N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C-H Alkynylation of Aldehydes with Alkynyliodonium Salts - Evidence for Alkynyl Transfer via Direct Substitution at Acetylenic Carbon

Article abstract of DOI:10.1021/acscatal.9b04394

Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent iodine group transfer reagent allowed for metal-free C-H functionalization and C-C bond formation. The reaction proceeds under mild conditions, at -40 °C and in the presence of an amine base, providing access to an array of heteroaryl-propargyl ketones containing various substituents in good to excellent yields. The mechanism of the reaction was investigated by means of both experiments and density functional theory calculations. ¹³C-labeling and computations determined that the key alkynyl transfer step occurs via an unusual direct substitution at an acetylenic carbon, wherein an iodine-based leaving group is exchanged by a Breslow intermediate nucleophile. Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the generation of the Breslow intermediate, whereas the subsequent C-C bond formation is a fast process. These results are fully reproduced and rationalized by the calculated full free energy profile of the reaction, showing that the largest energy span is located between the protonated form of NHC catalyst and the transition state for the carbene attack on the aldehyde substrate.

Full text of DOI:10.1021/acscatal.9b04394

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Article
N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H
Alkynylation of Aldehydes with Alkynyliodonium Salts – Evidence
for Alkynyl Transfer via Direct Substitution at Acetylenic Carbon
Adam Ado Rajkiewicz, Natalia Wojciechowska, and Marcin Kalek
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04394 • Publication Date (Web): 05 Dec 2019
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N-Heterocyclic Carbene-Catalyzed Synthesis of
Ynones via C–H Alkynylation of Aldehydes with
Alkynyliodonium Salts – Evidence for Alkynyl
Transfer via Direct Substitution at Acetylenic
Carbon
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Adam A. Rajkiewicz†,‡, Natalia Wojciechowska†,‡, 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
ABSTRACT
Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic
carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent
iodine group-transfer reagent allowed for metal-free C–H functionalization and C–C bond
formation. The reaction proceeds under mild conditions, at –40 ⁰C and in the presence of an amine
base, providing access to an array of heteroaryl-propargyl ketones containing various substituents
in good to excellent yields. The mechanism of the reaction was investigated by means of both
experiments and density functional theory calculations. 13C-labeling and computations determined
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that the key alkynyl transfer step occurs via an unusual direct substitution at an acetylenic carbon,
wherein an iodine-based leaving group is exchanged by a Breslow intermediate nucleophile.
Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the
generation of the Breslow intermediate, whereas the subsequent C–C bond-formation is a fast
process. These results are fully reproduced and rationalized by the calculated full free energy
profile of the reaction, showing that the largest energy span is located between the protonated form
of NHC catalyst and the transition state for the carbene attack on the aldehyde substrate.
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Keywords: NHC organocatalysis, ynones, hypervalent iodine, alkynylation, mechanistic studies
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INTRODUCTION
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Over the last two decades, the organocatalysis with N-heterocyclic carbenes (NHCs) has
established a strong position in synthetic organic chemistry. Its success stems primarily from
enabling a smooth access to a group of versatile nucleophilic species, such as Breslow intermediate
(acyl anion equivalent), homoenolate, acylazolium enolate, and other, via the umpolung of
abundant carbonyl substrates. The coupling of these nucleophiles with a plethora of electrophiles
has allowed for the development of numerous highly useful synthetic methods.1 In the recent years,
the applicability of NHC catalysis is being further expanded by employing novel unconventional
electrophilic partners, which provide a direct entry to important structural motiffs.2 One class of
such electrophilic reagents that has recently opened new opportunities in NHC organocatalysis are
hypervalent iodine compounds. Due to the ability of iodine atom to undergo a very energetically
favorable reduction from +III to +I oxidation state, accompanied by a simultaneous bond formation
involving its ligands (resembling a reductive elimination at a metal center), the hypervalent iodine
species are superior electrophilic atom- and group-transfer reagents.3 At the same time, they lack
the toxicity and high price of transition metal catalysts, making them a good alternative from the
environmental and economical viewpoints.4 The group transfer reagents based on hypervalent
iodine have been used in a number of organocatalyzed reactions,5 but there is so far only a handful
examples of NHC-promoted processes utilizing these unique electrophilic coupling partners.6
Ynones, or propargyl ketones, are a prominent class of organic compounds. First, the ynone
motif is present in several biologically active molecules.7 Even more importantly, the combined
reactivities of the triple bond and the carbonyl group give rise to numerous reactions, wherein
ynones serve as precursors for the preparation of a diverse array of molecular scaffolds.8,9 The high
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synthetic utility of ynones is proven by their application as key intermediates in multiple total
syntheses.10
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Ynones have traditionally been synthesized by one of three methods: (1) the reaction of metal
acetylides with acyl chlorides or other carboxylic derivatives; (2) the oxidation of propargylic
position in alkynes or of propargylic alcohols; and (3) a carbonylative cross-coupling.8f,11 An
interesting alternative to these standard approaches that has recently gained attention is the direct
alkynylation of the C–H bond in aldehydes (Scheme 1).12 Such strategy possesses the advantage
of providing propargyl ketones in a single synthetic step from abundant and stable starting
materials. The first example employing this concept was reported by Zhou and co-workers in 2015,
who described a rhodium- and iridium-catalyzed alkynyl transfer from ethynylbenziodoxolone
(EBX) to aromatic aldehydes (Scheme 1a).13 The reaction proceeds via the incipient directing
group-assisted activation of the formyl C–H to form a metal carbonyl complex. The second
existing approach to effect the alkynylation of aldehydes relies on the homolytic cleavage of the
C–H bond. The groups of Wei, Yu, and Li described independently the synthesis of ynones in the
presence of tert-butyl hydroperoxide as a radical initiator (Scheme 1b).14 Despite the robustness
and simplicity of these methods, their considerable disadvantage is the high reaction temperature
required, imposing constraints on the scope. To alleviate the above drawback, Glorius and co-
workers employed photoredox catalysis to generate radicals from aldehydes (Scheme 1b).15 By the
application of iridium complex, the alkynylation of a variety of aldehydes with EBX could be
carried out at room temperature.
