Three-Component Reaction for the Synthesis of Highly Functionalized Propargyl Ethers

Article abstract of DOI:10.1002/chem.202001317

Multicomponent reactions provide efficient means to access molecular complexity. Herein, we report a copper-catalyzed three-component reaction of diazo compounds, alcohols and ethynyl benziodoxole (EBX) reagents for the synthesis of propargyl ethers. Extensive variations of the three partners of the reaction is possible, leading to highly functionalized and structurally diverse products under mild conditions. Alkynylation of a copper ylide intermediate is postulated as key step for this transformation.

Full text of DOI:10.1002/chem.202001317

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Accepted Article
Title: Three-Component Reaction for the Synthesis of Highly
Functionalized Propargyl Ethers
Authors: Guillaume Pisella, Alec Gagnebin, and Jerome Waser
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To be cited as: Chem. Eur. J. 10.1002/chem.202001317
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10.1002/chem.202001317
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Three-Component Reaction for the Synthesis of Highly
Functionalized Propargyl Ethers
Guillaume Pisella, Alec Gagnebin and Jérôme Waser*
partners in the three-component reaction, whereas the work of
Abstract: Multicomponent reactions provide efficient means to
access molecular complexity. Herein, we report a copper-catalyzed
three-component reaction of diazo compounds, alcohols and ethynyl
benziodoxole (EBX) reagents for the synthesis of propargyl ethers.
Extensive variations of the three partners of the reaction is possible,
leading to highly functionalized and structurally diverse products
under mild conditions. Alkynylation of a copper ylide intermediate is
postulated as key step for this transformation.
Szabo-and co-workers was limited to fluoride or trifluoromethyl as
one of the partners. Therefore, there is an urgent need for more
general three-component reactions of diazo compounds,
nucleophiles and hypervalent iodine reagents, allowing for
extensive variation of the three partners with diverse functional
groups in order to maximize the structural diversity of the products.
Herein, we report the copper-catalyzed three-component reaction
of diazo compounds, ethynylbenziodoxoles (EBXs) and alcohols,
which overcomes this limitation (Scheme 1C). The three
components of the reaction can be extensively varied, leading to
a broad range of important propargylic ether building blocks with
high structural diversity.[12] In particular, primary, secondary and
tertiary alcohols, as well as a broad range of functional groups
(including alkene, alkyne, fluoro, chloro, bromo, ether, ester,
ketone, carbamate, imide, cyano, boronic ester and heterocyclic
groups) were well tolerated, which would be difficult to achieve
using traditional etherification methods under strongly basic or
acidic conditions. The transformation can be performed using
simple copper salts as catalyst, and does not require the use of
one of the partners in large excess.
Multicomponent reactions are ideally suited for a fast entry into
molecular complexity.[1] It is therefore not surprising that classical
multicomponent reactions such as the Ugi or the Passerini
reactions have had a major impact on both synthetic and
medicinal chemistry.[2] Recently, diazo compounds have emerged
as ideal partners in multicomponent reactions, with or without the
help of transition metal catalysts.[3] In particular, transient ylide
intermediates generated from the insertion of protic nucleophiles
(alcohols, amines, thiols and aromatic compounds) into metal-
carbenes generated from diazo compounds have been
intercepted with various electrophiles (carbonyl compounds,
imines, Michael acceptors, azodicarboxylates, electrophilic
halogen sources,…) to simultaneously generate two new bonds
(Scheme 1A).[4] To further develop the use of this strategy in
multicomponent reactions, it is now important to extend the scope
of compatible nucleophiles/electrophiles for achieving a higher
molecular diversity.
