Carboxyboronate as a Versatile In Situ CO Surrogate in Palladium-Catalyzed Carbonylative Transformations

Article abstract of DOI:10.1002/anie.202010211

The application of carboxy-MIDA-boronate (MIDA=N-methyliminodiacetic acid) as an in situ CO surrogate for various palladium-catalyzed transformations is described. Carboxy-MIDA-boronate was previously shown to be a bench-stable boron-containing building block for the synthesis of borylated heterocycles. The present study demonstrates that, in addition to its utility as a precursor to heterocycle synthesis, carboxy-MIDA-boronate is an excellent in situ CO surrogate that is tolerant of reactive functionalities such as amines, alcohols, and carbon-based nucleophiles. Its wide functional-group compatibility is highlighted in the palladium-catalyzed aminocarbonylation, alkoxycarbonylation, carbonylative Sonogashira coupling, and carbonylative Suzuki–Miyaura coupling of aryl halides. A variety of amides, esters, (hetero)aromatic ynones, and bis(hetero)aryl ketones were synthesized in good-to-excellent yields in a one-pot fashion.

Full text of DOI:10.1002/anie.202010211

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Carboxyboronate as a Versatile in situ CO surrogate in
Palladium-Catalyzed Carbonylative Transformations
Authors: Andrei K. Yudin, Chieh-Hung Tien, Alina Trofimova,
Aleksandra Holownia, Branden S. Kwak, and Reed T. Larson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010211
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10.1002/anie.202010211
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RESEARCH ARTICLE
Carboxyboronate as a Versatile in situ CO surrogate in Palladium-
Catalyzed Carbonylative Transformations
Chieh-Hung Tien,[a] Alina Trofimova,[a] Aleksandra Holownia,[a] Branden S. Kwak,[a] Reed T. Larson,[b]
and Andrei K. Yudin*,[a]
[a]
[b]
C.-H. Tien, A. Trofimova, A. Holownia, B. S. Kwak, A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: ayudin@chem.utoronto.ca
R. T. Larson
Process Research & Development
Merck & Co., Inc., Rahway, NJ 07065 (USA)
Supporting information for this article is given via a link at the end of the document.
Abstract: The application of carboxy-MIDA-boronate as an in situ CO
surrogate for various palladium-catalyzed transformations is
described. Carboxy-MIDA-boronate was previously shown to be a
bench-stable boron-containing building block for the synthesis of
borylated heterocycles. The present study demonstrates that, in
addition to its utility as a precursor to heterocycle synthesis, carboxy-
MIDA-boronate is an excellent in situ CO surrogate that is tolerant of
reactive functionalities such as amines, alcohols, and carbon-based
nucleophiles. Its wide functional group compatibility is highlighted in
the palladium-catalyzed aminocarbonylation, alkoxycarbonylation,
carbonylative Sonogashira coupling, and carbonylative Suzuki-
Miyaura coupling of aryl halides. A variety of amides, esters,
(hetero)aromatic ynones, and bis(hetero)aryl ketones were
synthesized in good to excellent yields in a one-pot fashion.
