N -Heterocyclic Carbene-Catalyzed Olefination of Aldehydes with Vinyliodonium Salts to Generate α,β-Unsaturated Ketones

Article abstract of DOI:10.1021/acs.orglett.8b00447

An organocatalyzed metal-free, direct olefination of aldehydes with vinyliodonium salts has been achieved by an N-heterocyclic carbene-promoted C-H bond activation. The reaction proceeds under very mild conditions, delivering a range of (hetero)aryl-vinyl ketones in good yields. The retention of the double bond configuration is uniformly observed, and the application of 2-methoxyphenyl auxiliary group in iodonium salts secures a complete selectivity of the vinyl transfer.

Full text of DOI:10.1021/acs.orglett.8b00447

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Heterocyclic Carbene-Catalyzed Olefination of Aldehydes with
Vinyliodonium Salts To Generate α,β-Unsaturated Ketones
Adam A. Rajkiewicz†,‡ and Marcin Kalek*,†
†Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland
‡Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
S
* Supporting Information
ABSTRACT: An organocatalyzed metal-free, direct olefination
of aldehydes with vinyliodonium salts has been achieved by an
N-heterocyclic carbene-promoted C−H bond activation. The
reaction proceeds under very mild conditions, delivering a range
of (hetero)aryl-vinyl ketones in good yields. The retention of
the double bond configuration is uniformly observed, and the
application of 2-methoxyphenyl auxiliary group in iodonium
salts secures a complete selectivity of the vinyl transfer.
α,β-Unsaturated ketones constitute aprivileged group of reagents
in organic chemistry. The overwhelming numbers of their
synthetic applications include such landmark processes as a
Michael addition,1 Diels−Alder reaction,2 and Morita−Baylis−
Hillman reaction.3 This class of compounds is also well
represented among natural products and pharmaceutically
important molecules.4
Not surprisingly, a plethora of synthetic routes have been
developed for the preparation of the vinyl ketone moiety.5
However, there exist only a handful methods wherein the α,β-
unsaturated ketones are obtained by the simplest logical
disconnection, that is, by a direct olefination of the C−H bond
of aldehydes. The most explored in this context are the transition
metal-catalyzed hydroacylations of alkynes, proceeding by the
activationoftheformylC−Hbondviaanoxidativeadditiontothe
metal center (eq 1).6 In 2013, Lei and co-workers reported an
Herein, we describe our work on a novel, metal-free, direct
olefination of aldehydes employing organocatalysis with N-
heterocyclic carbenes (NHCs) to activate the formyl C−H bond
by the formation of Breslow intermediate.8 We hypothesized that
this nucleophilic species may undergo a reaction with vinyl(aryl)-
iodonium salts, which would serve as the donor of the vinyl group
(eq 3). An analogous reactivity of the Breslow intermediate
toward diaryliodonium salts has been previously described by
Gaunt and co-workers.9
Vinyl(aryl)iodonium salts have recently become an increas-
ingly important class of electrophilic vinyl transfer reagents.10
Under noncatalytic conditions, they have been predominantly
used for the olefination of heteroatom nucleophiles.11 However,
only isolated examples of direct reactions with carbon
nucleophiles exist.12 In the majority of cases, the application of
a transition metal catalyst, typically Cu or Pd, has been required to
achieve such transformations.13 Thereby, the organocatalysis
with NHC would establish a metal-free alternative for the vinyl
transfer using vinyliodonium salts, resulting in a C−C bond
formation.
We started our investigations by examining the reaction
betweenamodelaldehyde1aandphenyl(styryl)iodoniumtriflate
2a, under the conditions described previously for the coupling of
diaryliodonium salts,9 i.e., using N-pentafluorophenyl-triazolium
carbeneprecursorNHC-1,4-(dimethylamino)pyridine(DMAP)
as the base, and CH2Cl2/i-PrOH solvent mixture at −40 °C. We
were pleased to see that already this initial attempt resulted in the
formation of the desired product 3a, however, accompanied by an
approximately equal amount of ketone 3a′, originating from the
transfer of the aryl group of iodonium salt 2a (Table 1, entry 1).