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Scheme 1. Synthesis of Ynones via Direct C–H Alkynylation of Aldehydes.
Building on the seminal work by Gaunt on the NHC-catalyzed arylation of aldehydes,6a as well
as on our own studies on the vinylation of aldehydes,6b we envisioned that the formation of a
Breslow intermediate by the action of an NHC catalyst on aldehyde substrate may constitute an
alternative mean to activate the formyl C–H bond allowing for the subsequent alkynyl group
transfer. Herein, we present our work on the development of a novel NHC-catalyzed direct C–H
alkynylation of aldehydes outlined in Scheme 1c. Importantly, the reaction makes use of
alkynyl(aryl)iodonium salts as the alkynyl group donor, in contrast to all of the previously reported
methods that employ EBX reagents (Schemes 1a and 1b).16 While alkynyl(aryl)iodonium salts
have been widely applied for the direct alkynylation of heteroatom nucleophiles and enolates of
-dicarbonyl compounds,17,18 their use for transferring alkynyl moiety to less trivial carbon
nucleophiles have usually required transition metal catalysis.19 On the contrary, the application of
NHC organocatalyst gives rise to an efficient metal-free C–C bond formation involving an acyl
anion equivalent. In addition to the synthetic studies, we perform a thorough mechanistic
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investigations of this new transformation by the combination of experimental and computational
approaches. In particular, we identify the turnover-limiting step of the catalytic cycle and elucidate
that the transfer of alkynyl moiety from the iodonium salt to the Breslow intermediate follows an
unusual pathway of a direct substitution at an acetylenic carbon atom.
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RESULTS AND DISSCUSSION
Synthetic studies. First, we investigated the effect of a number of reaction parameters on a model
coupling between 2-quinoxalinecarbaldehyde 1a and phenylethynyl(aryl)iodonium salts
containing different auxiliary aryl groups and counter-ions (Table 1). The established optimal
conditions consist of N-pentafluorophenyl-triazolium carbene precursor NHC-1,
tetramethylethylenediamine (TMEDA) as the base, and toluene at –40 ⁰C, affording ynone 3a in
86% yield (entry 1). The structure of the iodonium salt was found to be crucial for the selective
and efficient alkynyl group transfer.20 Mesityl was identified as the superior auxiliary aryl group,
securing the formation of product in high yield (entry 1). Less sterically hindered, including singly
ortho-substituted, aryls lead to a loss of the selectivity of the transfer, and to the formation of a
bisaryl ketone side-product (entries 2–4). The presence of two ortho substituents in 2,6-
dimethylphen-1-yl suppresses the side aryl-transfer, but the desired ynone is furnished is a lower
yield than for the mesityl-containing salt 2a (entry 5 vs. 1). A significant effect of the counter-ion
was also observed. The best result was obtained with a tosylate salt (entry 1), whereas iodonium
trifluoromethanosulfonate and trifluoroacetate display only a moderate reactivity (entries 6–7),
and a tetrafluoroborate salt is quite ineffective (entry 8). Finally, we tested EBX reagent 4, but it
provides only traces of product under these conditions (entry 9). Importantly, the optimal
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alkynyl(mesityl)iodonium tolsylates of type 2a are stable and easy to handle, and they can be very
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conveniently prepared by the method reported by Stang.21
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Table 1. Effect of Reaction Parametersa
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entry
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deviation from the standard conditions
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yield (%)b
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Ar = Ph (2b), instead of Ar = Mes
Ar = o–anisyl (2c), instead of Ar = Mes
Ar = o–tolyl (2d), instead of Ar = Mes
Ar = 2,6-dimethylphen-1-yl (2e), instead Ar = Mes
X = OTf (2f), instead of X = OTs
38 (16)c
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NHC-4, instead of NHC-1
NHC-5, instead of NHC-1
NHC-6, instead of NHC-1
NHC-7, instead of NHC-1
5 mol% of NHC-1
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<1
<1
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no NHC-1
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0 °C, instead of –40 °C
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N (3.0 equiv.), instead of TMEDA
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DMAP, instead of TMEDA
DABCO, instead of TMEDA
K
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CH Cl , instead of toluene
MeCN, instead of toluene
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aAll data are the average of two experiments. Determined through analysis by H NMR
spectroscopy. The formation of bisaryl ketone side-product was observed, its yield is given in
parenthesis. At –35 °C. Mes = 2,4,6-trimethylphen-1-yl; OTs = p-tolenesulfonate; OTf =
trifluoromethanesulfonate; TClP = 2,4,6-trichlorophen-1-yl; DCE = 1,2-dichloroethane.