In this context, hypervalent iodine reagents in general[5] and cyclic
derivatives in particular[6] have demonstrated their versatility for
the Umpolung of the reactivity of functional groups, giving access
to a broad range of non-classical electrophiles. However, their use
in multi-component reactions involving diazo compounds is not
yet well established. In the absence of a metal-catalyst, Murphy
and co-workers have first reported dihalogenation reactions.[7]
More recent examples involve acetoxyaminoalkylation[8] and
azidoaminoalkylation.[9] The first transformations involving metal
carbene intermediates were reported independently by our
group[10] and Szabo and co-workers.[11] We developed a copper-
catalyzed oxy-alkynylation using ethynylbenziodoxolone (EBX)
reagents, whereas Szabo and co-workers successfully
implemented a rhodium-catalyzed oxy-fluoro/trifluoromethylation
with benziodoxole reagents (Scheme 1B). These two
transformations constitute efficient multi-bond forming reactions
combining hypervalent iodine reagents and diazo compounds and
most probably proceed via ylide intermediates generated from
metal carbenes. Nevertheless, they remain strongly limited in the
diversity of structures accessible: our work allowed exclusively
the introduction of iodo-benzoate derivatives as nucleophilic
Scheme 1. Multi-component reactions of diazo compounds involving ylide
intermediates and new disconnections enabled by hypervalent iodine reagents.
We first investigated the three-component reaction of TIPS-EBX
(1), ethyl diazoacetate (3a) and ethanol (4a) (Table 1). In our
previous work on the two-component process, diimine an
bisoxazoline ligands on the copper catalyst led to best results.[10]
[*]
G. Pisella, A. Gagnebin, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique
Fédérale de Lausanne, EPFL, SB ISIC LCSO, BCH 4306
1015 Lausanne (Switzerland)
Using Cu(MeCN)4BF4 as catalyst, diimine
8 or tert-butyl
bisoxazoline (tBu-BOX (9)) as ligands and ethanol as solvent, the
desired product 5a could be obtained in 50% and 63% yield,
respectively (entries 1 and 2). However, despite using ethanol as
solvent, a significant amount (30-32%) of the two-component
product 7a was still obtained. Furthermore, when only 10
Email: jerome.waser@epfl.ch
Homepage : http://lcso.epfl.ch/
Supporting information for this article is given via a link at the end of
the document.
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equivalents of ethanol were used, the yield of 6a dropped to 22%
(entry 3), showing that these conditions would not be useful to
develop a general three-component reaction.
result was obtained when only 10 equivalents of ethanol (4a) were
used (entry 6). The yield of 5a decreased to 80% and 53%
respectively with 4 and 2 equivalent of ethanol (4a) (entries 7 and
8). Using a higher catalyst loading, 5a could be still obtained in
62% with only 2 equivalents of ethanol (4a) (entry 9). At this point,
different copper salts were examined. Complexes with non-
coordinating counterions performed better (entries 10-12) than
copper halogenides (entries 13 and 14) or thiophenecarboxylate
Table 1. Optimization of the three-component reaction
-
(TC, entry 15).[14] The best result was obtained with PF6 as
counterion, giving 5a in 74% yield, with only 18% of O-H insertion
product 6a formed (entry 10). We then wondered if basic condition
may slow down the formation of 6a. However, a lower yield was
observed in presence of sodium hydrogen carbonate (entry 16)
and the reaction completely stopped in presence of other bases
such as carbonate, acetate or hydroxide salts (result not shown,
see Supporting Information). For cheap alcohols a larger excess
is reasonable, and 5a could be obtained in 94% yield with 4
equivalents of ethanol (4a) (entry 17). Unfortunately, the
formation of the alcohol insertion side product cannot be fully
suppressed and it was observed for most transformations
described in this study. Nevertheless, 5a was still formed in 37%
yield when EBX 2a, diazo compound 3a and ethanol (4a) were
used in equimolar amounts (entry 18).