catalyzed carbonylative cross-coupling using CO gas has
experienced tremendous growth.6 However, since CO gas is
odorless and highly toxic, pressurized tanks and special
equipment such as autoclaves and CO detectors are required to
ensure safe handling techniques. To circumvent the use of
gaseous CO, research efforts have been focused on molecules
that could stoichiometrically release CO for carbonylative
transformations via either an ex situ, or in situ approach.8
Activated formyl derivatives,9 metal carbonyls,10 and acid
chlorides11 have been investigated and employed as CO
surrogates for various carbonylative transformations (Scheme
1).8 A few of the major drawbacks to the CO surrogates reported
thus far are their high toxicity and volatility,12 and functional group
incompatibility, most notably towards nucleophiles such as
amines and alcohols.13 Furthermore, chemical activators such as
Ac2O,9a,b,h,I,k alkaline base,14 or even Pd catalysts11 are often
required to ensure the facile generation of CO.8 As such, when
applied as an in situ CO source, many CO surrogates are limited
to transformations that are not affected by these reactive
functional groups and activators.8 To circumvent this challenge,
Skrydstrup11 and Wu15 developed COware and In-Ex tube,
respectively, that effectively separates the CO generation process
and the main carbonylation process in different chambers that are
connected via the headspace.16 Although the two-chamber
approach circumvents the incompatibility issues described thus
far, it requires the use of specialized two-chamber glassware and
sophisticated experimental setups. The Wu group reported
benzene-1,3,5-triyl triformate (TFBen) as a suitable in situ CO
surrogate for metal-catalyzed carbonylations.17 Although
examples have been shown to work using the in situ approach,17a-
Introduction
The carbonyl motif is one of the most versatile synthetic
handles in organic synthesis.1 The development of methodologies
that enable the installation of the C=O functionality into organic
molecules has been of significant interest.2 Typical strategies
include the reduction of carboxy-derivatives,3 oxidation of
unsaturated functional groups or alcohols,4 acylation of
nucleophiles,5 and transition-metal catalyzed carbonylations.6
Since the original report by Heck and co-workers,7 the area of Pd-
d
several cases required the use of two-chamber systems to
achieve optimal conversion.17e-h A general in situ CO surrogate
that is compatible with a wide range of functional groups is still
underexplored.
Recently, our lab reported the synthesis of carboxy-MIDA-
boronate, 1 (Scheme 2).18 We demonstrated its utility as a
versatile C1-building block in the synthesis of various oxycarbo-,
carbamoyl-, and thiocarboboronate derivatives. We further
demonstrated their ability to participate in condensation-driven
transformations to afford novel borylated heterocycles that were
previously inaccessible via other methods. During our
investigations, we discovered that upon heating, 1 was capable of
Scheme 1. Decarbonylation of [a] activated formic acid derivatives,
[b] metal carbonyls, [c] acid chlorides, and [d] carboxy-MIDA-
boronate.
1
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10.1002/anie.202010211
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RESEARCH ARTICLE
releasing CO, which was further utilized in an example of Pd-
catalyzed aminocarbonylation of an aryl iodide using a two-
chamber approach. The by-product of CO release of 1 is hydroxy-
MIDA-boronate, 2, which is insoluble in non-polar organic
solvents. Since 1 undergoes decarbonylation without the use of
chemical activators, and the by-product is inert under cross-
coupling conditions, we envisaged 1 to find application as a
general CO surrogate for in situ carbonylative transformations.
Herein, we demonstrate that 1 is a competent in situ CO surrogate
for various Pd-catalyzed carbonylative transformations.
equiv.), NEt3 (0.22 mmol, 2.2 equiv.), Pd(dba)2 (0.003 mmol, 3 mol %), PPh3
(0.006 mmol, 6 mol %) in dioxane (0.5 mL) at 80 ˚C for 18 h.
We commenced our studies by optimizing the
aminocarbonylation of 3 using the two-chamber approach. Using
conditions adapted from our previous report,18 and a slight excess
of 1 as an ex situ CO source, we were pleased to observe the
near-quantitative conversion of 3 (Table 1, entry 1). Adjusting the
CO release conditions by changing or omitting solvent in
Chamber B only reduced the yields (entries 2 and 3). Increasing
catalyst loading or decreasing equivalence of 1 led to lower yields
(entries 4 and 5). Encouragingly, by directly subjecting 1 into the
main reaction chamber (in situ), we were able to observe modest
formation of the desired product without altering the optimized
condition (entry 6). Upon further optimization, near-quantitative
consumption of o-iodotoluene (3) while using stoichiometric
amount of 1 as an in situ CO source to afford 5a was realized
(entry 8).