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As far as the other reaction parameters are concerned, we found that the different types of NHCs
commonly used in organocatalysis (entries 10–15) are inferior to the commercially available
NHC-1, bearing an electron deficient pentafluorophenyl group. Lowering of the catalyst loading
from 10 to 5 mol% decreases the yield to a moderate level (entry 16) and no product formation is
observed in the absence of catalyst (entry 17). Elevated temperatures have an adverse effect on the
reaction (entries 18–19). Application of other organic amine bases results in moderate to good
yields (entries 20–23), while inorganic bases are ineffective in this transformation (e.g., entry 24).
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The good performance of TMEDA cannot be attributed to just providing a double number of amine
groups, as an increased amount of triethylamine did not lead to an improved yield, quite the
contrary (entry 21). Interestingly, more polar solvents (entries 25-27) that completely solubilize
the reactants are not as efficient as toluene, which affords a heterogenous reaction mixture.
Having established the optimal conditions for the NHC-catalyzed alkynylation of aldehydes, we
proceeded to evaluate the scope and limitations of this reaction. An array of heteroaromatic
aldehydes could be efficiently alkynylated (Scheme 2). In particular, arylpropargyl ketones
containing heterocyclic six-membered rings with nitrogen, such as quinoxaline (3a), quinoline
(3b), and pyridine (3g–3l), as well as five-membered rings, e.g., pyrazole (3c–3d) and thiazole
(3e–3f), were synthesized in good to excellent yields. The ability to incorporate these moieties is
highly advantageous, as they are prevalent in therapeutically important molecules.22 A number of
functional groups is tolerated under the reaction conditions, including aryl bromide (3i), double
(3k), and triple (3l) bonds, providing useful handles for further functionalization and built-up of
the molecular complexity. The method is also compatible with fluorinated substituents (3h and
3j), which adds to its value for the synthesis of pharmaceutically relevant compounds.23 On the
downside, benzaldehydes are poor substrates and only the one containing a strongly electron-
withdrawing nitro group afforded the desired product in an admissible yield (3m). Also, aliphatic
aldehydes and enals were found to be incompetent starting materials.24
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Scheme 2. Scope with Regard to the Aldehyde
Next, we examined the scope with regard to the alkynyliodonium salt. The method could be
applied to transfer a range of arylethynyl groups, containing a multitude of substituents (Scheme
3). All the alkyl-substituted (3n, 3o), aryl-substituted (3p), as well as extended (3q) aryl systems
can be incorporated into the product. The reaction proceeds equally well for arylethynyl moieties
bearing both electron-withdrawing and electron-donating groups. Thus, regardless of the
substituent position, ynones containing halogens (3r and 3t), trifluromethyl (3s), cyano (3u),
ketone (3v), ester (3w), and ether (3x–3y) functionalities were synthesized in good to excellent
yields. Notably, we also prepared propargyl ketones with a phtalamide-masked amine (3z) and a
sulfonamide (3aa), demonstrating a broad functional group tolerance of the developed
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methodology. Unfortunately, when iodonium salts containing alkylethynyl and silylethynyl groups
were tested, the desired products were formed in low yields under these conditions.24
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Scheme 3. Scope with Regard to the Alkynyliodonium Salt (Qx = quinoxalin-2-yl)
Finally, to validate the synthetic utility of the developed procedure, we have applied it to
synthesize compound 3y on a gram scale, which was obtained without any appreciable loss in the
yield (80%, 1.64 g of product).
Experimental mechanistic studies. The hypervalent iodine compounds bearing an alkynyl group
contain three distinct electrophilic centers: the iodine atom, the -carbon of the triple bond, and
the -carbon of the triple bond. Therefore, the reactions involving such reagents may in principle
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follow three general mechanistic pathways, outlined in Scheme 4 for the particular case of the
NHC-catalyzed alkynylation of aldehydes with alkynyliodonium salts.
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Scheme 4. Outline of Possible General Mechanisms
In the first scenario the nucleophile, Breslow intermediate, is incorporated into the coordination
sphere of iodine (Scheme 4a). After the expulsion of NHC catalyst, the key C–C bond-formation
takes place via a reductive ligand coupling, affording the ynone product. This type of mechanism
is common for related aryl transfer reactions with diaryliodonium salts, as revealed by several
computational investigations, but it has never been implicated for an alkynylation with hypervalent
iodine reagents.25 The second possibility is a direct substitution at the -acetylenic carbon, i.e., the
displacement of iodine acting as a leaving group by the attacking nucleophile (Scheme 4b). Such
a mechanistic route has so far been shown to operate only in a single instance of alkynyl transfer
from hypervalent iodine species, namely for the alkynylation of thiols with EBX reagents.26,27
Nevertheless, it has been demonstrated that this pathway is not the exclusive mechanism in that
case, and depending on the substituents present in the starting materials it may contribute to a
larger or a lesser extent to the formation of product.26b In the final alternative, the nucleophile
attacks at the -carbon of the triple bond in a Michael-type conjugate addition (Scheme 4c). The
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resulting iodonium ylide, after a prior elimination of NHC, undergoes a fragmentation producing
a vinylidene carbene intermediate. Subsequently, the vinylidene carbene rearranges to the final
product by a 1,2-shift of the aryl substituent. It is generally accepted that the majority of
alkynylations with hypervalent iodine reagents follow this last mechanism, as there exists strong
experimental evidence supporting it. In particular, first, in multiple cases the iodonium ylide could
be trapped by protonation, yielding isolable vinyliodonium derivatives.28 Secondly, in the absence
of any substituents prone to migration, the emergence of products originating from the insertion
of the vinylidene carbene into C–H bonds has been observed.18k,29 Finally, the acetylenic carbons
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have been shown to swap their positions during the reactions with C-labeled alkynyliodonium
starting materials, in line with the 1,2-shift step.26b,29a,30
The fact that alkylethynyliodonium salts are not effective in the NHC-catalyzed reaction (vide
supra) suggested that it may follow the most common pathway staring with the nucleophilic attack
on the -carbon (Scheme 4c), since the alkyl substituents are not likely to undergo the 1,2-
migartion. On the other hand, we did not observe any products originating from the insertion of
the vinylidene carbene into the C–H bonds of the alkyl chains, either. Therefore, in order to obtain
a more direct proof distinguishing between the different possible mechanisms, we carried out the
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alkynylation of aldehyde 1a using iodonium salt 2w that was labeled with C at the -carbon
(Scheme 5). The resulting product 3ab was generated in an unchanged yield compared to its
unlabeled counterpart (cf. 3a in Scheme 2) and it contained the 13C label exclusively incorporated
at the acetylenic carbon adjacent to the carbonyl group. Such an outcome allows to unambiguously
eliminate the attack of Breslow intermediate on the -carbon of the alkynyliodonium salt (Scheme
4c) as the valid pathway of the investigated reaction.
