Counterion effects in the catalytic stereoselective synthesis of 2,3′-pyrrolidinyl spirooxindoles

Article abstract of DOI:10.1039/c3cc47767c

A Lewis acid-catalyzed stereoselective [3+2] annulation of crotylsilanes with iminooxindoles is reported to access 2,3′-pyrrolidinyl spirooxindoles with four stereocenters. The addition of NaBArF significantly enhances reactivity, allowing either metal salts or acidic clay to be effective catalysts for the stereoselective reaction. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc47767c

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Counterion effects in the catalytic stereoselective
synthesis of 2,30-pyrrolidinyl spirooxindoles†
Cite this: Chem. Commun., 2014,
50, 5242
Jacob P. MacDonald, Benjamin H. Shupe, John D. Schreiber and
Annaliese K. Franz*
Received 9th October 2013,
Accepted 9th December 2013
DOI: 10.1039/c3cc47767c
www.rsc.org/chemcomm
A Lewis acid-catalyzed stereoselective [3+2] annulation of crotyl-
silanes with iminooxindoles is reported to access 2,30-pyrrolidinyl
spirooxindoles with four stereocenters. The addition of NaBArF
significantly enhances reactivity, allowing either metal salts or
acidic clay to be effective catalysts for the stereoselective reaction.
Based on their occurrence in natural products, spirocyclic
oxindoles are an attractive three-dimensional structure often
considered a privileged scaffold for the discovery of new
medicinal compounds.1–4 In particular, spiropyrrolidine oxin-
doles have shown an important array of biological activity.5–7
Elegant synthetic routes have been reported for the stereo-
selective synthesis of 3,30-spiropyrrolidine oxindoles,8–11 while
the synthesis of 2,30-pyrrolidinyl spirooxindoles remains less
developed.12,13 Herein we report the catalytic stereoselective
synthesis of 2,30-pyrrolidinyl spirooxindoles containing four
Scheme 1 Product selectivity for reactions of allylic silanes with
iminooxindoles.
stereocenters via a [3+2] annulation between an enantio- spirocyclic carbamate oxindoles 6 via N-Boc trapping of the
enriched crotylsilane and N-Boc-iminooxindoles. This reaction b-silyl carbocation intermediate (Scheme 1).24 In continued
represents the first example of allylic silanes in the synthesis of pursuit of spiropyrrolidines, we turned to investigate the use
spiropyrrolidine oxindoles and also provides a unique platform of crotylsilanes and to identify the elements controlling reac-
to compare counterion effects on the activity and selectivity of tivity and product selectivity.
Lewis acidic metal salts and heterogeneous clay catalysts.
We identified that several Lewis acidic metal salts catalyze
Allylic silanes are versatile nucleophiles14 that can function the annulation of (S)-crotylsilane 2 with N-Boc-iminooxindoles
as [1,2]-dipole15,16 and [1,3]-dipole17,18 synthons for efficient access 1 to afford N-Boc spiropyrrolidine 3 as a single diastereomer as
to functionalized heterocycles and carbocycles. Due to their mild judged using 1H NMR spectroscopy (Table 1). A mixture of
nucleophilicity,14 reactions with allylsilanes generally require annulation (3) and crotylation (5) was observed depending on
the use of Lewis or Brønsted acids.19,20 Previously, Panek and the catalyst and temperature; however, solely the [3+2] mode of
co-workers have utilized reactions of enantioenriched crotyl- annulation was observed with no trace of the spirocarbamate
silanes (e.g. 2) with in situ-derived iminium ions for selective product. While Sc(OTf)3 showed good reactivity (e.g. 3 h), the
pyrrolidine formation.21–23 In an attempt to access spiropyr- N-Boc crotylation was also observed (entry 1). Metal chloride
rolidines such as 3, we investigated Lewis acid-catalyzed spiro- salts afforded selective formation of the spiropyrrolidine, albeit
cyclization of allylsilanes with N-Boc iminooxindoles (1); however, with low reactivity (cf. 168 h, entry 2).
instead of accessing the pyrrolidine, this reaction produced novel
The addition of sodium tetrakis[3,5-bis(trifluoromethyl)-
phenyl]borate (NaBArF) significantly enhanced the reaction
rate, allowing several metal salts to catalyze the spirocyclization
reaction with the competing crotylation observed (entries 2–7).
Triflic acid (at ꢀ78 1C) also afforded a mixture of the annulation
and crotylation products (entry 10). The optimal conditions were
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, USA. E-mail: akfranz@ucdavis.edu
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data for all compounds. See DOI: 10.1039/c3cc47767c
5242 | Chem. Commun., 2014, 50, 5242--5244
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Table 1 Optimization of [3+2] annulation to access spiropyrrolidine 3a
afford any product, presumably due to competitive binding of
the oxindole substrate to the copper catalyst (entries 7 and 8).
