Transition-Metal-Free Carbonylative Suzuki-Miyaura Reactions of Aryl Iodides with Arylboronic Acids Using N-Formylsaccharin as CO Surrogate

Article abstract of DOI:10.1002/adsc.201900306

Unprecedented, high yielding, transition-metal-free carbonylative Suzuki-Miyaura reactions of aryl iodides with arylboronic acids using N-formylsaccharin as CO surrogate have been developed. Notably, this general protocol was adapted to the synthesis of the triglyceride and cholesterol regulator drug, fenofibrate, and carbon-13 labeled biaryl ketone. (Figure presented.).

Full text of DOI:10.1002/adsc.201900306

Title: Transition-Metal-Free Carbonylative Suzuki–Miyaura Reactions
of Aryl Iodides with Arylboronic Acids Using N-Formylsaccharin
as CO Surrogate
Authors: Dezhong Yu, Fangning Xu, Dan Li, and Wei Han
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900306
Link to VoR: http://dx.doi.org/10.1002/adsc.201900306

10.1002/adsc.201900306
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition-Metal-Free Carbonylative Suzuki–Miyaura
Reactions of Aryl Iodides with Arylboronic Acids Using N-
Formylsaccharin as CO Surrogate
Dezhong Yu,†a Fangning Xu,†b Dan Li,c and Wei Hanbc*
a
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemistry and Environmental
Engineering, Wuhan Institute of Technology, Wuhan 430205, China
Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biofunctional
b
Materials, Key Laboratory of Applied Photochemistry, School of Chemistry and Materials Science, Nanjing Normal
University, Nanjing 210023; Fax: +86-25-8589-1455; phone: +86-25-85891455 China; E-mail: whhanwei@gmail.com
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry
c
and Biological Engineering, Changsha University of Science and Technology, Changsha 410114, China
These authors contributed equally to this work.
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
transition-metal catalyst is of great significance but a
free carbonylative Suzuki–Miyaura reactions of aryl big challenge.[8] Although a few examples of
Abstract. Unprecedented, high yielding, transition-metal-
iodides with arylboronic acids using N-formylsaccharin as
CO surrogate have been developed. Notably, this general
protocol was adapted to the synthesis of the triglyceride
and cholesterol regulator drug, fenofibrate, and carbon-13
labeled biaryl ketone.
transition-metal-free carbonylation of aryl halides (or
pseudo-halides) have been developed, most of them
limit to radical alkoxycarbonylation under high
pressures of CO (50–80 atm).[9] Recently, we
achieved transition-metal-free carbonylative cross
couplings between aryl halides/benzyl chlorides and
arylborons with gaseous CO as the carbonyl source.[10]
Despite a powerful strategy, the use of toxic,
colorless, and flammable gaseous CO limits the
application of this method. Therefore, it would be
highly desirable if a CO surrogate could serve as the
carbonyl source.[11]
Keywords: biaryl ketones; carbonylative Suzuki coupling
reaction; N-formylsaccharin; synthetic methods ; transition-
metal free carbonylation
Three-component
cross-couplings
of
aryl
halides/pseudo-halides, aryl boronic acids, and
carbon monoxide, generally known as carbonylative
Suzuki–Miyaura
reactions,[1]
possess
unique
advantages, such as easy availability and high
stability of the reactants, broad substrate scope and
good functional-group compatibility.[2] Nowadays,
the transformation represents one of the most
efficient and convenient processes for synthesizing a
myriad of biaryl ketones, which are exists widely in
photosensitizers,[3] advanced organic materials[4] and
pharmaceuticals.[5]
Scheme 1. Carbonylative Suzuki–Miyaura reactions of
aryl iodides with arylboronic acids using N-
formylsaccharin as CO substitute.