With the optimized conditions, we began to explore the
scope of the reaction using both the in situ and ex situ approaches
(Scheme 3). ortho-Substituted amide 5a was formed with high
yields using both the in situ and ex situ protocols (Scheme 3). Aryl
iodides with diverse electronic properties were well-tolerated, and
the corresponding amides were afforded with comparable yields
between both in situ and ex situ approaches (5b-5e). meta-Di-
substituted aryl amide was isolated with good yields (5f). An aryl
bromide containing a sulfonyl functional group was well-tolerated
to furnish 5g with good yields, albeit with extended reaction time
(40 h). In addition to 4, cyclic amine such as morpholine was also
well-tolerated using both the in situ and ex situ protocols (5h). The
pyridyl functional group and sterically hindered 1-adamantylamine
were compatible with the employed conditions, and amide 5i was
formed with good yield using the ex situ protocol. Whereas the
isolated yield of 5i was lower when the reaction was performed in
one pot. Although aniline was not a suitable nucleophile under the
optimized conditions (5j), the aniline functional group was well-
tolerated, and p-iodoaniline was successfully coupled with an
alkyl amine to afford the corresponding N-alkyl amide in high
yields without protection of the aniline functionality (5k). In
addition to alkyl amines, heteroaroyl hydrazide was also
Scheme 2. Synthesis of novel oxycarbo-, carbamoyl-,
thiocarboboronates, and borylated heterocycles using 1. Subsequent
Pd-catalyzed
cross-coupling
of
borylated
heterocycles.
Decarbonylation of 1 to give 2 as by-product. [B] = BMIDA.
Results and Discussion
Table 1. Optimization for the in situ and ex situ Pd-catalyzed
aminocarbonylation of 3 using 1 as the CO surrogate.[a]
Entry
Deviations from Standard
Yield (%)[b]
successfully coupled to
a di-substituted aryl iodide in a
carbonylative fashion to afford 5l. Bis-hydrazide 5l was
subsequently cyclized in one pot to tricyclic bis-heterocycle 6 in
good yield.
1
None
97 (94)
49
2
DMSO instead of dioxane in Chamber B
No solvent in Chamber B
In light of the exceptional compatibility of 1 in the in situ
aminocarbonylation transformation, we decided to proceed with
subsequent studies by only carrying out the reactions using the in
situ approach, where 1 is directly added to the reaction mixture.
Similar to amines, alcohols have been widely employed as
nucleophiles for the alkoxycarbonylation of aryl halides to
generate esters.19 Using an adapted protocol reported by Beller
and co-workers19a and a stoichiometric amount of CO source, 7
could be coupled with n-BuOH to form butyl ester 8a, albeit with
low yield (Table 2, entry 1). By increasing the loading of the pre-
catalyst and base, a higher yield was obtained (entry 2).
Subsequent screening revealed NEt3 to be the optimal base in
this in situ approach (entries 3-5). A slight increase in yield was
observed when 1.5 equivalence of 1 was employed (entry 6).
Gratifyingly, by further increasing the equivalence of 1 and NEt3,
quantitative conversion of 7 was achieved, and 8a could be
isolated in high yield (entry 7).
3
85
4
Pd(dba)2 (8 mol %), PPh3 (12 mol %)
1 (1.2 equiv.)
90
5
94
6
In situ instead of ex situ
74
7
In situ instead of ex situ, 1 (1.1 equiv.)
In situ instead of ex situ, 1 (1.0 equiv.)
