Catalytic Generation of Donor-Acceptor Cyclopropanes under N-Heterocyclic Carbene Activation and their Stereoselective Reaction with Alkylideneoxindoles

Article abstract of DOI:10.1002/adsc.201700198

Formylcyclopropanes undergo activation in the presence of an N-heterocyclic carbene catalyst generating a donor-acceptor cyclopropane intermediate with the ability to undergo ring-opening followed by formal [4+2] cycloaddition with alkylideneoxindoles. This enables the direct enantio- and diastereoselective synthesis of tetrahydropyrano[2,3-b]indoles through the use of a chiral NHC catalyst. (Figure presented.).

Full text of DOI:10.1002/adsc.201700198

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DOI: 10.1002/adsc.201700198
Very Important Publication
Catalytic Generation of Donor-Acceptor Cyclopropanes under
N-Heterocyclic Carbene Activation and their Stereoselective
Reaction with Alkylideneoxindoles
Liher Prieto,a Eduardo Sꢀnchez-Dꢁez,a Uxue Uria,a Efraꢁm Reyes,a,*
Luisa Carrillo,a and Jose L. Vicarioa,*
a
Department of Organic Chemistry II, University of the Basque Country (UPV/EHU). P. O. Box 644, 48080 Bilbao, Spain
Fax : (+34)-94-601-2748; phone: (34)-94-601-5454; e-mail: efraim.reyes@ehu.es or joseluis.vicario@ehu.es
Received: February 15, 2017; Revised: March 7, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201700198.
Abstract: Formylcyclopropanes undergo activation
in the presence of an N-heterocyclic carbene cata-
lyst generating a donor-acceptor cyclopropane inter-
mediate with the ability to undergo ring-opening
followed by formal [4+2] cycloaddition with alkyli-
deneoxindoles. This enables the direct enantio- and
diastereoselective synthesis of tetrahydropyra-
no[2,3-b]indoles through the use of a chiral NHC
catalyst.
initiate the ring-opening event on carefully designed
cyclopropane substrates. Several reports also illustrate
the ability of N-heterocyclic carbenes to catalyze reac-
tions with formylcyclopropanes but these are either
non-enantioselective versions[7] or, alternatively, are
reactions of rather limited scope.[8]
With all these precedents in mind, we directed our
attention to the capacity of N-heterocyclic carbenes[9]
to catalytically generate a donor-acceptor cyclopro-
pane upon interaction with a formylcyclopropane in-
corporating two electron-withdrawing groups at the
three-membered ring (Scheme 1). The condensation
between the carbene with the formyl group would
Keywords: asymmetric catalysis; cycloaddition; cy-
clopropanes; N-heterocyclic carbenes
The use of cyclopropanes as reagents in synthesis has
experienced a renaissance in the last few years.[1] The
strain energy associated to the cyclopropane ring and
the tendency to release this strain through ring-open-
ing has been used as a useful platform to find unusual
reactivity profiles. In particular, cyclopropanes which
are simultaneously substituted with an electron-donat-
ing and an electron-withdrawing group are particular-
ly attractive because the synergistic electronic nature
of these substituents strongly favours the ring-opening
process, generating an intermediate with the potential
to undergo a wide range of subsequent reactions.[2] In
this context, most reports involve the use of Lewis
acids as promoters of the ring-opening event, which
has also been applied to enantioselective versions
through the incorporation of a chiral ligand.[3] In con-
trast to the important number of reports that make
use of this approach, the alternative capacity of orga-
nocatalysts to activate these strained substrates has
only been very recently documented. In particular,
there are some precedents showing the application of
Scheme 1. Catalytic generation of D-A cyclopropanes and
iminium,[4] enamine[5] and H-bonding activation[6] to their reactivity towards alkylideneoxindoles.