Although this transformation offers a powerful tool
in organic synthesis, it frequently requires the
employment of the combination of a transition metal
(often Pd) and an expensive ligand (often
organophosphine) as the catalyst,[6] thus leading to
several limitations, such as cost of the transition-
metal catalyst, deactivation of the catalyst (CO is a
strong -acidic ligand), and generation of residual
metal contamination, which is intractable with respect
to being removed.[7] Therefore, the development of an
efficient and nonhazardous strategy without a
Recently, some surrogates have been developed as
carbonyl
sources,
such
as
molybdenum
hexacarbonyl,[12] acetic formic anhydride,[13] 9-
methylfluorene-9-carbonyl
chloride[14]
and
chloroform,[15] presenting attractive alternatives to
CO gas in the carbonylative Suzuki–Miyaura
reactions. N-Formylsaccharin was applied as a CO
surrogate, initially used for the palladium-catalyzed
reductive carbonylation of aryl halides by Manabe
and co-workers.[16] Lately, Bhanage and co-workers
1
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10.1002/adsc.201900306
Advanced Synthesis & Catalysis
reported the first carbonylative Suzuki–Miyaura
cross-coupling using N-formylsaccharin as a CO
surrogate, albeit with a palladium catalyst (Scheme 1,
a).[17] Encouraged by our recent studies on transition-
metal-free carbonylation where the performance is
highly desirable,[10] we herein report unprecedented,
high yielding, transition-metal-free carbonylative
Suzuki–Miyaura reactions of aryl iodides with
arylboronic acids using N-formylsaccharin as CO
surrogate (Scheme 1, b).
Our investigation began with the transition-metal-
free carbonylative Suzuki–Miyaura reaction of 1-
chloro-4-iodobenzene (1a) and phenylboronic acid
(2a) with N-formylsaccharin as the carbonyl source
using Li2CO3 as the base and PEG-400 as the solvent
at 120 °C. However, only 6% of desired product 3aa
was obtained (Table 1, entry 1). Subsequently,
various bases were evaluated, and it turned out that
Na2CO3 resulted in a superior yield of 3aa, albeit
along with high yield of side product 3a’a’ (Entry 7).
To our delight, a higher yield with satisfying
selectivity was then observed with increased amounts
of N-formylsaccharin to 3.0 equiv (Entry 8).
Additionally, by using DIPEA instead of Et3N
(tertiary amine promoting decarbonylation of N-
formylsaccharin to generate CO),[16] a superior result
was obtained (Entry 9). Further optimization showed
that this reaction could be improved by the addition
of K3PO4 (0.5 equiv) (Entry 12), consistent with our
previous study.[10b,18] None of the other solvents, such
as toluene, glycol (ethylene glycol) and DMF, could
substitute the PEG-400 (Table 1, entries 15–17).
Finally, ICP-AES was used to analyze the model
reaction mixture (including the solvent) and found
that the concentrations of Pd, Cu, Ni, and Fe were
lower than the detection limits of the machine,
excluding the slightest doubt of a transition-metal
catalyzed process.
Under the optimized reaction conditions, we next
turned to evaluate the generality of this transition-
metal-free carbonylation (Scheme 2). To our delight,
aryl iodides having electron-donating and electron-
withdrawing substituents was tested, and gave the
desired products 3aa-3na in moderate to high yields.
The reaction conditions were also compatible with
chloro, fluoro, trifluoro, ester, and methoxy groups.
In addition, prominent sterically hindered 2,4,6-
trimethyliodobenzene (1k) did not hamper the
transformation, delivering 3ka in 67% yield.
Table 1. Transition-metal-free carbonylative Suzuki
reaction of 1a with 2a.[a]
Yiel Yield
d of
3aa/ 3a’a’/
of
Entry
Base
Additive
Solvent
%
6
%
1
2
3
4
5
6
7
Li2CO3
K2CO3
Na3PO4
NaF
-
-
-
-
-
-
-
-
PEG-400
0
72
0
0
0
3
50
5
6
0
8
5
14
5
0
PEG-400 25
PEG-400
PEG-400
PEG-400
PEG-400
5
5
5
1
KF
KOAc
Na2CO3
Na2CO3
Na2CO3
-
PEG-400 40
PEG-400 65
PEG-400 69
8b
9c
10c
11c,d
-
-
PEG-400
0
Na2CO3
K3PO4
K3PO4
KOAc
PEG-400 75
PEG-400 75
PEG-400 70
12 c,e Na2CO3
13 c,f
Na2CO3
14 c,g Na2CO3
15 c,e Na2CO3
16 c,e Na2CO3
NaHCO3 PEG-400 69
K3PO4
K3PO4
K3PO4
Toluene
Glycol
DMF
3
5
0
92
0
17 c,e Na2CO3
a)
Reaction conditions (unless otherwise stated): 1a (0.10
mmol), N-formylsaccharin (0.15 mmol, 1.5 equiv), 2a
(0.15 mmol, 1.5 equiv), base (0.15 mmol, 1.5 equiv), Et3N
(0.15 mmol, 1.5 equiv), solvent (1.5 mL), 120 °C, and 12 h.