82
8[c]
92 (88)
[a] Chamber A: 3 (0.1 mmol, 1 equiv.), 4 (0.2 mmol, 2 equiv.), NEt3 (0.2 mmol,
2.0 equiv.), Pd(dba)2 (0.005 mmol, 5 mol %), PPh3 (0.01 mmol, 10 mol %) in
dioxane (0.3 mL) at 80 ˚C for 18 h. Chamber B: 1 (0.14 mmol, 1.4 equiv.) in
dioxane (0.3 mL) at 80 ˚C for 18 h. [b] Determined by 1H NMR spectroscopy
using mesitylene as an internal standard; numbers in brackets refer to isolated
yields. [c] 3 (0.1 mmol, 1 equiv.), 4 (0.22 mmol, 2.2 equiv.), 1 (0.1 mmol, 1
2
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Scheme 3. Scope of Pd-catalyzed aminocarbonylation of aryl iodides and an aryl bromide with alkyl amines using 1 as both an ex situ and in
situ CO surrogate. [a] Chamber A: aryl halide (0.1 mmol, 1 equiv.), amine (0.2 mmol, 2 equiv.), NEt3 (0.2 mmol, 2 equiv.), Pd(dba)2 (0.005 mmol,
5 mol %), PPh3 (0.01 mmol, 10 mol %), dioxane (0.3 mL), 80 ˚C, 18 h. Chamber B: 1 (0.14 mmol, 1.4 equiv.), dioxane (0.3 mL), 80 ˚C, 18 h. [b]
Aryl halide (0.1 mmol, 1 equiv.), amine (0.22 mmol, 2.2 equiv.), 1 (0.1 mmol, 1 equiv.), NEt3 (0.22 mmol, 2.2 equiv.), Pd(dba)2 (0.003 mmol, 3
mol %), PPh3 (0.006 mmol, 6 mol %), dioxane (0.5 mL), 80 ˚C, 18 h. [c] Isolated yield using the ex situ approach. [d] Isolated yield using the in
situ approach. [e] Reaction performed on a 1 mmol scale using the in situ approach. [f] Reaction performed with the corresponding aryl bromide.
[g] Reaction performed at 100 ˚C.
Table 2. Optimization for the Pd-catalyzed alkoxycarbonylation of 8
using 1 as the in situ CO surrogate.[a]
Entry
1
Deviations from Standard
None
Yield (%)[b]
27
2[c]
DBU (2 equiv.)
45
3[c]
NEt3 (2 equiv.) instead of DBU
TMEDA (2 equiv.) instead of DBU
Pyridine (2 equiv.) instead of DBU
NEt3 (3 equiv.), 1 (1.5 equiv.)
NEt3 (4 equiv.), 1 (2 equiv.)
52
4[c]
21
5[c]
trace
6[c,d]
7[c,d]
58
Quant. (98)
[a] 7 (0.1 mmol, 1 equiv.), 1 (0.1 mmol, 1 equiv.), DBU (0.11 mmol, 1.1 equiv.),
cataCXium® A Pd G3 (0.002 mmol, 2 mol %) in n-butanol (0.25 mL) at 120 ˚C
for 18 h. [b] Determined by 1H NMR spectroscopy using mesitylene as an
internal standard; numbers in brackets refer to isolated yields. [c] CataCXium®
A Pd G3 (0.005 mmol, 5 mol %) was used. [d] NEt3 instead of DBU.
The scope of the reaction was subsequently investigated
(Scheme 4). Along with 7, electronically neutral and electron-poor
aryl bromides were tolerated under the in situ conditions (Scheme
5, 8a, b, e). nBuOH can be substituted with other alcohols by
using toluene as the solvent (8c, d). Other electron- withdrawing
Scheme 4. Scope of Pd-catalyzed alkoxycarbonylation of aryl
bromides and n-butanol using 1 as an in situ CO surrogate. See
Supporting Information for exact conditions. All numbers refer to
isolated yields. [a] Reaction performed on a 1 mmol scale. [b]
Reaction performed with PhOH (20 equiv.) in toluene (0.5 M). [c]
Reaction performed with BnOH (20 equiv.) in toluene (0.5 M).
