Electrophilic Activation of Iodonium Ylides by Halogen-Bond-Donor Catalysis for Cross-Enolate Coupling

Article abstract of DOI:10.1002/anie.201703641

The umpolung alkylation of silyl enol ethers with an iodonium(III) ylide proceeds under mild conditions to afford various 1,4-dicarbonyl compounds in high yields in the presence of a halogen-bonding catalyst. Unlike typical transition-metal activation processes of such ylide precursors, which tend to proceed via carbenoid intermediates, experimental and computational studies indicate that halogen bonding (XB) between the XB donor catalyst and the iodonium ylide plays a crucial role in promoting the reaction. The identification of a compatible Bronsted base catalyst enabled the extension of this method to enols generated in situ to give the corresponding adducts in good yields.

Full text of DOI:10.1002/anie.201703641

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Accepted Article
Title: Electrophilic activation of iodonium ylides via halogen bond donor
catalysis for cross-enolate coupling
Authors: Masato Saito, Yusuke kobayashi, Seiji Tsuzuki, and Yoshiji
Takemoto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703641
Angew. Chem. 10.1002/ange.201703641
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10.1002/anie.201703641
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Electrophilic activation of iodonium ylides via halogen bond
donor catalysis for cross-enolate coupling
Masato Saito,[a] Yusuke Kobayashi,[a] Seiji Tsuzuki,[b] Yoshiji Takemoto*[a]
ylides, for which an XB donor was found to be effective. In
addition, we have developed the first XB donor/Brønsted base
cooperative catalytic system, which enables in situ formation of
the nucleophilic component without deactivation of the XB-donor
catalyst.
Abstract: The umpolung alkylation of silyl enol ethers with an
iodonium(III) ylide has been achieved under mild conditions to afford
various 1,4-dicarbonyl compounds in high yields by the
implementation of
a halogen-bonding catalyst. Unlike typical
transition metal activation of such ylide precursors which typically
proceed via carbenoid intermediates, experimental and
computational studies indicate that halogen bonding (XB) between
the XB donor catalyst and the iodonium ylide plays a crucial role in
promoting the reaction. Identification of a compatible Bronsted-base
catalyst enabled extension of this methodology to enols generated in
situ to give the corresponding adducts in good yields.
First, we studied the interaction between XB donors and
iodonium ylide 2a[21] by reaction of 2a with silyl enol ether 1a as
pre-activated nucleophile (Table 1). As expected, both 2-
iodoimidazolium and 2-iodobenzimidazolium salt-type XB
donors[13‒18] 4 and 5 efficiently promoted the umpolung C‒C
bond formation to furnish desired product 3a in excellent yields
(Table 1, entries 1–2). In sharp contrast, imidazolium salt 6,
which does not contain an iodine atom did not promote the
reaction at all (Table 1, entry 3). These results indicate that
hydrogen bonding (HB) and a cationic heteroaromatic ring were
not effective for the activation of the iodonium ylide, and strongly
suggest that an XB interaction plays a crucial role in the
promotion of the reaction.