Yields were determined by GC analysis using hexadecane
b)
as an internal standard. N-formylsaccharin (0.3 mmol,
3.0 equiv), base (0.20 mmol, 2.0 equiv), Et3N (0.30 mmol,
3.0 equiv). N-formylsaccharin (0.3 mmol, 3.0 equiv),
Scheme 2. Transition-metal-free carbonylative Suzuki
reactions of aryl iodides 1 with phenylboronic 2a using N-
formylsaccharin as CO surrogate. Reaction conditions
c)
base (0.20 mmol, 2.0 equiv), DIPEA (0.30 mmol, 3.0
d)
e)
equiv).
K3PO4 (0.025mmol, 0.25 equiv).
K3PO4
(unless otherwise noted):
1
(0.25 mmol), N-
(0.05mmol, 0.5 equiv). f) KOAc (0.05mmol, 0.5 equiv).
NaHCO3 (0.05mmol, 0.5 equiv).
formylsaccharin (0.75 mmol), 2a (0.375 mmol), Na2CO3
(0.5 mmol), K3PO4 (0.125 mmol), DIPEA (0.75 mmol),
PEG-400 (2 mL), 120 °C. a) Na2CO3 (1 mmol).
g)
2
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10.1002/adsc.201900306
Advanced Synthesis & Catalysis
Moreover, 1-iodonaphthalene (1m) can be utilized as
a coupling partner to furnish carbonylative product
3ma in 75% yield, albeit with increasing the loading
of Na2CO3 to 4 equiv. The reaction also worked well
with
a
heterocyclic
substrate,
4-iodo-3,5-
dimethylisoxazole (1n) and gave the desired product
3na in moderate yield. Additionally, some poor
results were observed: 4-Iodobenzoic acid and 4-
iodophenol were tested under normal conditions and
provided the desired products in 14 and 5% yields,
respectively while 4-iodoaniline didn’t afford the
expected product.
Further, we investigated the scope of the
carbonylative
Suzuki–Miyaura
cross-coupling
reaction with other arylboronic acids under the
optimized conditions (Scheme 3). They could
effectively couple with typical aryl iodides to deliver
desired products in good to excellent yields (3ab-
3lm). To our delight, reactive functional groups, such
as methoxy, trifluoromethoxy, nitro, nitrile, fluoro,
chloro, and ester groups, were also well tolerated.
Notably, naphthalen-2-ylboronic acid (2e) worked
well with the protocol and gave the expected product
(3ae) in 74% yield. Furthermore, the sterically
hindered arylboronic acids, 2-tolylboronic acid (2f)
and 2-chlorophenylboronic acid (2j), were
successfully transformed to the desired products in
68% (3cf) and 77% (3gj) yields, respectively.
Scheme 4. Radical-trapping experiment.
demonstrated by the synthesis of pharmaceutically
relevant molecules. For instance, the marketed drug
Fenofibrate (3ol),[19] a triglyceride and cholesterol
regulator, was readily prepared in 69% yield under
normal reaction conditions [eqn (1)]. Similarly, a
naphthylphenstatin (3pe),[20] which shows substantial
tubulin polymerisation inhibitory activity as well as
cytotoxic activity against cancer cell lines, was easily
prepared from simple and readily available 5-iodo-
1,2,3-trimethoxybenzene (1p), N-formylsaccharin,
and naphthalen-2-ylboronic acid (2e) in 84% yield
[eqn (2)]. To our delight, by simply substituting the
CO precursor with its carbon-13 labeled version
under standard reaction conditions, the desired 13C-
labeled benzophenone (13C-3aa) was obtained in
yield identical to that of the unlabeled reaction [eqn
(3)]. Furthermore, the recyclability of the PEG system was
tested for the model reaction of 1a with 2a and N-
formylsaccharin. The reaction system maintained its high
yield and selectivity for eight consecutive cycles and gave
3aa in 84, 84, 84, 83, 83, 83, 83, and 82% in yields,
respectively.