3
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groups such as nitrile, formyl, and acetyl were compatible with the
optimized conditions, and the corresponding esters could be
isolated with good to excellent yields (8f-i). In addition, the
reaction was not affected negatively when an unprotected phenol
group is present (8g). An aryl bromide containing the
benzodioxole functional group, which is an important bioactive
scaffold in various pesticides and pharmaceuticals,20 was
employed to afford ester 8j in good yield. Weak electron-donating
groups such as sulfide and chloride were also well-tolerated under
the optimized condition (8l and 8m). Ester 8m derived from 2-
bromomesitylene was isolated with low yield, likely due to steric
hindrance. The pyridine functionality was well-tolerated as it was
in the amine scope (8n).
We subsequently turned our attention towards carbon-
based nucleophiles as cross-coupling partners; more specifically,
aryl acetylenes in the carbonylative Sonogashira coupling
reaction. Using Pd(dppf)Cl2 as the pre-catalyst, iodobenzene (9)
and phenylacetylene (10) was coupled in a carbonylative fashion
to afford ynone 11a in excellent yield with < 5% formation of
diphenylacetylene as the side product (Table 3, entry 1). While
XantPhos was reported to be
a suitable ligand for the
carbonylative Sonogashira coupling of aryl bromides,11
a
decrease in yield was observed when 9 was employed (entry 2).
By lowering the loading of Pd(dppf)Cl2, near quantitative yield of
11a was obtained (entry 3). Using a lower excess of 1 furnished
the product in poorer yields (entry 4).
Scheme 5. Scope of Pd-catalyzed carbonylative Sonogashira
coupling of aryl iodides and aryl acetylenes using 1 as the in situ CO
surrogate. See Supporting Information for exact conditions. All
numbers refer to isolated yields. [a] Reaction performed on a 1 mmol
scale using 1 mol % of Pd(dppf)Cl2 · DCM.
Table 3. Optimization for the Pd-catalyzed carbonylative Sonogashira
coupling of 9 using 1 as the in situ CO surrogate.[a]
Nevertheless, upon protection of the pyrazole by benzylation, the
corresponding ynone can be isolated in good yield (11h, 54%). By
placing a chloride on the ortho-position of the aryl iodide,
formation of the ynone (11i) is less favourable when using 3-
ethynylthiophene as the coupling partner. However, by replacing
the chloride with an electronically more neutral, but bigger, methyl
group, 11j can be isolated in significantly better yield. The 2-
aminopyridine motif is also well-tolerated under the reaction
conditions (11k), however, protection of the primary amine is
necessary to prevent side-reactions with the carbonyl functional
group in the product. An alkyne containing a benzofuran group
was successfully coupled to a di-functionalized aryl iodide to
furnish 11l in good yield.
We began studying the in situ carbonylative Suzuki-Miyaura
reaction between aryl iodides and arylboronic acids to generate
diarylketones. Using adapted conditions by Suzuki and Miyaura,21
9 was smoothly coupled with phenylboronic acid (12) to afford
benzophenone (13a) in excellent yield (Table 4, entry 1). By
switching the ligand to a more electron-rich mono-dentate
phosphine (cataCXium® A), the yield was decreased (entry 2).
Switching to more polar solvents (THF, MeCN) drastically
reduced the yields (entries 3 and 4). Using another nonpolar
solvent such as anisole did not significantly impact the yield (entry
5). Lastly, by lowering the equivalence of 12, 13a could be
Entry
Deviations from Standard
None
Yield (%)[b]
1
95
2[c]
3
Pd / XantPhos instead of Pd / dppf
Pd(dppf)Cl2 · DCM (5 mol %)
Pd(dppf)Cl2 · DCM (5 mol %), 1 (1.4 equiv.)
40
Quant. (97)
4
54
[a] 9 (0.1 mmol, 1 equiv.), 10 (0.15 mmol, 1.5 equiv.), 1 (0.2 mmol, 2 equiv.),
NEt3 (0.3 mmol, 3 equiv.), Pd(dppf)Cl2 · DCM (0.01 mmol, 10 mol %) in THF
(0.5 mL) at 80 ˚C for 18 h. [b] Determined by 1H NMR spectroscopy using
mesitylene as an internal standard, numbers in brackets refer to isolated yields.