Equiv
EtOH (4a)
Yield 5a/6a/7a
Entry EBX
Catalyst/Ligand(additive)
[%][a]
1
2
1
as solvent
4 mol% Cu(MeCN)4BF4/8
4 mol% Cu(MeCN)4BF4/9
4 mol% Cu(MeCN)4BF4/9
4 mol% Cu(MeCN)4BF4/9
4 mol% Cu(MeCN)4BF4
4 mol% Cu(MeCN)4BF4
4 mol% Cu(MeCN)4BF4
4 mol% Cu(MeCN)4BF4
10 mol% Cu(MeCN)4BF4
10 mol% Cu(MeCN)4PF6
10 mol% CuOTf-toluene
10 mol% CuOTf2
50/n.d./32
63/n.d./30
22/n.d./52
62/n.d./-
100/48/-
100/47/-
80/49/-
1
as solvent
3
1
10
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
as solvent
5
as solvent
With optimized conditions in hand, we started to investigate the
scope of the three-component reaction. First, we employed a
variety of alcohols with EBX 2a and ethyl diazo acetate 3a as the
two other partners (Scheme 2A). On 0.3 mmol scale, propargylic
ether 5a was isolated in 93% yield.[15] Benzyl alcohol provided the
6
10
4
2
2
2
2
2
2
2
2
2
7
corresponding product 5b in
a slightly diminished yield.
8
53/51/-
Introducing a bromo substituent in the para position gave 5c in
73% yield. A heteroaromatic ring was also tolerated providing
product 5d from furfuryl alcohol in 63% yield. We also examined
secondary alcohols. Cyclohexanol was well tolerated and
furnished the corresponding product 5e in 90% yield. We were
pleased to see that the more electron-poor 1,3-difluoro-2-
propanol gave the desired product 5f in good yield. Sterically
hindered tert-butanol still reacted remarkably well to give the
corresponding three-component product 5g in 69% yield. Such
9
62/38/-
10
11
12
13
14
15
16[b]
74/18/-
60/33/-
47/11/-
tert-butyl ethers represent
a synthetic challenge and are
10 mol% CuBr
16/24/-
classically accessed by strong acid-catalyzed addition of
isobutene to alcohols.[16] In the case of an allyl substituent, no
reaction was observed at room temperature, but at 40 °C 5h was
obtained in moderate yield. A similar temperature was needed to
access the bis-propargyl ether derivative 5i in 42% yield. These
results may indicate a coordination of  bonds to the cationic
copper catalyst.[17] Dissociation would be needed to allow the
diazo compound to coordinate and form the metal carbene,
requiring a higher reaction temperature. We then examined other
O-nucleophiles than alcohols. Water was a suitable partner and
gave the functionalized propargylic alcohol 5j in 33% yield.
However, only trace amount of the desired product was observed
with acetic acid, while a complex reaction mixture was obtained
with phenol.
Next, we turned our attention to more complex alcohol-
containing natural products (Scheme 2B). We were pleased to
see that several terpenes such as (-)-menthol and (-)-borneol
were easily functionalized and gave the corresponding three-
component products 5k and 5l in very good yields. (+)-Cedrol,
possessing a tertiary alcohol, was converted to 5m in 60% yield.
Geraniol was a successful nucleophile partner, providing 5n in
57% yield, despite the presence of two potentially coordinating
double bonds. Other types of natural products and biomolecules
were then engaged in the three-component reaction. Notably,
testosterone, protected galactose, protected thymidine and
protected serine all furnished the desired propargylic ether (5o,
5p, 5q and 5r) in moderate yields showing the breadth of the
scope for alcohols.
10 mol% CuCl2
30/17/-
10 mol% CuTC
10/40/-
10 mol% Cu(MeCN)4BF4/NaHCO3
50/36/-
17
2a
2a
4
1
10 mol% Cu(MeCN)4PF6
10 mol% Cu(MeCN)4PF6
94/11/-
37/17/-
18[c]
[a]Determined by 1H NMR analysis of the crude reaction mixture. The
hypervalent iodine reagent 1/2a and the diazo compound 3a are used as limiting
reagents to calculate the yield of 5a/7a and 6a respectively. Reactions were run
on a 0.08 mmol scale. n.d. = not determined. [b]With 2 equivalents of sodium
bicarbonate. [c]One equivalent of diazo compound 3a was used.