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generate the corresponding Breslow intermediate in
Changing the aryl substituent from mesityl to a pen-
which the enaminol moiety would operate as the elec- tafluorophenyl substituent (3d, entry 4) resulted in
tron-donating substituent, therefore facilitating the the complete deactivation of the catalyst towards the
subsequent ring-opening event. The resulting inter- reaction, in line with previous reports that indicate
mediate would have the capacity to undergo formal that the mesityl substituent accelerates those reac-
[4+2] cycloaddition with a suitable substrate such as tions involving the activation of a-functionalized alde-
an alkylideneoxindole.[10] The overall process would hydes under NHC catalysis.[12] The counteranion of
result in a useful catalytic and enantioselective ap- the triazolium salt did not prove to have a relevant
proach to the tetrahydropyrano[2,3-b]indole substruc- impact on the performance of the reaction, as it can
ture, which is a relevant scaffold present in com- be seen with the experiment using precatalyst 3e
pounds with interesting biological activities.[11]
(entry 5). We next surveyed different bases for the
We started our studies by surveying a variety of generation of the carbene active species (entries 6–8),
chiral triazolium salts 3a–e as the N-heterocyclic car- observing a slight increase in the yield of the reaction
bene precursor, using the reaction between formylcy- when (i-Pr)2EtN was used (entry 8) without decreas-
clopropane 1a and alkylideneoxindole 2a as model ing the high stereocontrol obtained before. Finally,
substrates (Table 1). We initially surveyed a set of tri- other solvents were also examined (entries 9–11), ob-
azolium catalysts with different chiral backbone struc- serving that the use of a highly polar solvent like
tures (precatalysts 3a–c, entries 1–3), observing that THF resulted in a poor yield of cycloadduct 4a
aminoindol-based precatalyst 3c provided excellent (entry 9), while a non-polar solvent like hexane led to
results in terms of stereocontrol, and furnished cyclo- no reaction even after prolonged stirring of the reac-
adduct 4a in a promising 60% yield (entry 3).
tion mixture (entry 10). Remarkably, slightly increas-
Table 1. Optimization of the reaction conditions.[a]
Entry
3
Base
Solvent
Yield [%]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3c
3c
3c
3c
3c
3c
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
DBU
(i-Pr)2NEt
(i-Pr)2NEt
(i-Pr)2NEt
(i-Pr)2NEt
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
<5
25
60
<5
52
22
57
66
18
<5
94
n.d.[d]
>20:1
>20:1
n.d.[d]
>20:1
>20:1
>20:1
>20:1
n.d.[d]
n.d.[d]
n.d.[d]
46
99
n.d.[d]
99
92
98
99
9
10
11
n.d.[d]
n.d.[d]
99
n-hexane
CH2Cl2
>20:1
[a]
Reaction carried out using 0.30 mmol of 1a, 0.20 mmol of 2a, 10 mol% of precatalyst 3 and 20 mol% of base in 2 mL of
solvent at room temperature for 3 h.
Determined by H NMR analysis of crude reaction mixture.
Determined by HPLC in a chiral stationary phase (see the Supporting Information for details).
n.d.=not determined.
[b]
[c]
[d]
1
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ing the polarity from toluene to CH2Cl2 led to a signif- sulted in very poor conversion (adduct 4i). Changing
icant improvement of the yield of the reaction, fur- the nature of the b-substituent at the alkylideneoxin-
nishing 4a as a single diastereoisomer of very high dole scaffold was also feasible, the reaction was also
enantiopurity (entry 11).
very effective with different ester groups (compounds
With an optimized experimental protocol for the 4k–4m) and also with a benzoyl substituent (com-
reaction in hand, we next proceeded to explore the pound 4n). Finally, different substituents could also
scope of the reaction with respect to the formylcyclo- be successfully incorporated at the aryl moiety of the
propane and the alkylideneoxindole reagents alkylideneoxindole reagent (compounds 4o and 4p).
(Scheme 2).
In all cases adducts 4a–4p were isolated as single dia-
stereoisomers with enantioselectivities of over 90% ee
The absolute configuration of compound 4k was es-
tablished by X-ray analysis of a monocrystalline
sample[13] and this was extended to all other adducts
4a–4p based on mechanistic analogy.
We also decided to explore the possibility of carry-
ing out the reaction using b,g-unsaturated a-keto
esters as highly reactive Michael acceptors in this
formal [4+2] cycloaddition process (Table 2). In fact,
the reaction performed excellently with a variety of
substrates 5a–5n using the enantiomer of the same
catalyst (ent-3a) and under closely related conditions,
only requiring a lowering of the temperature of the
reaction.
