Transition-metal-free carbonylation of aryl halides with arylboronic acids by utilizing stoichiometric CHCl3 as the carbon monoxide-precursor

Article abstract of DOI:10.1039/c9gc00598f

Under transition-metal-free conditions, carbonylative Suzuki couplings of aryl halides with arylboronic acid using stoichiometric CHCl₃ as the carbonyl source has been developed. The simple, efficient, and environmentally benign method was successfully applied to the synthesis of Fenofibric acid, naphthyl phenstatin, and carbon-13 labeled biaryl ketone.

Full text of DOI:10.1039/c9gc00598f

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DOI: 10.1039/C9GC00598F
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COMMUNICATION
Transition-metal-free carbonylation of aryl halides with
arylboronic acids by utilizing stoichiometric CHCl3 as the carbon
monoxide-precursor
Received 00th January 20xx,
Accepted 00th January 20xx
Fangning Xu,a Dan Li b and Wei Han,*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
The reported work
Under transition-metal-free conditions, carbonylative Suzuki
couplings of aryl halides with arylboronic acid using stoichiometric
CHCl3 as the carbonyl source has been developed. The simple,
efficient, and environmentally benign method was successfully
applied to the synthesis of Fenofibric acid, naphthyl phenstatin,
and carbon-13 labeled biaryl ketone.
a)
CO
Mo(
)6, [Pd]
b) CO
H
OH, Ac2O, [Pd]
CO
Cl
X
BYn
O
C
c)
[Pd]
[Pd]
R'
R''
+
R'
R''
O
O
C
H
X=I, Br BYn=B(OH)2,
and/or B(OH)3Na,
DABO boronate
d)
N
O
S
O
Biaryl ketone represents a key scaffold that is commonly
prevalent in advanced organic materials, biologically active
molecules, natural products and drugs.1 For instance, top
selling drugs such as Evista,2 Tricor,3 and Sector4 contain biaryl
ketone units, which play a vital role in their extraordinary
biological and pharmaceutical properties. Hence, establishing a
general, effective and practical method for the preparation of
biaryl ketones is of great significance. Among many synthetic
protocols of biaryl ketones, carbonylative Suzuki reaction,5
cross-coupling between aryl halides and arylboronic acids with
carbon monoxide as the C1 source,6 prevails, as it possesses
excellent features, such as readily accessible and nontoxic, air-
Transition-metal-free
CHCl3 (3.0 equiv)
This work
Scheme 1 CO precursors for carbonylative Suzuki reactions.
reactions, albeit with high palladium catalyst loadings (10
mol%) (Scheme 1). Recently, acetic formic anhydride, in situ
generated from the reaction of formic acid and acetic
anhydride, as a CO precursor was also successfully used in the
transformation, but sensitive to moisture and active groups,
consequently leading to potential substrate scope limitation.12
CHCl3 is widely available and inexpensive, stable and easy to
handle, and possesses a unique potential as a CO precursor in
carbonylation. Indeed, CHCl3 instead of gaseous carbon monoxide
as C1 source has been caused considerable interest and successfully
applied in aminocarbonylation,13 Heck-type domino cyclization,14
and carbonylative Sonogashira coupling.15 Recently, our group first
introduced stoichiometric CHCl3 as carbonyl source to carbonylative
Suzuki reaction utilizing iron as catalyst.16 Subsequently, Jain and
co-workers reported palladium catalysis for this process.17 Although
these protocols represent the important advancements of
carbonylative Suzuki coupling, the necessity to employ transition-
metals leads to generation of metal residue, which is intractable
with respect to being removed. Residual metal contamination in
pharmaceutical industry is strictly regulated by stringent
specifications;18 similar concerns are also present in the modern
electronics industry, where metal residues undermine the
performance of organic electronic devices.19 Hence, the
and
moisture-stable
substrates,
high
regio-
and
stereoselectivity, broad substrate scope, and wide functional
group compatibility.7