We therefore decided to modify the hypervalent iodine reagent.
We turned to hexafluoroisopropanol derivative 2a,[13] expecting a
lower nucleophilicity of the oxygen atom. Indeed, in this case only
the three-component product 5a was obtained in 62% yield (entry
4). An enhanced reactivity was observed in absence of the BOX
ligand, resulting in quantitative formation of product 5a together
with O-H insertion product 6a (entry 5). Gratifyingly, the same
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versatile functional groups were tolerated on the alcohols,
including a bromide (5t), a ketone (5y), protected hydroxy (5u and
5aa) or a boronic ester (5ac) groups. Several carbocyclic or
heterocyclic motifs important for medicinal chemistry such as
cyclopropyl (5s), cyclobutyl (5z), azetidinyl (5ab), or adamantyl
(5v) were also tolerated on the alcohol. In general, the reactions
occurred smoothly, affording products in good yields. By-products
and a diminished yield were obtained for the synthesis of 5s,
cyclopropyl alcohols being prone to ring-opening in presence of
Cu(I) catalyst.[18] The multiple unsaturations of substrate 5w could
explain why only partial conversion of the EBX reagent was
observed, resulting in a moderate yield.
Scheme 3. Substrate scope with simultaneous variation of the three
components. Unless otherwise noted, the reaction conditions are as follows: 2a-
h (0.3 mmol), 3a-k solution in 1.0 mL DCM (0.6 mmol), 4s-4ac (1.2 mmol), DCM
(2.0 mL). All yields refer to the isolated products. [a]Reaction conducted at 40 °C.
Scheme 2. Copper(I)-catalyzed three-component reaction of alcohols with ethyl
diazoacetate and TIPS-EBX. Unless otherwise noted, the reaction conditions
are as follows: 2a (0.3 mmol), 3a solution in 1.0 mL DCM (0.6 mmol), 4a-r (1.2
mmol), DCM (2.0 mL). All yields refer to the isolated products. When applicable,
ca. 1:1 d.r. was obtained. [a]Reaction conducted at 40 °C. [b]10.0 equiv. of water
was used. [c]3.0 equiv. of alcohol was used.
Next, we used disubstituted diazo compounds (Scheme 4A).
Diazo compounds bearing a methyl or a phenyl substituent
furnished 5ad and 5ae in 43% and 57% yield respectively, without
the need to reoptimize the reaction conditions. A cyclic diazo
compound provided 5af in moderate yield. Finally, we
investigated a substrate having a pendant hydroxy group for
intramolecular nucleophile attack. The desired tetrahydropyran
5ag was formed, albeit in low yield.