Such behavior is somewhat unusual for vinyl(aryl)iodonium salts
since in practically all of their applications reported so far, the
alternativestrategythatreliesonahomolyticcleavageoftheC−H
bond using copper catalyst in the presence of hydroperoxide,
effecting an oxidative coupling of aldehydes and alkenes (eq 2).7
Received: February 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00447
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
a,b
Table 1. Evaluation of Auxiliary Aryl Groups
Table 2. Effect of Reaction Parameters
a
b
All data are the average of two experiments. Determined through
1
analysis by H NMR spectroscopy.
exclusive transfer of the vinyl group has been observed.14 To
address this apparent selectivity issue, we synthesized15 and
evaluated several aryl(styryl)iodonium salts, bearing differently
substituted aryl moieties (Table 1). Thus, the presence of
sterically hindered and electron-rich aryl groups promotes a
highly selective vinyl transfer (entries 2−5), whereas electron-
deficient aryl ligands lead to poor selectivities (entries 6−8).16 2-
Methoxyphenyl is identified as the most efficient auxiliary aryl,
securing the formation ofvinyl ketone 3ain81% yield(entry 4).17
The observed trends in the reaction selectivity are in a good
agreement with the results of studies on unsymmetric diary-
liodonium salts, which tend to donate the less bulky and more
electron-poor of the two aryl groups.18 Importantly, all the
reactions in Table 1 proceed uniformly with a complete retention
of the double bond configuration; no trace of the (Z)-configured
product was detected in any case.19
Having established the optimal structure of the auxiliary aryl
group, we proceeded to the refinement of other reaction
parameters. For the model coupling between aldehyde 1a and
vinyliodonium salt 2d, we have been able to develop conditions
that provide further improvement in the yield of the desired
product (Table 2, entry 1). The commercially available N-
pentafluorophenyl-triazolium carbene precursor NHC-1 proved
tobeasuperiorcatalyst, whereasrelatedspecies, NHC-2-NHC-6,
do not furnish satisfactory results (entries 2−6). This result is
consistent with N−C6F5-substituted triazolium NHCs being
effective catalysts in the reactions involving Breslow intermedi-
ates.8,20 Also, no reaction is observed in the absence of the catalyst
(entry 7). Elevation of the temperature to 0 °C has a detrimental
effect on the efficiency of the coupling (entry 8). Solvent
screening disclosed that, while the addition of small amount of i-
PrOH is beneficial when using CH2Cl2 (entries 9 vs 10), if the
reaction is performed in DCE alone, a slightly better yield is
a
Results of further screening of the reaction parameters are given in
b
c
the SI. All data are the average of two experiments. Determined
d
1
through analysis by H NMR spectroscopy. Minor amount of side
product 3a′ was observed. Mes = 2,4,6-trimethylphenyl. TCIP = 2,4,6-
trichlorophenyl.
obtained. Application of bases other than DMAP leads to a
considerable decrease in the amount of product, in part due to the
emergence of ketone 3a′ (entries 11−13). Finally, we evaluated
the effect exerted on the reaction outcome by a counterion
present in the iodonium salt. It is found that tetrafluoroborate salt
is completely ineffective as a donor of the vinyl group (entry 14).
The more strongly coordinating ions, namely, trifluoroacetate,
tosylate, and fluoride give moderately to slightly lower yields,
compared to triflate (entries 15−17).21
With the optimized conditions in hand, we set out to explore
the scope of the reaction. A range of heterocyclic aldehydes,
containing both five- and six-membered rings, are olefinated,
producing heteroaryl-vinyl ketones in good yields (Scheme 1,
3a−3f). Substituted benzaldehydes are found to be more
challenging substrates, requiring the presence of an electron-
withdrawing group in the phenyl ring for the yields to be
acceptable (3g−3i).22 Notably, a propargyl aldehyde can also be
used as the starting material, furnishing synthetically versatile
enynone scaffold (3j). Finally, we applied the developed protocol
for the preparation of a pharmaceutically relevant ketone 3k in
39% yield.23 As far as the limitations are concerned, aliphatic
aldehydes are not efficient substrates for the olefination under the
developed conditions.