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Scheme 5. NHC-Catalyzed Alkynaltion of Aldehyde 1a with Alkynyliodonium Salt 2w Labelled
with 13C at the -Carbon.
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Stimulated by the result of above experiment, demonstrating that the developed reaction does
not follow the most prevalent mechanism for alkynylations with hypervalent iodine compounds,
we decided to perform more thorough investigations of this interesting process. To obtain insight
into its course, we carried out kinetics investigations. First, the progress of the reaction under the
optimized conditions was monitored over time (Figure 1a). The analysis of the decay of the starting
material shows that the reaction displays overall second order in the concentrations of the
substrates, as the linear dependence of reciprocal substrate concentration vs. time was observed
(Figure 1b).31
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Figure 1. (A) Time-course of the NHC-Catalyzed Alkynylation of Aldehyde 1a with
Alkynyliodonium salt 2a in d
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-Toluene at –40 °C.a,b (B) Corresponding Plot of Reciprocal
Substrate Concentration vs. Time.
aThe concentrations were determined by 1H NMR spectroscopy relative to internal standard. bThe
initial leap in the concentrations is due to a temporary heating of the sample during the addition of
the initiating reagent (TMEDA).
In order to ascribe the orders to the concentrations of specific reagents, we conducted an initial
rate study. Our first attempts to follow the initial rates under the optimized conditions were
unsuccessful, as highly erratic and irreproducible time curves were being obtained. We were able
to trace this problem to the heterogeneity of the reaction mixture, and, thus, upon switching the
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solvent from d
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-toluene to CDCl
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–40 °C, better quality data could be acquired. However, due to the technical difficulties of
measuring the reaction kinetics at so low temperature, in particular the problem to start the reaction
cleanly at –40 °C using NMR as the measurement method, the alignment of the data points is still
far from perfect (see the Supporting Information for the experimental details and the data handling
procedure). Anyhow, despite the very preliminary character of these kinetic studies and
considerable uncertainties of the obtained orders, we believe that we were able to grasp the general
kinetic characteristics of the transformation.
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Figure 2. Initial Rate Measurements for the NHC-Catalyzed Alkynylation of Aldehyde 1a with
Alkynyliodonium Salt 2a in CDCl at –40 °C, with Varied Concentration of (a) 1a, (b) 2a, (c)
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TMEDA, and (d) NHC-1. The Insets Show the Corresponding LN-LN Plots.a
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a Product concentration was determined by 1H NMR spectroscopy relative to internal standard.
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Figure 2 presents the initial rate plots measured with varied concentrations of the respective
reagents and the catalyst precursor. The analysis of this data results in an experimental rate law,
wherein the reaction is first order in the concentrations of 1a, TMEDA, and NHC-1, whereas
zeroth order in the concentration of 2a (eq 1). This is in agreement with the overall second order
in the substrates (i.e., 1a and TMEDA), determined from the reaction monitored over a longer
period (Figure 1; the concentration of NHC-1 is constant with conversion, hence its influence on
the rate does not appear in that experiment).
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[
]
[
]
푟푎푡푒 = 푘 1a [TMEDA] NHC-1
(1)
The presence of the aldehyde and the NHC precatalyst concentrations in rate law (1) directly
implies that the formation of Breslow intermediate is the turnover-limiting step of the catalytic
cycle. In turn, since the concentration of the alkynyliodonium salt does not impact the rate, the
subsequent key C–C bond formation must be a fast step, demonstrating a very high mutual affinity
between the alkynyliodonium salt and the Breslow intermediate. Taking this into account, the
appearance of the concentration of TMEDA in the rate law indicates its involvement also during
the generation of the Breslow intermediate, in addition to the deprotonation needed to expel NHC
toward the end of the mechanism (Scheme 4).
