Synthesis of 2-Alkynoates by Palladium(II)-Catalyzed Oxidative Carbonylation of Terminal Alkynes and Alcohols

Article abstract of DOI:10.1002/chem.201602558

A homogeneous Pd^IIcatalyst, utilizing a simple and inexpensive amine ligand (TMEDA), allows 2-alkynoates to be prepared in high yields by an oxidative carbonylation of terminal alkynes and alcohols. The catalyst system overcomes many of the limitations of previous palladium carbonylation catalysts. It has an increased substrate scope, avoids large excesses of alcohol substrate and uses a desirable solvent. The catalyst employs oxygen as the terminal oxidant and can be operated under safer gas mixtures.

Full text of DOI:10.1002/chem.201602558

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Accepted Article
Title: Synthesis of 2-Alkynoates via Pd(II)-Catalyzed Oxidative Carbonylation of Ter-
minal Alkynes and Alcohols
Authors: Qun Cao; Nicola Louise Hughes; Mark James Muldoon
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Synthesis of 2-Alkynoates via Pd(II)-Catalyzed Oxidative
Carbonylation of Terminal Alkynes and Alcohols
Qun Cao, N. Louise Hughes and Mark J. Muldoon*
Abstract: A homogeneous Pd(II) catalyst utilizing a simple and
inexpensive amine ligand (TMEDA) allows 2-alkynoates to be
prepared in high yields via an oxidative carbonylation of terminal
alkynes and alcohols. The catalyst system overcomes many of the
limitations of previous palladium carbonylation catalysts. It has an
increased substrate scope, avoids large excesses of substrate and
uses a desirable solvent. The catalyst employs oxygen as the
terminal oxidant and this can be operated under safer gas mixtures.
used as the solvent and when this is not the case it is used in
very large excess.
More recently, an aerobic system which used
a
heterogeneous palladium catalyst (Pd on carbon) was
reported. 14 High yields of the desired 2-alkynoate could be
produced when 1,4-dioxane was used as a solvent (THF was
the next best solvent). A number of alkynes were shown to be
suitable but only primary alcohols acted as suitable nucelophiles.
An attractive feature of this system is the ability to recycle the
catalyst, however the inability to oxidize secondary alcohols and
the use of 1,4-dioxane as the solvent are significant drawbacks.
2-Alkynoates (alkynoate esters) are incredibly valuable building
blocks for organic synthesis as they can be transformed into a
diverse range of other desirable products.1 Unfortunately the
synthesis of 2-alkynoates often has a number of drawbacks.
There are a number of synthetic methods for preparing these
esters. For example, lithiated alkynes can be reacted with an
alkyl chloroformate, 2 , 3 and alkynyl carboxylic acids can be
esterified using carbodiimide coupling reagents such as DCC4
and EDCI.5 Such methods utilize stoichiometric reagents and
also have substrate limitations. 2-Alkynoates can be prepared
catalytically with alkynes, CO2 and alkyl halides. 6 Whilst the use
of CO2 is desirable, employing alkyl halides can have
disadvantages and there has been a limited substrate scope
demonstrated to-date using this route. An alternative is to carry
out a catalytic oxidative carbonylation of terminal alkynes and
alcohols. Replacing alkyl halides with alcohols is preferable as a
wide range of alcohols are commercially available and are
normally inexpensive. Carbon monoxide is a widely available,
sustainable and inexpensive carbonyl source. Palladium
catalyzed carbonylation is well established, however oxidative
7
carbonylations have been less developed to-date.
This
underdevelopment is apparent in the case of 2-alkynoates.
Oxidative carbonylation of alkynes with alcohols using Pd(II)
catalysts dates back some time, however reactions do not
always produce 2-alkynoates and in some cases dicarbonylation
is prevalent and a range of products can be produced.8 In terms
of catalyst systems that can prepare 2-alkynoates, there are only
a
few
reports
to-date
using
homogeneous
Pd(II)
Figure 1. Examples of methods for preparation of 2-alkyonates
catalysts,9, 10,11,12,13 and there are some significant limitations. In
.
these examples, the catalyst loadings are high and there is only
one example of O2 being used to directly re-oxidize the
Our aim was to try and address the limitations of previous
catalyst systems and develop a more efficient and widely
applicable method. We are interested in exploiting ligands to
improve the performance of Pd(II) catalyzed oxidation reactions,
and developing systems which use sustainable oxidants such as
O2 and H2O2. 15 Ligand modulation has been successfully
developed for other Pd(II) catalyzed reactions,16 but as Beller
and co-workers highlighted in their recent review,7c this is an
area that needs to be addressed in the field of oxidative
carbonylations. Another aim was to demonstrate that these
aerobic systems could be operated under safer oxygen
concentrations and with a safer solvent.
catalyst.13
A
limited number of substrates have been
demonstrated so far and simple alcohols (such as methanol)
have been the main focus. Furthermore, the alcohol is generally
[a] Mr Q. Cao, Ms N. L. Hughes and Dr. M.J. Muldoon
School of Chemistry and Chemical Engineering
Queen’s University Belfast, Stranmillis Road,
Belfast, BT9 5AG, Northern Ireland
Web: www.markmuldoon.com
E-mail: m.j.muldoon@qub.ac.uk
Supporting information for this article is available via www…………