[c] Pd(dba)2 (0.01 mmol, 10 mol %), XantPhos (0.01 mmol, 10 mol %) were
used.
The scope of the reaction was explored using the optimal
conditions (Scheme 5). para-Substituted aryl ynones were
afforded with slightly lower yields than the non-substituted variant
(Scheme 6, 11a-c). However, switching out 9 for its bromo-
equivalent afforded 11a in 22% yield (see Supporting Information).
Electron-rich p-iodoanisole and
a fluorinated electron-poor
arylacetylene were coupled to afford ynone 11d in good yield.
Conversely, an electron-poor aryl iodide was reacted with an aryl
alkyne containing an electron-donating group to furnish ynone
11e in excellent yield. Ynones synthesized from heteroaryl
iodides such as 2-iodothiophene and 3-iodopyrazole can also be
afforded in modest to excellent yields under the optimized
conditions (11f-h). However, without protection of the free N-H on
the pyrazole, the efficiency of the reaction is impacted (11g, 28%).
obtained in almost quantitative yield (entry 6).
Table 4. Optimization for the Pd-catalyzed carbonylative Suzuki-
Miyaura of 9 using 1 as the in situ CO surrogate.[a]
4
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10.1002/anie.202010211
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fibroblast growth factor receptor (FGFR), used for cancer
treatment.22 Diarylketone 13j, precursor to a potent and selective
inhibitor against Mycobacterium tuberculosis,23 could be
synthesized in excellent yield using the corresponding aryl iodide
and arylboronic acid. The reaction proceeded smoothly with an
aminopyrazole-containing aryl iodide to afford 13k in good yield
without protection of the free amine.24 In addition, the
pyrazolo[1,5,ɑ]pyrimidine scaffold was also amenable to the
reaction conditions to afford the corresponding bis-heteroaryl
ketone 13l in modest yield (47%; 65% based on recovered
starting material). Attempts to increase the yield of 13l by
increasing reaction temperature or increased loading of the
nucleophile only led to more side reactions including
protodehalogenation, and biaryl formation. Nevertheless, the
facile construction of ketone-containing privileged drug scaffolds25
such as aminopyrazole and pyrrolopyrimidine should present 1 as
an attractive alternative to other CO surrogates due to its wide
functional group compatibility in an in situ approach. Additionally,
since carbonylations using 1 can be performed in non-specialized
glassware (see Supporting Information SI-Figure 1), transition to
high-throughput experimentation (HTE) without the need for
pressurized screening platforms can be envisaged.26
Entry
Deviations from Standard
Entry (%)[b]
1
None
90
2[c]
3
Pd / cataCXium® A instead of Pd / PPh3
THF instead of toluene
MeCN instead of toluene
Anisole instead of toluene
12 (1.1 equiv.)
68
7
4
16
5
89
6
95 (94)
[a] 9 (0.1 mmol, 1 equiv.), 12 (0.13 mmol, 1.3 equiv.), 1 (0.2 mmol, 2 equiv.),
K2CO3 (0.3 mmol, 3 equiv.), Pd(PPh3)2Cl2 (0.005 mmol, 5 mol %) in toluene (0.5
mL) at 80 ˚C for 20 h. [b] Determined by 1H NMR spectroscopy using mesitylene
as an internal standard, numbers in brackets refer to isolated yields. [c]
CataCXium® A Pd G3 (0.005 mmol, 5 mol %) was used.