Computational studies. To gain insight into the details of the catalytic cycle and complement the
mechanistic picture obtained in the previous section, we performed a computational density
functional theory (DFT) investigation. The alkynylation of 2-pyridinecarboxaldehyde (1g) with
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(mesityl)(phenylethynyl)iodonium tosylate (2a) using precatalyst NHC-1 was employed as a
model reaction in the calculations. The computations were carried out at B3LYP-D3BJ/Def2-
QZVP//B3LYP-D3BJ/6-31+G(d,p) (LANL2DZ(d) for I) level of theory with the modelling of
toluene solvation using SMD method for both the geometry optimizations and the final energy
calculations (see the Supporting Information for the full computational details).32 Figure 3 shows
the free energy profile for the mechanism established by the calculations.
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The initial formation of the Breslow intermediate was found to occur according to the standard
mechanism implicated for the NHC-catalyzed processes.1c Thus, the reaction begins by a facile
deprotonation of catalyst precursor NHC-1 with TMEDA via transition state TS1. The resulting
free carbene A is higher in energy by 2.4 kcal/mol compared to its protonated form. In the
following step, the NHC attacks aldehyde 1g, generating alkoxide species B. The overall barrier
for this transformation is calculated to be 16.7 kcal/mol relative to NHC-1. In the next step, B
undergoes a barrierless protonation at oxygen by the salt of TMEDA, yielding the corresponding
alcohol C. Finally, Breslow intermediate D is furnished upon the deprotonation of C at the carbon
atom by TMEDA via a low-barrier TS3. Overall, the formation of the Breslow intermediate is
exergonic by 2.1 kcal/mol relative to the catalyst precursor. The highest energy span along the
way, amounting to 16.7 kcal/mol, is located between NHC-1 and TS2. Importantly, within this
part of the energy diagram all three species, whose concentrations are present in the experimental
rate-law (1), are involved, that is: the catalyst precursor, the aldehyde substrate, and TMEDA. The
subsequent stepwise proton-shuttling (B → D) is facile and does not contribute to the reaction rate.
Although, the computations did not reveal any involvement of the second amine group of
TMEDA in any of the transition states, in TMEDAH+BF –
salt, the lone electron pair of the second
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nitrogen is pointing toward the proton (with a 2.58 Å separation), providing some stabilization (on
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the order of 1 kcal/mol, judging from the energies of other conformations of this salt lacking such
interaction). Thus, the presence of this interaction leads to the lowering of the energy of
intermediate A, in turn lowering the rate-determining barrier. This effect is most likely responsible
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for the better performance of TMEDA compared to simple amines, such as Et
reaction.
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N, in promoting the
Figure 3. Free Energy Profile for the Alkynylation of Aldehyde 1g with Alkynyliodonium Salt 2a
Using Precatalyst NHC-1 in Toluene, Calculated at B3LYP-D3BJ/Def2-QZVP(SMD)//B3LYP-
D3BJ/6-31+G(d,p)(SMD) Level of Theory.
Next, we examined the possible options for the reaction of Breslow intermediate D with
alkynyliodonium salt 2a. It was quickly established that the direct coordination of D to the iodine
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center is not feasible, as it does not result in a stable structure that constitutes a minimum on the
energy surface. Therefore, the mechanism involving the inner-sphere reductive ligand coupling
(Scheme 4a) can be discarded. On the other hand, we were capable of finding the plausible
transition states, TS4 and TS, for the other two alternative pathways, i.e., the direct substitution
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at the -carbon (Scheme 4b) and the Michael-type addition to the -carbon (Scheme 4c),
respectively. The former one is calculated to be clearly energetically favorable over the latter (by
6.2 kcal/mol), thus, it constitutes the actual pathway of the C–C bond-formation. The transfer of
the alkynyl group via TS4 is found to be a very exergonic, thus, irreversible process (by 55.9
kcal/mol). This is due to the accompanying reduction of iodine from +III to +I oxidation state and
the loss of hypervalency. For completeness, we calculated the transition state for the transfer of
the mesityl group in 2a (TS-Mes), instead of the alkynyl group. Such course of the reaction would
require crossing a very high barrier of 24.6 kcal/mol, explaining the excellent performance of the
mesityl substituent as the auxiliary non-transferable aryl group in the alkynyl(aryl)iodonium salts.
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Figure 4. Optimized Structures of (a) Alkynyliodonium Salt 2a, (b) TS4, (c) TS, and (d) TS-
Mes (Distances Are Given in Å).
The optimized structures of transition states TS4, TS, and TS-Mes, as well as of
alkynyliodonium salt 2a, are depicted in Figure 4. In all three transition states the ligand
participating in the new C–C bond formation occupies the hypervalent position. Hence, in the case
of TS4 and TS(Figure 4b and 4c, respectively), the arrangement of ligands around the iodine
center is the same as in the parent salt (Figure 4a), while in TS-Mes the phenylethynyl and mesityl
groups are swapped (Figure 4d). Such opposite orientation of the ligands is probably the most
significant contributor to the high barrier associated with TS-Mes, as the calculated energy of the
isomer of 2a having the mesityl group in the hypervalent position and the alkynyl group in the
equatorial position is higher by as much as 10.0 kcal/mol compared to the energy of 2a. As far as
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the energy difference between TS4 and TSis concerned, it most likely originates from distorting
the conjugation between the forming double C–C bond and the phenyl substituent, which due to
steric reasons must rotate nearly perpendicularly, in the latter transition state. On the other hand,
in TS4, the phenyl ring can align itself in way allowing for a complete -conjugation over the
triple bond to both the breaking C–I bond and the newly forming C–C bond, providing
stabilization. Importantly, in all the transition states, the hydroxyl group of Breslow intermediate
is interacting with the iodine center. This is somewhat similar to the case of alkynylation of thiols
with EBX, wherein the thiolate nucleophile has been shown to simultaneously interact with the
alkynyl group and iodine in a three-center transition state structure.26 However, we could also
locate other, higher in energy, conformations of the TSs lacking this interaction, hence it is not
absolutely required, but it renders the C–C bond formation more facile.