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We screened a wide variety of ligands and other reaction
conditions and these are detailed in full in the Supplemental
Information (SI). It was found that adding tetrabutylammonium
iodide (TBAI) was essential for good performance, an additive
previously employed in these reactions.14 In terms of solvents,
we were pleased to find that ethyl acetate was the best solvent
for these reactions. Ethyl acetate is a solvent which is a
“recommended” choice by pharmaceutical companies, 17 unlike
solvents such as DMF or 1,4-dioxane and THF which have
previously been used for these reactions. DMF and 1,4-dioxane
are classed as “hazardous” and are to be avoided, while THF is
“problematic”.17 Furthermore, aerobic reactions in ethereal
solvents such 1,4-dioxane and THF are particularly dangerous
due to their propensity to form potentially explosive peroxides. It
is possible that peroxide formation in 1,4-dioxane plays a role in
the catalysis, as this solvent has not only been used for
oxidative synthesis of 2-alkyonates, but it has also been the
solvent of choice for oxidative aminocarbonylation to synthesize
2-ynamides.18 There are examples of other palladium oxidation
catalysis where in situ formation of peroxides in THF19 or 1,4-
dioxane20 are responsible for the reactivity. One would assume
that the dangers of peroxide forming solvents would severely
limit the use of these catalyst systems on a larger scale.
amine. Interestingly, the ethylene spacer was very important
and having a methylene (TMDAM), propylene (TMPDA) or
butylene (TMBDA) spacer did not result in high selectivity to the
desired product.
We utilized Pd(OAc)2 as the palladium source and as
shown in Table 2, found that the counter ion was very important.
Successful catalysis was only obtained with alkyl carboxylate
anions and there are a few possible reasons for this. Acetate
(and similar carboxylate anions) are known to play a key role in
C-H activation reactions21 and acetate effects have also been
shown for Pd(II) catalyzed hydration and dimerization reactions
of terminal alkynes. 22 Although some of the homogeneous
systems that were previously reported used PdCl2 and PdBr2
salts, these methods also added NaOAc to the reaction.9,10
However, when alcohols are replaced with amines in these
oxidative carbonylation reactions, to produce 2-ynamides, there
is not a need for a source of acetate.18 Therefore it is possible
that the need for a carboxylate anion is related to its ability to
deprotonate the Pd(II) coordinated alcohol. Previous work on
aerobic Pd(II) catalyzed oxidation of alcohols has found that
acetate is often key in this regard.23
Table 2. Influence of Pd(II) salts on catalytic performance
We screened a range of ligands and found that ligands
had a significant effect on substrate conversion and selectivity to
the desired 2-alkynoate. Table 1 shows a few examples and
further details are in the SI.
Table 1. Some examples of ligand effects
In terms of gas compositions, on a small scale we can
manage the dangers of using pressurized O2 or air in our
laboratory, and although we used such gas mixtures in our
optimization experiments (see SI), we wanted to demonstrate
that reactions could be carried out under safer conditions.
Carbon monoxide is a flammable gas and pure CO:O2 mixtures
are within the explosion limits as the lower flammability limit
(LFL) of carbon monoxide in air is 11.5 vol% at 100 ºC.24
Additionally, we also need to take into account that we are using
organic solvents and those have their own flammability limits, so
it is important when using batch conditions to try and use limiting
oxygen concentrations (LOC). The LOC of ethyl acetate at
100 ºC is 9.4 vol% O2 at a pressure of 1 bara and 9.9 vol% O2 at
a pressure of 20 bara. 25 Therefore we carried out our substrate
To-date the only example of using O2 directly with a Pd(II)
catalyst, used PPh3 as a ligand.13 However, phosphine ligands
are not ideal candidates for oxidation reactions and it can be
seen from our screening studies that other ligands delivered
superior performance. The best performance overall, in terms of
rate and selectivity was
obtained with
N,N,N’,N’-
tetramethylethylenediamine (TMEDA) (e.g. Entry 6 in Table 1).
After optimization, we found that a ratio of 10:1 (TMEDA:Pd)
was optimal. The performance of TMEDA was very pleasing due
to the fact that this is a readily available and very inexpensive