As it can be seen in Table 2, cycloadducts 6a–6e
were obtained in high yields and stereocontrol regard-
less the nature of the ester substituent at the b,g-unsa-
turated-a-keto ester reagent 5 (entry 1 vs. 2) and the
reaction also performed excellently for substrates
with a wide range of substitution patterns at the g-po-
sition, including aryl groups with either electron-with-
drawing or electron-donating groups located at differ-
ent positions on the aryl moiety (entries 3–8). Sub-
strates with g-heteroaryl substituents also provided
the corresponding adducts with good yield and enan-
tioselectivity, although as 2:1 mixtures of diastereoiso-
mers (entries 9 and 10). Moreover, the very challeng-
ing g-alkyl-substituted b,g-unsaturated a-keto esters
also performed very well in the reaction, furnishing
the corresponding cycloadducts in high yields, diaster-
eo- and enantioselectivities (entries 11–14). Remarka-
bly, we could also demonstrate that the reaction can
be carried out using
a lower catalyst loading
(entry 15), just requiring to stir the mixture for
a longer time (36 vs. 60 h). The absolute stereostruc-
ture of these 3,4-dihydro-2H-pyran-2-one adducts 6
was also established by X-ray analysis of monocrystals
grown for compound 6b,[14] extending the obtained
absolute configuration to the other derivatives 6a–n
Scheme 2. Scope of the reaction.
As it can be seen in this Scheme 2, the reaction per- by assuming the same mechanistic pathway for all
formed excellently regardless of the nature of the pro- cases.
tecting group at the indole moiety, although N-alkyl-
In conclusion, formylcyclopropanes with two elec-
substituted alkylideneoxindoles provided inferior tron-withdrawing alkoxycarbonyl substituents are
yields than those with an N-carbamate protecting able to undergo condensation with an N-heterocyclic
group. In the same line, the reaction also tolerated carbene catalyst, generating the corresponding Bre-
well the incorporation of different substituents at the slow intermediate that subsequently undergoes strain-
two ester groups on the starting cyclopropane 1 (ad- driven ring-opening followed by formal [4+2] cyclo-
ducts 4a–4j), although very bulky groups like i-Pr re- addition with an activated alkene such as an alkyli-
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Table 2. Reaction using b,g-unsaturated a-keto esters.[a]
Entry
6
R1
R2
Yield [%]
dr[b]
ee [%][c]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6e
Ph
Ph
Me
Et
73
77
72
81
85
82
66
78
46
68
83
85
58
72
82
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
97
>99
>99
>99
99
4-FC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
3,4-OCH2O-C6H3
2-furyl
2-thienyl
Me
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Me
99
>99
>99
>99
>99
>99
>99
>99
97
9
10
11
12
13
14
15[d]
2:1
>20:1
>20:1
>20:1
>20:1
>20:1
CH2OBn
CH2CH2Ph
4-MeC6H4
99
[a]
Reaction carried out using 0.20 mmol of 1a, 0.20 mmol of 5, 10 mol% of precatalyst ent-3c and 20 mol% of base in 2 mL
of solvent at 48C for 24–36 h.
Determined by H NMR analysis of crude reaction mixture.
Determined by HPLC in a chiral stationary phase (see the Supporting Information for details).
5 mol% of catalyst and 10 mol% of base were used.
[b]
[c]
[d]
1
conditions indicated for each case. X-ray data collections
were performed in an Agilent Supernova diffractometer
equipped with an Atlas CCD area detector, and a CuKa
micro-focus source with multilayer optics (l=1.54184 ꢅ,
250 mm FWHM beam size). The sample was kept at 120 K
with a Oxford Cryosystems Cryostream 700 cooler. Miscel-
laneous: Analytical grade solvents and commercially avail-
able reagents were used without further purification. For
flash chromatography Silicycle 40–63, 230–400 mesh silica
gel was used.
ACHTUNGTRENNUNGdeneoxindole or a b,g-unsaturated a-keto ester. In the
presence of precatalyst 3c and under the optimized
conditions, the reaction proceeds with excellent yield,
diastereo- and enantioselectivity for a variety of sub-
strates tested.