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The catalytic cycle is closed by a barrierless deprotonation of intermediate E, followed by TS5,
which releases the final product 3g and regenerates free NHC A. Importantly, as A is not the most
stable form of the catalyst, it is converted to the more favorable off-cycle resting state NHC-1.
Overall, the total thermodynamics of the reaction is calculated to –59.9 kcal/mol.
The mechanistic picture emerging from the calculations is in a full agreement with the results of
experimental studies described in the previous section. First, the lowest energy pathway
established for the C–C bond formation, i.e., the direct substitution at -acetylenic carbon via TS4,
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explains the direct transfer of the C-label between iodonium salt 2w and product 3ab without
swapping (Scheme 5). Secondly, the computed free energy profile is in line with the experimental
rate-law (1). It correctly predicts that only the NHC precatalyst, the aldehyde, and TMEDA are
involved in the turnover-limiting step, constituted by the largest energy span between NHC-1 and
TS2 (overall 16.7 kcal/mol).33 The height of this turnover-limiting barrier is also quantitatively
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consistent with the experimental rate of the reaction at –40 °C. Conversely, the iodonium salt enters
the free energy profile within a lower barrier, later in the catalytic cycle (13.9 kcal/mol, D to TS4),
thus, its concentration does not influence the overall rate.
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To better understand the characteristics and limitations of the developed transformation, we re-
calculated the key stationary points in the free-energy profile for other substrates, in particular
those that did not provide satisfactory results (Table 2). Hence, as far as propionaldehyde (1n) and
benzaldehyde (1o) are concerned (entries 1 and 2), although the Breslow intermediates derived
from them could readily react with iodonium salt 2a (8.9 kcal/mol and 14.9 kcal/mol barriers,
respectively), the preceding barriers for their formation (20.3 kcal/mol and 19.3 kcal/mol,
respectively) are considerably higher than that calculated for 2-pyridinecarboxaldehyde 1g (16.7
kcal/mol; Figure 3). Thus, the electron-poor aldehyde substrates are required to efficiently furnish
the corresponding Breslow intermediates. We evaluated computationally also the barrier for the
alkynyl group transfer for Ph-EBX reagent (4, entry 3). It was found to be appreciably higher
compared to the one obtained in the case of the iodonium salt 2a (13.9 kcal/mol; Figure 3). We
believe that this is due to the considerable basicity of the carboxylate moiety in EBX, which lowers
the leaving group ability of iodine, rendering the alkynyl transfer more challenging.
Table 2. Relative Free-Energies of Key Stationary Points for the Reactions Involving Other
Substrates, Calculated at B3LYP-D3BJ/Def2-QZVP(SMD)//B3LYP-D3BJ/6-31+G(d,p)(SMD)
Level of Theory.
Alkynyliodonium
Reagent
NHC-1
(initial state)
Entry Aldehyde
1
TS2
D
TS4
0.0
20.3
6.2
15.1
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16.7
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18.2
21.2
–2.1
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CONCLUSIONS
In summary, we have developed an NHC-catalyzed direct C–H alkynylation of aldehydes using
alkynyliodonium salts as alkynyl donors, expanding the scope of the NHC organocatalysis. The
proper choice the auxiliary aryl substituent secured the selective transfer of the alkynyl substituent
from iodine, providing a facile entry to a variety of ynones in good to excellent yields. In particular,
the method is well-suited for the synthesis of compounds bearing pharmaceutically relevant
heterocyclic scaffolds. Due to the mild reaction conditions, in terms of both the reaction
temperature and the use of a weak amine base, a range of fragile functional groups is tolerated.
Specifically, alkenes, alkynes, nitriles, ketones, esters, and amides can be incorporated into the
products. Finally, the application of the organocatalyst in the combination with a hypervalent
iodine reagent, allowed for a completely metal-free C–H functionalization, rendering the
developed reaction a green alternative for the preparation of propargylic ketones from abundant
aldehyde starting materials.
The mechanism of the reaction has been thoroughly studied by both experimental and
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computational methods. The C-labbeling and DFT calculations have shown that the alkynyl
group transfer proceeds via a direct substitution of iodine by the Breslow intermediate occurring
at -acetylenic carbon, and not by the prevalent pathway involving the initial attack of nucleophile
at the -positionThis constitutes the second reported example of such a course of the alkynylation
reaction with a hypervalent iodine reagent and the first wherein it is the clearly preferred, exclusive
mechanistic pathway. Therefore, the finding may implicate that analogous mechanisms can be
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more common than previously thought. Additionally, the kinetic studies, corroborated by the
computed free energy profile, have identified the formation of Breslow intermediate to be the
turnover-limiting step of the catalytic cycle. This demonstrates that the subsequent C–C bond-
forming reaction between the Breslow intermediate and the alkynyliodonium salt is a very facile,
low-barrier process. Above result opens opportunities for the application of alkynyliodonium salts
as efficient alkynyl-transfer reagents for other non-trivial nucleophilic species, including
catalytically generated ones, in the future.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: m.kalek@cent.uw.edu.pl
ORCID
Adam A. Rajkiewicz: 0000-0002-9550-6287
Marcin Kalek: 0000-0002-1595-9818
Notes
The authors declare no conflict of interest.