Hypervalent iodine compounds have become essential in
organic synthesis because a variety of oxidation and oxidative
bond-forming reactions can be achieved with these reagents.[1]
In particular, recent advances in the use of iodonium(III) salts
have enabled the -functionalization of various carbonyl
compounds under mild conditions. In these reactions,
a
copper(I) catalyst[2] or a stoichiometric amount of acid[3] is used
to activate the iodonium salts (Scheme 1a). Compared with -
arylation and alkynylation, C(sp3)‒C(sp3) bond-forming
reactions[4] are less well developed, despite the utility of the
resulting products. [1‒3] We envisioned that cross coupling of an
iodonium(III) ylide[1,5] with carbonyl compounds would enable
C(sp3)‒C(sp3) bond formation and provide 1,4-dicarbonyl
compounds (Scheme 1c), which found in a variety of important
natural product scaffold, or used in their preparations.[6] Many
approaches have been investigated for the synthesis of these
important synthetic intermediates; [7‒10] however, the activation of
iodonium ylides seems to be the most challenging aspect of
such a potential reaction. This is the result of their facile
decomposition, insertion, and trans-ylidation under hard Lewis
acidic conditions,[5,11] even though such reactions generally
occur via metal carbenoids in the presence of rhodium or copper
catalysts (Scheme 1b).[1,5]
We thus focused on halogen bonding (XB), which is a non-
covalent interaction between halogenated compounds and
Lewis bases.[12] Although XB donors have recently begun to be
used in synthetic organic chemistry as easy-to-handle organo-
Lewis acids,[13] their activation mode is mainly limited to the sp2-
hybridized nitrogen atoms of quinolines and imines,[14] carbonyl
oxygen atoms,[15] and alkyl halides.[16,17] We envisaged that the
soft Lewis acidity of XB donors[18‒20] would allow them to
preferentially interact with soft electrophiles (Scheme 1c). Herein,
we report the first efficient electrophilic activation of iodonium(III)
Scheme 1. Summary of this work
[a]
[b]
M. Saito, Dr. Y. Kobayashi, Prof. Dr. Y. Takemoto, Graduate School
of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
It is worth noting that other potential catalysts, including
Schreiner’s thiourea 7,[22] phosphoric acid 8,[23] Lewis acid
metals,[3] and transition metals,[1,5] did not accelerate the reaction
efficiently (Table 1, entries 4–10), either because of catalyst
decomposition (Table 1, entries 5–6) or degradation of the
iodonium ylide[11] (Table 1, entries 6–10). When Rh2(OAc)4,
which is known to form metal–carbenoid species[1,5] with
iodonium ylides, was employed, neither 2a nor the
corresponding cyclopropane intermediate were observed (Table
E-mail: takemoto@pharm.kyoto-u.ac.jp
Dr. S. Tsuzuki, Research Initiative of Computational Sciences
(RICS), Nanosystem Research Institute (NRI), National Institute of
Advanced Industrial Science and Technology (AIST), 1-1-1
Umezono, Tsukuba, Ibaraki 305-8568, Japan
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201703641
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COMMUNICATION
1, entry 10). From these results, formation of 3a through
cyclopropanation of 1a followed by ring opening is highly unlikely
as the operative mechanistic pathway. Solvent effects were
found to be important; dichloromethane and toluene gave lower
yields than THF (Table 1, entries 11–12). This could be
explained by the coordination of THF to the iodine(III) center,
which suppresses the decomposition of the iodonium ylides. [24]
Table 1: Optimization of umpolung C–C bond formation with 1a and iodonium
ylide 2a
Yield (%)[a]
Entry Catalyst
Solvent
THF
THF
1
4
99[b]
91[b]
0
2
5
3
6
THF
4
5
7
8
THF
THF
19
0
6
BF3•OEt2
THF
0
7
8
Sc(OTf)3
TMSOTf
THF
THF
16
0
9
I2
THF
0
10
11
12
Rh2(OAc)4
5
5
THF
Toluene
CH2Cl2
0
60
54
[a] Unless otherwise noted, 1H NMR yields are based on dimethylsulfone as
an internal standard. [b] Isolated yields.
Figure 1. (a) 13C NMR spectra of ylide 2a and XB donor 4 in THF-d8. (b) Two
possible interaction modes for 2a and XB donor (mode A and B), and plots of
B97D/6-311G** level interaction energies calculated for these modes with and
without the evaluation of the effects of solvation by THF using PCM
calculations.
To gain insight into the reaction mechanism, we performed a 13C
NMR experiment (Figure 1a). Upon mixing XB donor 4 and the
iodonium ylide in THF-d8, the 13C NMR peak of the C2 position
of 4 broadened and shifted downfield in accordance with
previous reports.[14,18] Notably, the peaks of the ylide carbon
atom of the iodonium ylide shifted significantly downfield (ca. 9
ppm), which clearly indicates the increased electrophilicity of 2a.