Experimental Section
General Methods and Materials
NMR: Monodimensional nuclear magnetic resonance
proton, carbon and fluorine NMR spectra (1H NMR,
13C NMR and 19F NMR) were acquired at 258C on a Bruker
AC-300 spectrometer (300 MHz for 1H, 75.5 MHz for 13C
and 282 MHz for 19F). IR: Infrared spectra (IR) were mea-
sured in a Jasco FT/IR 4100 in the interval between 4000
and 400 cmÀ1 with a 4 cmÀ1 resolution. MS: Mass spectra
(MS) were recorded on an Agilent 7890A gas chromato-
graph coupled to an Agilent 5975 mass spectrometer under
electronic impact (EI). HR-MS: High-resolution mass spec-
tra (HR-MS) were obtained on an Acquity UPLC coupled
to a QTOF mass spectrometer (SYNAPT G2 HDMS) using
electrospray ionization (ESI+ or ESIÀ). mp: Melting points
were measured in a Bꢃchi B-540 apparatus in open capillary
tubes and are uncorrected. HPLC: High performance liquid
chromatography on a chiral stationary phase was performed
in a Waters 2695 chromatograph coupled to a Waters 2998
photodiode array detector. Daicel Chiralpak AD-H, IA, IC,
OD-H columns (0.46 cmꢄ25 cm) were used in the specific
General Procedure for the Preparation of
Tetrahydropyrano[2,3-b]indole Adducts 4a–p
Triazolium salt 3c (0.02 mmol, 0.1 equiv.) was placed into an
oven-dried, screw-capped vial equipped with a magnetic stir-
ring bar. The vial was capped with a septum and purged
with argon for 5 min. Then, CH2Cl2 (1 mL), N,N-diisopropyl-
AHCTUNGTREGeNNNU thylamine (0.04 mmol, 0.2 equiv.), the corresponding for-
mylcyclopropane dicarboxylate 1a–f (0.30 mmol, 1.5 equiv.
as a solution in 1 mL of CH2Cl2) and the corresponding 3-
methylene-2-oxindole 2a–k (0.20 mmol, 1.0 equiv.) were suc-
cessively added. The reaction mixture was stirred at 238C
for 3 h and then the crude reaction mixture was concentrat-
ed and directly charged onto silica gel. Finally, it was sub-
jected to flash column chromatography purification (hexane/
EtOAc gradient from 19:1 to 9:1), affording the correspond-
ing adduct 4a–p. Racemic samples were obtained following
the same protocol but using 2-(pentafluorophenyl)-6,7-dihy-
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dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate
(0.1 mmol, 0.1 equiv.) as catalyst.
Kaicharla, T. Roy, M. Thangaraj, R. G. Gonnade, A. T.
Biju, Angew. Chem. 2016, 128, 10215; Angew. Chem.
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General Procedure for the Preparation of Lactones
6a–n
An ordinary vial was charged with pre-catalyst ent-3c
(0.02 mmol, 10 mol%), equipped with a magnetic stirring
bar and placed under an argon atmosphere. Dichlorome-
thane (1 mL) and N,N-diisopropylethylamine (7 mL,
20 mol%) were added at once and the mixture was stirred
for 10 min at room temperature. The mixture was next
cooled down to 58C and stirred for further 10 min prior to
the addition of aldehyde 1 (0.30 mmol as a solution in 1 mL
of dichloromethane) and keto ester 5 (0.20 mmol). The stir-
ring was maintained at this temperature until the reaction
was completed (TLC analysis). Solvents were evaporated
and the crude was charged onto silica gel and subjected to
flash column chromatography purification. Racemic stand-
ards for HPLC separation conditions were prepared using 2-
(pentafluorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tria-
zol-2-ium tetrafluoroborate (0.02 mmol, 10 mol%) as pre-
catalyst and running the reaction at room temperature.
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Acknowledgements
The authors gratefully acknowledge the Spanish MINECO
(FEDER-CTQ2014-52107),
the
Basque
Government
(Grupos IT908-16) and UPV/EHU (EHUA 16/10 and UFI
QOSYC11/22) for financial support. L. P. and E. S.-D. thank
UPV/EHU for their predoctoral grants
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[13] CCDC 1520076 contains the supplementary crystallo-
graphic data for this compound. These data can be ob-
tained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[14] CCDC 1520077 contains the supplementary crystallo-
graphic data for this compound. These data can be ob-
tained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Catalytic Generation of Donor-Acceptor Cyclopropanes
under N-Heterocyclic Carbene Activation and their
Stereoselective Reaction with Alkylideneoxindoles
7
Adv. Synth. Catal. 2017, 359, 1 – 7
Liher Prieto, Eduardo Sꢀnchez-Dꢁez, Uxue Uria,
Efraꢁm Reyes,* Luisa Carrillo, Jose L. Vicario*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢂ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!