ASSOCIATED CONTENT
Supporting Information:
Experimental procedures, compound characterization data, NMR spectra of compounds 2w and
3a–3ab, list of unsuccessful substrates, details of kinetic investigations, computational details,
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free-energy profile for the reaction in CHCl , calculated energies and energy corrections,
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optimized structures and Cartesian coordinates of stationary points (PDF).
ACKNOWLEDGMENT
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We acknowledge financial support from the National Science Centre, Poland
(2014/15/D/ST5/02579). Computer time was generously provided by the Interdisciplinary Centre
for Mathematical and Computational Modelling of the University of Warsaw (G75-0).
REFERENCES
1. (a) Moore, J. L.; Rovis, T. Lewis Base Catalysts 6: Carbene Catalysts. Top. Curr. Chem.
2010, 291, 77-144; (b) Bugaut, X.; Glorius, F. Organocatalytic Umpolung: N-heterocyclic
Carbenes and Beyond. Chem. Soc. Rev. 2012, 41, 3511-3522; (c) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Organocatalytic Reactions Enabled by N‑Heterocyclic
Carbenes. Chem. Rev. 2015, 115, 9307-9387; (d) Menon, R. S.; Biju, A. T.; Nair, V. Recent
Advances in N-heterocyclic Carbene (NHC)-Catalysed Benzoin Reactions. Beilstein J. Org.
Chem. 2016, 12, 444-461.
2. Biju, A. T.; Kuhl, N.; Glorius, F. Extending NHC-Catalysis: Coupling Aldehydes with
Unconventional Reaction Partners. Acc. Chem. Res. 2011, 44, 1182-1195.
3. (a) Zhdankin, V. V. Hypervalent iodine chemistry: preparation, structure, and synthetic
applications of polyvalent iodine compounds; Wiley: Chichester, 2013; (b) Top. Curr. Chem.,
Vol. 373; Wirth, T. Ed.; Springer: Switzerland, 2016; (c) Yoshimura, A.; Zhdankin, V. V.
Advances in Synthetic Applications of Hypervalent Iodine Compounds. Chem. Rev. 2016,
116, 3328-3435; (d) Hyatt, I. F. D.; Dave, L.; David, N.; Kaur, K.; Medard, M.; Mowdawalla,
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C. Hypervalent Iodine Reactions Utilized in Carbon–Carbon Bond Formations. Org. Biomol.
Chem. 2019, 17, 7822-7848.
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4. Yusubov, M. S.; Zhdankin, V. V. Hypervalent Iodine Reagents and Green Chemistry. Curr.
Org. Synth. 2012, 9, 247-272.
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5. Ghosh, M. K.; Rajkiewicz, A. A.; Kalek, M. Organocatalytic Group Transfer Reactions with
Hypervalent Iodine Reagents. Synthesis 2019, 51, 359-370.
6. (a) Toh, Q. Y.; McNally, A.; Vera, S.; Erdmann, N.; Gaunt, M. J. Organocatalytic C–H Bond
Arylation of Aldehydes to Bis-Heteroaryl Ketones. J. Am. Chem. Soc. 2013, 135, 3772-3775;
(b) Rajkiewicz, A. A.; Kalek, M. N-Heterocyclic Carbene-Catalyzed Olefination of Aldehydes
with Vinyliodonium Salts To Generate ,-Unsaturated Ketones. Org. Lett. 2018, 20, 1906-
1909; (c) Gelat, F.; Patra, A.; Pannecoucke, X.; Biju, A. T.; Poisson, T.; Besset, T. N-
Heterocyclic Carbene-Catalyzed Synthesis of -Trifluoromethyl Esters. Org. Lett. 2018, 20,
3897-3901; (d) Yang, W.; Ma, D.; Zhou, Y.; Dong, X.; Lin, Z.; Sun, J. NHC-Catalyzed
Electrophilic Trifluoromethylation: Efficient Synthesis of γ-Trifluoromethyl α,β-Unsaturated
Esters. Angew. Chem. Int. Ed. 2018, 57, 12097-12101.
7. (a) Fawcett, C. H.; Firn, R. D.; Spencer, D. M. Wyerone Increase in Leaves of Broad Bean
(Vicia faba L.) after Infection by Botrytis fabae. Physiol. Pl. Path. 1971, 1, 163-166; (b)
Kundu, N. G.; Das, B.; Spears, C. P.; Majumdar, A.; Kang, S. I. Synthesis and Biological
Activities of Novel 5-(2-Acylethynyl)uracils. J. Med. Chem. 1990, 33, 1975-1979; (c) Kundu,
N. G.; Mahanty, J. S.; Spears, C. P. Unusual Cytotoxicities of 5-(Acylethynyl)-1-(2-
hydroxyethoxy)methyluracils. Bioorg. Med. Chem. Lett. 1996, 6, 1497-1502; (d) Quesnelle,
C. A.; Gill, P.; Dodier, M.; St. Laurent, D.; Serrano-Wu, M.; Marinier, A.; Martel, A.;
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9
Mazzucco, C. E.; Stickle, T. M.; Barrett, J. F.; Vyas, D. M.; Balasubramanian, B. N. Sordaricin
Antifungal Agents. Bioorg. Med. Chem. Lett. 2003, 13, 519-524; (e) Kuklev, D. V.; Domb,
A. J.; Dembitsky, V. M. Bioactive Acetylenic Metabolites. Phytomedicine 2013, 20, 1145-
1159.