To obtain further information about the interaction, we performed
computational studies in which 2a and a simplified N,N-
dimethyliodoimidazolium cation were used as model structures
(Figure 1b). Starting from various initial structures, two possible
XB interaction modes were found; interaction between the -
hole of the XB donor and the carbonyl oxygen atom of 2a (mode
A), and XB between the donor and the ylide carbon atom (mode
B).[25] In both cases, calculation of the interaction energy
potentials indicated long-range attractive interactions in the gas
phase (red) and even under the effect of solvation (blue),
suggesting that electrostatic and dispersion forces greatly
contribute to the interaction. These results are in good
agreement with those for previously reported XB interactions.[26]
From the calculated interaction energies, the intermediate
interacting through the O atom (mode A) is more favorable than
that interacting through the C atom (mode B). Our present
understanding of the mechanism involves silyl enol ether 1
attack at the iodine atom of XB-activated ylide 2 to form an
enolonium species,[27] with subsequent rearrangement[4,28]
furnishes 1,4-dicarbonyls 3. However, further mechanistic
studies are in progress to distinguish between this and other
potential mechanistic scenario.[25]
Table 2: Substrate scope for umpolung C‒C bond formation[a]
[a] Isolated yields. [b] With 2a and 4. [c] With 2a and 5. [d] With
2b and 5. [e] With 2c and 5.
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10.1002/anie.201703641
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With the optimized conditions in hand, we next investigated the
substrate scope for the umpolung C‒C bond formation (Table 2).
Gratifyingly, both five- and six-membered cyclic silyl enol ethers
screened a series of XB donors in combination with PS,[25] and
found that XB donor 12, which contains a sterically hindered
counter anion, improved the yield of 11a to 71% (Table 3). In
1b‒1e, derived from cyclopentanone, indanones, cyclohexanone, contrast to previously reported oxidative cross-enolate coupling
and tetralones, gave desired products 3b‒3e in 71%‒94% yields. reactions,[6,7] this is the first example of a reaction that utilizes an
The chemical yields seem to be highly dependent on the
nucleophilicity of the silyl enol ethers, and aromatic ring-
conjugated silyl enol ethers 1c and 1e gave the corresponding
adducts in lower yields. In contrast, the 4-phenylcyclohexanone-
derived substrate was very effective for the synthesis of 1,4-
dicarbonyl compound 3d (94%). Notably, electron-rich
heteroaromatic indole rings were tolerated in the reaction and
provided product 3g in good yield. Such heteroaromatic rings
have been reported to react with iodonium ylides under acidic
conditions.[11] 1,4-ketoester 3h, which bears an all-carbon
quaternary center, was synthesized in somewhat lower yield.
enol generated in situ with a catalytic amount of base.
Figure 2. 1H NMR peak shifts of 4 (THF-d8) when mixed with equimolar
amounts of a base or iodonium ylide 2a
To further demonstrate the utility of this method, we next
investigated the late-stage functionalization[29] of biologically
active compounds, which is attracting increasing attention in
medicinal chemistry. For example, readily available ketones,
such as camphor and estrone derivatives, were successfully
functionalized to afford 3i and 3j in 40% and 96% yields,
respectively. Iodonium ylides 2b and 2c, which bear ketone and
cyano groups, respectively, were also applied in this coupling
reaction to give corresponding γ-ketoesters 3k and 3l in good
yields, thus demonstrating the synthetic utility of this
methodology. Silyl enol ether 1j was reacted with 2b under the
optimized conditions and then treated with NH4Cl in ethanol to
afford pentacyclic fused-pyrrole 9 in 50% yield over two steps
(Scheme 2).
Using the optimized reaction conditions, we next investigated
the substrate scope of the present acid/base catalysis (Table 3).
As expected, substrates containing simple alkyl chains, namely
ethyl or benzyl groups, at the C3 position of the oxindole gave
desired products 11b and 11c in 71% and 60% yields,
respectively. Fortunately, several functional groups, including –
NH and –OH groups, as well as heteroaromatic rings, such as
furan, indole, and pyridine, were tolerated in the oxidative
coupling reaction to give corresponding 3,3-disubstituted
oxindoles 11d‒11i in moderate to good yields. Notably,
production of 11e and 11i was markedly faster than reactions
with the other substrates, which suggests that coordination of a
hydroxyl group or pyridine to the iodonium ylide accelerates the
reaction. It should also be emphasized that neither O‒H
insertion nor ylide exchange were observed in these cases.