The high efficiency of the three-component reaction with
trifluoromethyl-substituted diazo compounds is especially
interesting, as organofluorine compounds are of significant
importance in the pharmaceutical, agrochemical and materials
industry.[19] For example, Efavirenz (10), which contains a CF3-
propargyl motif, is one of the most frequently prescribed
antiretroviral drug used in HIV treatment. We decided to apply our
methodology to access the Lonza intermediate 5ah, a direct
precursor to Efavirenz (10) (Scheme 4B).[20] We envisaged the
use of tert-butyl carbamate as nucleophile, anticipating that O-
attack followed by loss of the tert-butyl group could generate the
desired NH2-carbamate. In this case, the number of equivalents
of reagents, as well as the catalyst loading, could be reduced as
The main strength of multi-component reactions resides in
the structural diversity of accessible compounds. Therefore, we
decided to simultaneously vary each of the three components of
the reaction to further investigate the flexibility of our methodology,
(Scheme 3). We were pleased to see that diazo esters bearing
various substituents, such as alkyl (5s and 5t), aryl (5u), bulky aryl
(5v) or heteroaromatic (5w) were tolerated. Diazo amides were
not suitable reagents, furnishing only traces of the desired 3-
component products (not shown). Other diazo compounds
bearing diverse versatile functionalities (nitrile (5x), phosphonate
(5y), sulfonate (5z), and perfluorinated alkyls (5aa, 5ab and 5ac))
were successfully applied. The scope of EBX partners was also
broad, including alkyl chains (5s, 5t, 5u and 5z), alkenyl (5w) and
aromatic substituents (5y and 5aa) that contained several
functional groups like halide (5s and 5y) or a silyl ether (5z) and
carbocycles, such as a cyclopropane (5u). In addition, further
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10.1002/chem.202001317
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there was no competitive O-H insertion pathway. The desired
molecule 5ah was obtained in good yield without the formation of
products from N-H insertion.[21] Our methodology also gave
access to structurally diverse analogues. The poly-
trifluoromethylated compound 5ai, bearing a thiophene on the
alkyne, was synthesized in good yield, as well as ether 5aj
bearing a nitrile group.[22] Finally, the carbamate derivative 5ak
containing a protected amine and an aryl bromide was obtained
in 31% yield.
equiv.) were mixed together in CD2Cl2, no ligand exchange was
observed (See Figure S6 in Supporting Information). These NMR
studies indicated an interaction between the Cu catalyst and the
EBX reagent 2a, probably through the alkyne, but no complete
reaction, making oxidative addition of the reagent onto copper to
form a Cu(III) intermediate a less probable pathway.[23] We then
attempted the trapping of a potential Cu-carbene intermediate
through a cyclopropanation reaction using one equivalent of ethyl
diazoacetate (3a) and 4 equivalents of ethanol (4a) and styrene
(Eq. (3)). Cylcopropane 12 was obtained in 21% NMR yield, and
the three-component product 5a was formed in 62% yield. Aside
from supporting the existence of a metal carbene, this competitive
experiment, also shows that attack of ethanol to form a putative
oxonium ylide is faster than cyclopropanation. Finally, we re-
examined the reaction of 2a, 3a and benzyl alcohol (4b) in
presence of chiral ligand 9 under the optimized reaction
conditions. The product 5a was obtained in poor yield as a
racemic compound (Eq. (4)). This may indicate that ligand
decomplexation is required for the reaction to proceed, making
the development of an enantioselective method highly
challenging.
Scheme 4. Substrate scope with disubstituted diazo compounds and Efavirenz
analogues. Unless otherwise noted, the reaction conditions are as follows: 2a-
k (0.3 mmol), 3l-s solution in 1.0 mL DCM (0.6 mmol), 4a-4af (1.2 mmol), DCM
(2.0 mL). All yields refer to the isolated products. [a]The reaction was conducted
at RT. [b]No alcohol was used. [c]BocNH2 4ad (1.3 equiv), 3p-s (1.3 equiv) and
Cu(CH3CN)4PF6 (5 mol%) were used. [d]Yield determined by 19F NMR
spectroscopy.
To gain insights into the mechanism, several control experiments
were carried out (Scheme 5A). First, when ethyl diazoacetate (3a)
was reacted with ethanol (4a) in presence of 10 mol% of
1
Cu(CH3CN)4PF6, we observed the formation of 6a by H NMR
spectroscopy analysis of the reaction mixture (Eq. (1)). However,
no three-component product 5a was observed after the
subsequent addition of TIPS-EBX (2a) to this solution. This
indicates that 6a is not an intermediate in the catalytic cycle.
When mixing reagent 2a and diazo 3a in the presence of the
copper catalyst, rapid evolution of nitrogen occurred and we
mainly observed the formation of diethyl fumarate/maleate (11)
(Eq. (2)).[3d] Other products resulting from a minor decomposition
(ca. 10%) of the hypervalent iodine reagent 2a could not be
Scheme 5. Mechanistic studies and proposed catalytic cycle. [a]Yields
determined by 1H NMR analysis of the crude reaction mixture.