The scope of the in situ carbonylative Suzuki coupling was
subsequently investigated (Scheme 6). Phenyl- and tolylboronic
acids were well-tolerated (Scheme 6, 13a-c), and the
diarylketones were afforded in high yields. Switching out 9 for its
bromo-equivalent afforded 13a in 33% yield (see Supporting
Information). Both electron-rich and electron-poor arylboronic
acids were successfully coupled with the respective aryl iodides
to furnish the corresponding arylketones in good yields (13d and
13e). Diarylketone 13f synthesized from an ortho-substituted
electron-poor arylboronic acid and an electron-poor aryl iodide
was generated in modest yield (13f). Substituted heteroaromatics
such as benzofuran, pyrazole, indole, and pyridine were well-
tolerated under these conditions, and a diverse array of heteroaryl
ketones were afforded with good yields (13g-i). The in situ
strategy is also amenable to the synthesis of pharmaceutically-
relevant substrates. Ketone 13i is a simplified scaffold present in
clinical trial candidate, DEBIO-1347, which is an inhibitor of
We next conducted comparison studies with other known
CO surrogates; namely, COgen,11 NFS,9c,f and acetic formic
anhydride9a,b,h,i in the in situ aminocarbonylation of iodoxylene.
Using benzylamine as the nucleophile, significant side product
formation was observed for all of the CO surrogates tested, where
5f was only observed in trace quantities (Scheme 7; see
1
Supporting Information for crude H NMR spectra and TLC spot
comparison). This was expected since activated carbonyl
moieties readily react with nucleophiles such as amines to afford
amides.13a,b,e Although in situ carbonylation reactions have been
reported using NFS and acetic formic anhydride,9 this study
Scheme 6. Scope of Pd-catalyzed carbonylative Suzuki-Miyaura coupling of aryl iodides and arylboronic acids using 1 as an in situ CO
surrogate. See Supporting Information for exact conditions. All numbers refer to isolated yields. Number in bracket refers to isolated yield based
on recovered starting material. [a] Reaction performed using 1.3 equiv. of the corresponding arylboronic acid. [b] Reaction performed on a 1
mmol scale using 1 mol % of Pd(PPh3)2Cl2 and 1.1 equiv. of boronic acid. [c] Reaction performed using 1.5 equiv. of the corresponding DABO
boronic ester. [d] Reaction performed using 10 mol % of Pd(PPh3)2Cl2 and 4 equiv. of K2CO3 at 100 ˚C.
5
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demonstrates their limited utility in other carbonylative
transformations.
Based on the results from the kinetics studies, a proposed
mechanism for the in situ CO extrusion of 1 is depicted in Scheme
8. In presence of excess base, 1 is deprotonated to give boryl
carboxylate 17. The anionic oxygen atom is proposed to displace
the pendent N-Me to give 18,27 which builds on our recent
discovery of the hemilabile nature of the MIDA ligand.28
Subsequent chelotropic fragmentation and protonation would give
2 and CO, which would be incorporated into the carbonylation
catalytic cycle. Even though stoichiometric Pd (II) species was
shown to accelerate the decarbonylation of 1 (Figure 1), under
cross-coupling conditions using excess base and catalytic
amounts of Pd catalysts, it is unlikely for the Pd catalyst to have
significant impact on the decarbonylation process. This is
encouraging as it suggests that applications of 1 as an in situ CO
surrogate should not be limited to only Pd-catalyzed
transformations, but for any process that utilizes heat and/or base.
Scheme 7. Comparison of other CO surrogates in the in situ
aminocarbonylation of m-iodoxylene.
To gain clarification on the mechanism of the
decarbonylatiion process of 1, we conducted NMR kinetics
studies to monitor the decomposition of 1 under similar cross-
coupling conditions (Figure 1). Due to the limited solubility of
MIDA-containing compounds in THF-d8, DMSO-d6 was added to
ensure complete solvation of the sample at room temperature. In
the absence of any additives, it takes 16 h at 80 ˚C to achieve >
95% consumption of 1 with an observed first-order rate constant
of kobs = 6.31 x 10-5 s-1. In the presence of 1 equivalent of NEt3
however, full consumption of 1 was achieved in 5 h at 80 ˚C, which
corresponds to approximately a 4-fold increase in observed rate
constant (kobs = 2.41 x 10-4 s-1). In the presence of stoichiometric
Pd(PPh3)2 and iodobenzene, full conversion of 1 was observed in
11 h at 80 ˚C, with a slight acceleration in decarbonylation at kobs
= 8.94 x 10-5 s-1, or a 1.4-fold increase relative to the additive-free
experiment. When stoichiometric NEt3, Pd(PPh3)2, and
iodobenzene were present in the reaction mixture, a 2.7-fold
increase in kobs was observed (kobs = 1.71 x 10-4 s-1). This
corresponds to a 1.4-fold decrease in observed rate constant
when compared to the NEt3-mediated decarbonylation
experiment, which suggests that Pd(II) species slightly inhibits
decarbonylation under basic conditions.