We have also examined the scope with regard to the
vinyliodonium salt (Scheme 2). The olefination proceeds in
B
DOI: 10.1021/acs.orglett.8b00447
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
irrespective of the choice of the auxiliary aryl group and the salt
counterion, the olefination is outcompeted by the undesired aryl
transfer (see the Supporting Information for details).
Scheme 1. Scope with Regard to the Aldehyde
We endeavored to gain some insight into the mechanism of the
developed transformation by performing kinetic investigations.
The reaction is found to be very rapid at the outset, reaching over
30% yield within the first 5 min (Figure 1, black squares). This
Figure 1. Time-course of the NHC-catalyzed olefination of aldehyde 1f
with salt 2d: under standard conditions (black squares); with product 3f
(0.3 equiv) added from the outset (blue circles); and with DMAP·TfOH
(0.3 equiv) added from the outset (red triangles). The inset shows the
first 30 min period in detail.
Scheme 2. Scope with Regard to the Vinyliodonium Salt
demonstrates a very high propensity of Breslow intermediate for
reacting with vinyliodonium salt. Unfortunately, the fast rate
precludes quantitative initial rate measurements using standard
techniques.24 Interestingly, the reaction subsequently abruptly
decelerates, and it takes several hours to reach a full conversion of
the substrate. To probe for a possible inhibition of the reaction by
one of its products, we carried out the NHC-catalyzed olefination
witheitherketone3forDMAP·TfOHaddedfromtheoutset. The
obtained time-course profiles (Figure 1, blue circles and red
triangles, respectively) do not differ, within the experimental
error, from the one acquired under the standard conditions. We
thus speculate that the decrease in the rate is rather due to an
unidentified catalyst decomposition pathway.
In conclusion, we have developed an NHC-catalyzed direct
olefination of aldehydes using vinyliodonium salts. The reaction
proceeds under very mild conditions and delivers a range of α,β-
unsaturated ketones, in particular, those containing pharmaco-
phoric heteroaryl moieties. A careful optimization of the auxiliary
substituent of the vinyliodonium salt has allowed for a selective
and efficient vinyl transfer to a carbon nucleophile. We believe
that this finding has the potential to turn vinyliodonium salts into
broadly applicable and robust vinyl transfer reagents under metal-
free conditions.
synthetically useful yields for an array of β-styryl groups (3l−3q).
In particular, sterically hindered 2,6-dimethylphenyl moiety
(3m), as well as fluorinated and perfluorinated aryls can be
incorporated into the product (3p−4q). The electronic proper-
ties of the vinyl group seem to have an impact on the efficiency of
the reaction; the electron-deficient groups are transferred more
effectively than the electron-rich ones. A thiophene functional
unit in the β-position of the double bond is also tolerated (3r).
Noteworthy, β,β-disubstitutedvinylsundergoatransferunderthe
developed conditions, albeit in somewhat lower yields (3s−3t).
Unfortunately, none of the tested iodonium salts with an α-
substitutedvinylmoietyyieldedthedesiredproduct, showingthat
extensivesterichindranceclosetothereactioncenterimpedesthe
coupling. Finally, for β-alkyl-substituted vinyliodonium salts,
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b00447.
Results of additional investigations, experimental proce-
dures, analytical data, and copies of NMR spectra for
products 3a−3t(PDF)
C
DOI: 10.1021/acs.orglett.8b00447
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Letter
(c) Ochiai, M.; Sumi, K.; Takaoka, Y.; Kunishima, M.; Nagao, Y.; Shiro,
M.; Fujita, E. Tetrahedron 1988, 44, 4095−4112.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: m.kalek@cent.uw.edu.pl.
ORCID
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Marcin Kalek: 0000-0002-1595-9818
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Science
Centre, Poland (grant no. 2014/15/D/ST5/02579). We thank
Dominika Strzelecka and Tomasz R. Ratajczak (Centre of New
Technologies, University of Warsaw) for assistance with MS and
IR analysis.
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