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COMMUNICATION
scope studies using 5 bar of CO with 35 bar of an O2:N2 (8:92)
gas mixture. By using an O2:N2 (8:92) gas mixture we should not
only be below the LOC of the solvent but also the LFL of CO. A
lower catalyst loading could be employed with 35 bar of air (see
SI for details), but we wanted to demonstrate the use of a gas
mixture that should be safe with regards to the solvent and CO.
demonstrated that the corresponding alkynoates could be
produced with the chirality maintained. Previously, chiral 2-
alkynoates have been used for Pauson-Khand reactions.4 In this
case, the 2-alkynoates were prepared by more traditional
methods, using alkynyl carboxylic acid derivatives and in a
number of cases these methods were unable to make the
desired 2-alkyonate.
Figures 2-4 demonstrate that we could produce
a
significant number of 2-alkynoates, many of which in excellent
yields. We examined a number of different primary alcohols
using phenylacetylene as the alkyne (Fig 2) and a number of
alkynes using benzyl alcohol as the nucleophile (Fig 3). In
previous reports, a large excess of alcohol is normally required,
but in the case of primary alcohols we could employ equimolar
quantities of alkyne and alcohol. As shown in Figure 2, we could
utilize both activated and unactivated alcohols. Substrates with
electron withdrawing or donating substituents proceeded readily.
Heteroatoms were tolerated, although
a lower yield was
obtained with the pyridine substrate (11). Benzyl alcohols
bearing chloro and bromo substituents (6 and 7) worked well, as
did an aliphatic substrate bearing a terminal olefin (16). Such
products have potential to be further functionalized at a later
stage. Interestingly, the same substituents had a differing effect
on the alkyne and the alcohol. For example, compare 3 and 18
and 7 and 23.
Figure 3. Synthesis of 2-alkynoates with various alkynes
Figure 2. Synthesis of 2-alkynoates with various primary alcohols
Secondary alcohols are more challenging substrates which
is demonstrated by the fact that there are just a few examples in
the literature, which are restricted to simple substrates such as
2-propanol. We found that we could utilize secondary alcohols
with only a slight change to our method, employing slightly
higher catalyst loading (3 mol% Pd(OAc)2) and two equivalents
of the alcohol (Figure 4). In the case of chiral alcohols we
Figure 4. Synthesis of 2-alkynoates with secondary alcohols

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Chemistry - A European Journal
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COMMUNICATION
Qun Cao, N. Louise Hughes and Mark J.
Muldoon*
Page No. – Page No.
Synthesis of 2-Alkynoates via Pd(II)-
Catalyzed Oxidative Carbonylation of
Terminal Alkynes and Alcohols