Scheme 8. Proposed mechanism for the in situ decarbonylation of 1.
Conclusion
0.06
1
0.05
1 + NEt3
In summary, we have demonstrated that carboxy-MIDA-
boronate (1) is a competent in situ CO surrogate that could be
0.04
0.03
0.02
0.01
0
1 + Pd(dba)2 + 2 PPh3 + PhI
1 + NEt3+ Pd(dba)2 + 2 PPh3 + PhI
used
in
the
Pd-catalyzed
aminocarbonylation,
alkoxycarbonylation, carbonylative Sonogashira coupling, and
carbonylative Suzuki-Miyaura coupling of aryl halides. The
unprecedented functional group compatibility of 1 as an in situ CO
surrogate allows for the use of various nucleophiles such as
amines, alcohols, alkynes and boronic acids. In comparison with
other well-known CO surrogates, 1 performs extraordinarily well
under in situ conditions in the presence of amine nucleophiles. A
series of kinetics experiments reveal that base and Pd(II) species
accelerate the decarbonylation process, with rate enhancement
of the base-mediated process being more pronounced. Further
applications and DFT theoretical studies on the decarbonylation
of 1 are being investigated and will be reported in due time.
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17
Time (h)
1
-3
-4
-5
-6
-7
1 + NEt3
1 + Pd(dba)2 + 2 PPh3 + PhI
1 + NEt3 + Pd(dba)2 + 2 PPh3 + PhI
y = -0.2273x - 2.9216
R² = 0.997
y = -0.6141x - 3.155
R² = 0.9951
y = -0.8662x - 2.9307
R² = 0.9993
y = -0.3219x - 2.9919
R² = 0.9936
-8
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17
Acknowledgements
Time (h)
Figure 1. Top: Plot of [1] at 80 ˚C over time in the presence of
stoichoimetric additives. Bottom: Plot of ln([1]) at 80 ˚C over time.
Concentration of 1 was determined by H NMR spectroscopy using
The Natural Sciences and Engineering Research Council of
Canada (NSERC) is acknowledged for their financial support.
Merck & Co., Inc., Rahway, NJ, USA is gratefully acknowledged
1
1,3,5-trimethoxybenzene as the internal standard.
6
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10.1002/anie.202010211
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75, 3017-3020. (d) J.-B. Peng, F.-P. Wu, X. Qi, J. Ying, X.-F. Wu,
Commun. Chem. 2018, 1, 87.
for the supply of carboxy-MIDA-boronate. Drs. Karl Demmons,
Darcy Burns, and Jack Sheng (CSICOMP, U of T) are thanked for
NMR spectroscopy assistance. C.-H. T. would like to thank the
Connaught Fund (U of T) for funding. A. H. would like to thank
NSERC CGS-D for funding.
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Keywords: CO surrogate • palladium catalysis • carbonylation •
carboxyboronate • C1 building block
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Carboxy-MIDA-boronate, a multifunctional C1-building block, was shown to be an excellent in situ CO surrogate. A variety of
(hetero)aromatic amides, esters, ketones, and ynones were synthesized in good to excellent yields under palladium catalyzed
conditions without the use of pressurized apparatus or two-chamber set ups.
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