Table 3: XB donor/base co-catalyzed umpolung C‒C bond formation[a]
Scheme 2: Synthetic application of umpolung alkylation
A limitation of the silyl enol ether protocol is the necessity to pre-
activate the nucleophilic coupling partner. However, the
implementation of a basic co-catalyst to generate these species
in situ carries the associated risk of catalyst deactivation by
halogen bonding between 4 and the basic co-catalyst (as well as
competitive decomposition of the iodonium ylide). In order to
circumvent this, we examined the strength of the XB interaction
of 4 with various bases by 1H NMR. The changes in the chemical
shifts of the H4 and H5 signals of 4 (green) were determined
after mixing 4 with an equimolar amount of each base in THF-d8
(Figure 2). As expected, relatively large upfield shifts (0.05‒0.08
ppm) were observed when 4 was mixed with DABCO or
tetramethylguanidine, which are known strong XB acceptors.[30]
Interestingly, Et3N and proton sponge (PS) did not initiate such
upfield shifts (0.003‒0.013 ppm), despite their pKb values.[31]
More importantly, we confirmed that the upfield shift was
considerably greater (0.213 ppm) when XB donor 4 was treated
with 2a.[31] From these results, we chose PS as the cooperative
base catalyst for the umpolung C‒C bond formation.
[a] Isolated yields. [b] The substrates were consumed within 3 hours.
In conclusion, we have found that an XB donor effectively
promotes reactivity of an iodonium ylide via halogen bond
activation, and various silyl enol ethers were successfully
coupled to give the corresponding 1,4-dicarbonyl compounds in
good yields. Mechanistic studies suggested that there was an
XB interaction between the carbonyl oxygen atom on the
iodonium ylide and the iodine atom of the XB donor. It was also
revealed that the XB donor can be used in the presence of a
3-Substituted oxindoles were chosen as the substrates (Table 3)
because the resulting oxindoles with all-carbon quaternary
centers at the C3 position are attractive intermediates for
oxindole natural products.[32] In a preliminary screening, coupling
of 3-methyloxindole 10a and iodonium ylide 2a was performed in
the presence of XB donor 4 and several bases, and as expected,
the combination with PS was found to give the best yield of 11a
(23%, see Table S2 in the Supporting Information).[25] We then
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10.1002/anie.201703641
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base as a co-catalyst, which synergistically promotes otherwise
inaccessible reactions. We believe that the present soft XB-
donor/Brønsted base pair will expand the potential for
cooperative catalysis and broaden the utility of XB donor
catalysis. Further investigation of the detailed reaction
mechanism and the asymmetric version of this reaction is now
underway in our laboratory.
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Experimental Section
To a solution of oxindole 10a (0.05 mmol, 7.3 mg), proton sponge
(0.0075 mmol, 1.6 mg), and XB donor 12 (0.0075 mmol, 8.9 mg) in THF
(0.5 mL), iodonium ylide (0.075 mmol, 25.6 mg) was added at 0 °C. After
being stirred at the same temperature for 24 hours, the reaction mixture
was directly purified by preparative TLC to give 11a (9.8 mg, 71%).
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computational methods are shown in Supporting Information.
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We gratefully acknowledge
a
Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (Y. T.) and a Grant-in-Aid
for Challenging Exploratory Research (Y. K.) from MEXT, Japan.
M. S. is grateful for a JSPS Fellowship for Young Scientists. We
thank Prof. M. P. Sibi (North Dakota State University), Prof. F. D.
Toste, and Mark Levin (University of California, Berkeley) for
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Keywords: organocatalyst • umpolung • hypervalent iodine • XB
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[31] The chemical shifts of 4 were not changed at all when XB donor 4 was
mixed with an equimolar of silyl enol ether 1. In addition, we confirmed
that the chemical shifts of 2a were not changed at all when iodonium
ylide 2a was mixed with an equimolar of proton sponge.
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10.1002/anie.201703641
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Masato Saito, Yusuke Kobayashi, Seiji
Tsuzuki, Yoshiji Takemoto*
Page No. – Page No.
Electrophilic activation of iodonium
ylides via halogen bond donor
catalysis for cross-enolate coupling
The umpolung alkylation of silyl enol ethers with an iodonium(III) ylide has been
achieved under mild conditions to afford various 1,4-dicarbonyl compounds in high
yields by the implementation of a halogen-bonding catalyst. Identification of a
compatible Bronsted-base catalyst enabled extension of this methodology to enols
generated in situ to give the corresponding adducts in good yields.
This article is protected by copyright. All rights reserved.