The utility of the present method was next
It is well known that transition-metal-free
carbonylation proceeds by a radical mechanism.[9] To
gain further insight into our transition-metal- and
gaseous CO -free carbonylative Suzuki-Miyaura
reaction, we attempted to utilize a free-radical
scavenger galvinoxyl (2,6-di-tert-butyl-α-(3,5-di-tert-
butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-p-tolyloxy)
to trap the radical intermediate in the model reaction.
Consequently, the control experiment did not afford
the expected product 3aa but resulted in the
formation of the galvinoxyl-aryl adduct 4 (detected
by HRMS) originated from the interception of the
aryl radical (Scheme 4).[10a,10b] According to the
results mentioned above and previous studies, a free
Scheme 3. Transition-metal-free carbonylative Suzuki
reactions of aryl iodides 1 with arylboronic acids 2 using
N-formylsaccharin as CO surrogate. Reaction conditions
(unless otherwise noted):
1
(0.25 mmol), N-
formylsaccharin (0.75 mmol), 2 (0.375 mmol), Na2CO3
(0.5 mmol), K3PO4 (0.125 mmol), DIPEA (0.75 mmol),
a
b
PEG-400 (2 mL), 120 °C. Na2CO3 (1 mmol). Without
c
K3PO4 (0.125 mmol). NaHCO3 (0.5 mmol) instead of
Na2CO3 (0.5 mmol).
3
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10.1002/adsc.201900306
Advanced Synthesis & Catalysis
120 °C in a heating block for 24 h. After being allowed to
cool to room temperature, the reaction mixture was diluted
with 3 mL water and extracted with diethyl ether (3 x 5
mL). The organic phases were combined, and the volatile
components were evaporated in a rotary evaporator. The
residue was purified by column chromatography on silica
gel (petroleum ether: diethyl ether = 100 : 1 to 10 : 1) to
give the product 3aa in 84% (45 mg).
radical mechanism is proposed (Figure 1). Initially,
aryl iodide is thermally dissociated to give the aryl
radical (I) which is trapped by CO in situ generated
from N-Formylsaccharin in the presence of base to
form the acyl radical (II).[9,21] Subsequently, II reacts
with arylboronic acid under the assistance of a base to
generate the biaryl ketone radical anion (III),
followed by single electron transfer to another aryl
iodide to give the biarylketone product and regenerate
aryl radical (I).[9c]
In the recycling experiment, the residue was subjected to a
second run by charging it with the same substrates as
mentioned above without further addition of PEG 400. In
the fifth and seventh runs, another 0.3 mL of PEG-400 was
added to the reaction mixture.
Acknowledgements
The work was sponsored by the Natural Science Foundation of
China (21776139, 21302099), the Natural Science Foundation of
Jiangsu Province (BK20161553), the Natural Science
Foundation of Jiangsu Provincial Colleges and Universities
(16KJB150019), the Qing Lan project, and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
Figure 1. Proposed reaction mechanism.
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Experimental Section
General Procedure for the transition-metal-free
carbonylative Suzuki–Miyaura reactions of aryl iodides
with arylboronic acids: With no precautions to exclude air
or moisture, a 10-ml screw-cap vial equipped with a
magnetic stir bar was charged with aryl iodide (0.25 mmol),
arylboronic acid (0.375 mmol), Na2CO3 (53.3 mg, 0.5
mmol), K3PO4 (27.4 mg, 0.125 mmol), N-formylsaccharin
(161.6 mg, 0.75 mmol), DIPEA (125 μL, 0.75 mmol), and
PEG-400 (2.0 mL). The vial was capped and heated at
120 °C in a heating block for the indicated time. After
being allowed to cool to room temperature, the reaction
mixture was diluted with 3 mL water and extracted with
diethyl ether (3 x 5 mL). The organic phases were
combined, and the volatile components were evaporated in
a rotary evaporator. The residue was purified by column
chromatography on silica gel (petroleum ether: diethyl
ether = 100 : 1 to 10 : 1).
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