, C. Curti, G. Casiraghi et al.
SHORT COMMUNICATION
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[10]
[11]
[12] The origin of the adducts can be derived from the formula
abbreviation 4xy. The first letter identifies the indole donor,
whereas the second letter identifies the aldehyde acceptor.
[13] The adduct was isolated in 12% yield as a 64:36 Z/E isomeric
mixture. See the Supporting Information for preparation and
characterization.
[14] For all unsaturated candidates 4, the Z double bond geometry
was certified by 1H–1H NOESY NMR correlation analyses.
See the Supporting Information for details.
Received: October 3, 2011
Published Online: December 16, 2011
470
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Eur. J. Org. Chem. 2012, 466–470