Deprotection of the Boc group was accomplished using mont-
morillonite K10 to access N–H pyrrolidines 4, which were
isolated as pure material upon simple filtration.26,27
The selective formation of spiropyrrolidine 3 without N-Boc
trapping of the b-silyl carbocation (i.e. spirocarbamate for-
mation) is attributed to factors stabilizing the transient b-silyl
carbocation intermediates in the pathway.28–31 Overall, the
[1,2]-silyl shift must be favored relative to trapping by the
N-Boc group. An a-substituent enhances stability of the b-silyl
carbocation formed as the result of the 1,2-silyl shift. The ester
group may also contribute to the stabilization of the initial
b-silyl carbocation via a 5-membered ring chelate and may
block interactions with the N-Boc group. In order to test the
role of the ester substituent, we investigated the reaction of
allylsilane 7, which lacks the methyl substitution and has a
smaller silyl group. Indeed, this reaction still afforded spiro-
pyrrolidine 8 as a single diastereomer as judged by 1H NMR
spectroscopy, with no spirocarbamate observed (Scheme 2).
Based on the significant activating effect of NaBArF for
metal chloride catalysts, we investigated the activity of mon-
tmorillonite K10 as a solid Lewis acid catalyst with NaBArF as a
co-catalyst to promote the formation of 2,30-spiropyrrolidine
oxindoles. Although montmorillonite has been reported to
mediate the Hosomi–Sakurai reaction,32 there are no examples
of allylsilane annulation reactions catalyzed with solid Lewis
acids. Montmorillonite offers many advantages over traditional
metal salt catalysts because it is inexpensive, easy to handle,
reusable and eco-friendly.33 Although the use of cation-exchanged
montmorillonite is well explored,34 the use of homogeneous
co-catalysts is relatively unexplored.
We discovered that the addition of NaBArF with mont-
morillonite is also successful to promote the stereoselective
synthesis of spiropyrrolidine 3. The reaction affords a single
diastereomer of spiropyrrolidine 3, with no crotylation (5) or
spirocarbamate (6) observed. In the absence of NaBArF, only
deprotection/degradation of the iminooxindole starting mate-
rial was observed (Table 3, entry 1). Although the rate of
spirocyclization is fast (o1 h), the degradation of iminoisatin
persisted under all reaction conditions, despite investigation of
several reaction variables (entries 2–6). We also demonstrated
that montmorillonite–NaBArF conditions efficiently promote
the spirocyclization of allyltrimethylsilane with imine 1a to
afford spirocarbamate 6 in 80% yield with a 60 : 40 diastereo-
meric ratio (Scheme 3). Mechanistic studies and catalyst recovery
Counterion Temp. Time Yield of Yield of
Entry Catalyst
sourcea
(1C)
(h)
3a (%)
5 (%)
1
2
3
Sc(OTf)3
ScCl3
ScCl3
—
—
23
23
23
23
23
23
23
ꢀ20
ꢀ20
ꢀ78
3
61
37
61
42
61
51
64
79
41
68b
8
0
14
0
17
31
27
0
168
22
5
72
12
2
24
72
20
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaSbF6
—
4
5
6
7
8
9
10
InCl3
ZnCl2
SnCl2
CuCl2
CuCl2
CuCl2
TfOH
0
10c
a
b
Reaction performed with 22 mol% of counterion source. NH spiro-
pyrrolidine was also isolated in 8% yield. Crotylation product isolated
c
as an unprotected 3-aminooxindole (see ESI).
identified as CuCl2/NaBArF at ꢀ20 1C, where the crotylation
was not observed (entry 8).21 The enhanced reactivity with
NaBArF is attributed to formation of a cationic metal complex,
with a more diffuse counterion affording a higher the yield (entry
8 vs. 9). The reaction is highly stereoselective and the absolute
stereochemistry has been assigned based on the starting
configuration of the crotylsilane and reaction via anti-SE’ addi-
tion.21,22,25 The relative stereochemistry of spiropyrrolidine 4a
was confirmed by nOe experiments.
We then investigated the scope of the N-Boc-iminooxindoles
in the spiropyrrolidine annulation reaction with the Cu(II)/BArF
catalyst (Table 2). Various substituents on the oxindole back-
bone can be employed with yields ranging from 79–88%
(Table 2, entries 1–4). Phenyl and benzyl substitution on the
1-position also proceeded with comparable yields (entries 5 and 6);
however, the N-acyl (1g) and free N–H oxindole (1h) did not
Table 2 Scope of imine in crotylsilane annulation
Entry
R1
R2
Product
Yield of 3a (%)
Yield of 4a (%)
1
2
3
4
5
6
7
8
F
H
MeO
Cl
H
H
H
H
Me
Me
Me
Me
Ph
Bn
Ac
4a
4b
4c
4d
4e
4f
79
80
88
81
88
53
0
90
85
66
99
80
93
—
—
4g
4h
H
0
a
Scheme 2 Testing substituted allylsilanes for product selectivity.
Chem. Commun., 2014, 50, 5242--5244 | 5243
Isolated yield.
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Table 3 Montmorillonite-promoted synthesis of spiropyrrolidine oxindoles
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5244 | Chem. Commun., 2014, 50, 5242--5244
This journal is ©The Royal Society of Chemistry 2014