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8. Recent reviews: (a) Bagley, M. C.; Glover, C.; Merritt, E. A. The Bohlmann-Rahtz Pyridine
Synthesis: from Discovery to Applications. Synlett 2007, 2459-2482; (b) Arai, T.; Ikematsu,
Y.; Suemitsu, Y. Nickel-Catalyzed Multicomponent Coupling Reaction Using Ynones. Pure
Appl. Chem. 2010, 82, 1485-1490; (c) Sengee, M.; Sydnes, L. K. Specific Conjugate Addition
to α,β-Acetylenic Aetones. Pure Appl. Chem. 2011, 83, 587-596; (d) Fraile, A.; Parra, A.;
Tortosa, M.; Alemán, J. Organocatalytic Transformations of Alkynals, Alkynones,
Propriolates, and Related Electron-Deficient Alkynes. Tetrahedron 2014, 70, 9145-9173; (e)
Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E. Sequential Addition and Cyclization Processes
of Ynones and α,β-Ynoates Containing Proximate Nucleophiles. Synthesis 2014, 46, 687-721;
(f) Whittaker, R. E.; Dermenci, A.; Dong, G. Synthesis of Ynones and Recent Application in
Transition-Metal-Catalyzed Reactions. Synthesis 2016, 48, 161-183.
9. Selected examples: (a) Kel'i, A. V.; Gevorgyan, V. Efficient Synthesis of 2-Mono- and 2,5-
Disubstituted Furans via the CuI-Catalyzed Cycloisomerization of Alkynyl Ketones. J. Org.
Chem. 2002, 67, 95-98; (b) Silva, F.; Sawicki, M.; Gouverneur, V. Enantioselective
Organocatalytic Aldol Reaction of Ynones and Its Synthetic Applications. Org. Lett. 2006, 8,
5417-5419; (c) D'Souza, D. M.; Müller, T. J. J. Catalytic Alkynone Generation by Sonogashira
Reaction and Its Application in Three-Component Pyrimidine Synthesis. Nat. Protoc. 2008,
3, 1660-1665; (d) Willy, B.; Dallos, T.; Rominger, F.; Schönhaber, J.; Müller, T. J. J. Three-
Component Synthesis of Cryofluorescent 2,4-Disubstituted 3H-1,5-Benzodiazepines –
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Conformational Control of Emission Properties. Eur. J. Org. Chem. 2008, 4796-4805; (e)
Zhao, T.; Xu, B. Palladium-Catalyzed Tandem Amination Reaction for the Synthesis of 4-
Quinolones. Org. Lett. 2010, 12, 212-215; (f) Zora, M.; Kivrak, A. Synthesis of Pyrazoles via
CuI-Mediated Electrophilic Cyclizations of α,β-Alkynic Hydrazones. J. Org. Chem. 2011, 76,
9379-9390; (g) Zhou, J.; Zhang, G.-L.; Zou, J.-P.; Zhang, W. Synthesis of Phosphonylated
and Thiolated Indenones by Manganese(III)-Mediated Addition of Phosphorus- and Sulfur-
Centered Radicals to 1,3-Diarylpropynones. Eur. J. Org. Chem. 2011, 3412-3415; (h) Xu, B.-
H.; Kehr, G.; Fröhlich, R.; Wibbeling, B.; Schirmer, B.; Grimme, S.; Erker, G. Reaction of
Frustrated Lewis Pairs with Conjugated Ynones-Selective Hydrogenation of the Carbon–
Carbon Triple Bond. Angew. Chem. Int. Ed. 2011, 50, 7183-7186; (i) Khong, S.; Kwon, O.
One-Pot Phosphine-Catalyzed Syntheses of Quinolines. J. Org. Chem. 2012, 77, 8257-8267;
(j) Neumann, K. T.; Laursen, S. R.; Lindhardt, A. T.; Bang-Andersen, B.; Skrydstrup, T.
Palladium-Catalyzed Carbonylative Sonogashira Coupling of Aryl Bromides Using Near
Stoichiometric Carbon Monoxide. Org. Lett. 2014, 16, 2216-2219; (k) Peng, S.; Wang, Z.;
Zhang, L.; Zhang, X.; Huang, Y. Streamlined Asymmetric -Difunctionalization of Ynones.
Nat. Commun. 2018, 9, 375; (l) Li, J.; Yang, F.; Ma, Y.-T.; Ji, K. Gold(III)-Catalyzed
Intermolecular Oxidation-Cyclization of Ynones: Access to 4-Substituted Chroman-3-ones.
Adv. Synth. Catal. 2019, 361, 2148-2153.
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60
10. (a) Vong, B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E. A. Stereoselective Total Synthesis
of (−)-Borrelidin. Angew. Chem. Int. Ed. 2004, 43, 3947-3951; (b) Forsyth, C. J.; Xu, J.;
Nguyen, S. T.; Samdal, I. A.; Briggs, L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O.
Antibodies with Broad Specificity to Azaspiracids by Use of Synthetic Haptens. J. Am. Chem.
Soc. 2006, 128, 15114-15116; (c) Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Total Synthesis
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