1
identified. A H NMR titration experiment was then carried out
using Cu(CH3CN)4PF6 in combination with EBX 2a. Progressive
shifts of the aromatic 1H were observed upon addition of the
copper salt, with a significant diminution after one equivalent (See
Figure S3 in Supporting Information). A 13C NMR spectrum of an
equimolar mixture of Cu(CH3CN)4PF6 and 2a in CD2Cl2 showed
major changes in the 13C-alkyne signals, while other peaks
remained nearly constant (See Figure S5 in Supporting
Information). When ethanol (4 equiv.) and Cu(CH3CN)4PF6 (1
Based on the results of our control experiments and the
relevant literature on metal-ylide based multicomponent
reactions,[3] our proposed catalytic cycle is presented in Scheme
5B. Starting with Cu(I) catalyst I, reaction with diazo compound 3
and the hypervalent iodine reagents generates electrophilic
copper-carbene II with alkyne-bound EBX. At this stage, it is
difficult to establish if coordination of the hypervalent iodine
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reagents is occurring before or after carbene formation. From II,
two pathways are possible: With carboxylate reagent 1,
intramolecular oxygen attack directly followed by alkynylation
leads to two-component product 7; With bis-trifluoromethyl
reagents 2, the oxygen atom of the benziodoxole is not
nucleophilic enough, and attack of the external alcohol 4 forms
oxonium-ylide intermediate III. Intramolecular alkynylation by EBX
reagent 2 with simultaneous deprotonation then generates the 3-
component product 5 and iodide 13, releasing the copper catalyst.
Undesired 1,2-H shift on the transient ylide III produces the O-H
insertion product 6. Further studies will be needed to establish the
mechanism of the alkynylation step.
Szabó, Org. Lett. 2017, 19, 4548; r) M. Lübcke, D. Bezhan, K. J. Szabó,
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In conclusion, we have reported a general copper-catalyzed
three-component reactions of alcohols, diazo compounds and
alkynyl benziodoxole reagents. The reaction can be done under
mild conditions and each of the three partners can be extensively
varied, leading to maximal structural diversity. Preliminary
[8]
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followed by electrophilic alkynylation. Future work in our
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reaction mechanism, the development of an enantioselective
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Acknowledgements
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We thank the Swiss National Science Foundation (Grant No.
200021_165788) and EPFL for financial support. We thank Dr R.
Scopelliti and Dr F. F. Tirani from ISIC at EPFL for X-ray analysis.
[14] No product 5a was obtained when using CuI, CuCN,
Cu(II)trifluoroacetylycetonate or Cu(OAc)2 as catalyst.
Keywords: multi-component reactions (MCR); copper catalysis;
molecular complexity; hypervalent iodine reagents; carbenes.
[15] On scope scale, better results were obtained when diazo compound 3
was added slowly as a solution in CH2Cl2 (0.6 M, addition rate 1 mL/h).
[16] H. C. Beyerman, G. J. Heiszwolf, Recl. Trav. Chim. Pays-Bas 1965, 84,
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This article is protected by copyright. All rights reserved.

10.1002/chem.202001317
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Guillaume Pisella, Alec Gagnebin and
Jerome Waser*
Page No. – Page No.
Three-Component Reaction for the
Synthesis of Highly Functionalized
Propargyl Ethers
Power 3: A copper-catalyzed three-component reaction of hypervalent iodine
reagents, diazo compounds and alcohols has been developed. The
transformation gives access to functionalized propargylic ethers with high
structural diversity, as variation of the three partners with numerous functional
groups was tolerated. The reaction is speculated to proceed via a copper
oxonium ylide intermediate.
This article is protected by copyright. All rights reserved.