Despite being a powerful protocol, the usage of gaseous
carbon monoxide limits the applications of carbonylative
Suzuki reaction because carbon monoxide gas is odorless and
toxic, colorless and flammable, awkward to handle and
typically delivered in pressurized cylinders.8 Therefore,
employing in situ generation of carbon monoxide would be
more appealing. In this context, molybdenum hexacarbonyl,9
9-methylfluorene-9-carbonyl,10 and N-formylsaccharin11 have
been employed as CO surrogates for carbonylative Suzuki
a. Jiangsu Collaborative Innovation Center of Biomedical Functional Materials,
Jiangsu Key Laboratory of Biofunctional Materials, Key Laboratory of Applied
Photochemistry, School of Chemistry and Materials Science, Nanjing Normal
University, Nanjing 210023, China; E-mail: whhanwei@gmail.com
b. Hunan Provincial Key Laboratory of Materials Protection for Electric Power and
Transportation, School of Chemistry and Biological Engineering, Changsha
University of Science and Technology, Changsha 410114, China
development of
a
transition-metal-free20 strategy using
stoichiometric CHCl3 as the CO source for the carbonylative Suzuki
reaction is highly desirable but a formidable challenge.21
Herein, we report unprecedented, transition-metal-free
carbonylative Suzuki reactions of aryl halides with arylboronic
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
acids utilizing stoichiometric CHCl3 as the CO precursor, and (entries 5-9). The use of various bases was also examined: K2CO3,
View Article Online
DOI: 10.1039/C9GC00598F
demonstrate that this general and robust protocol is suitable K3PO4, NaHCO3, and NaOAc were far more efficient than PivOK and
for the synthesis of drugs and a 13C-labeled active molecule.
DIPEA, but inferior to Na2CO3 (entries 10-15). The choice of solvents
Inspired by our recent studies on carbonylations where the was crucial for this reaction. No desired product was observed
performance of the catalytic systems based on PEG- when the reaction was conducted in DMSO or CH3CN (entries 16-
400[poly(ethylene glycol)-400] is highly desirable in the 17), while good results can be achieved in glycol (85%), PEG-200
presence of PivOH (pivalic acid),16,22 our investigation began by (83%), and PEG-600 (58%) (entries 19-21).25 On the basis of the
carrying out the reaction of 1-iodo-4-(trifluoromethyl)benzene results of the optimization and control experiments, we decided to
1a with phenylboronic acid 2a and CHCl3-CsOH.H2O (CO is employ 1.0 equiv of NaI as the promoter, 2.0 equiv of Na2CO3 as the
released from CHCl3 in the presence of CsOH.H2O).13c,13d,15,16,23 base, 0.75 equiv. of PivOH as the additive, and 5.0 equiv of
with Na2CO3 as a base (This base plays an important in CsOH.H2O and 3.0 equiv of CHCl3 as the CO precursor in glycol (2
promoting carbonylative cross-coupling process), PivOH as an mL) in a sealed vial at 120 °C for the reaction. When the reaction
additive, and PEG-400 as solvent in a sealed vial (Table 1). To was performed under the conditions except that CO (1 atm)
our delight, the desired product 3aa was obtained in 42% yield replaced both CHCl3 and CsOH.H2O, a comparable result was also
in the absence of any transition-metal catalyst (entry 1). In obtained (entry 22), suggesting that CO is released from CHCl3 in
agreement with previous reports,16,24 addition of an iodide the presence of a hydroxide base. Additionally, the use of ultrapure
additive promoted the formation of the desired product, reagents such NaI (99.99% based on trace metals), Na2CO3 (99.997%
particularly using 1.0 equiv of NaI (entry 3). Replacing PivOH based on trace metals), CsOH.H2O (99.95% based on trace metals),
with AcOH or TFA as the additive resulted in lower yields
and purified PivOH and CHCl3, resulted in a slightly better yield
(86%) of 3aa (data not shown) and indicated that trace quantities of
transition metals do not affect the efficiency of the carbonylation.
Furthermore, inductively coupled plasma atomic emission
spectroscopy (ICP-AES) analysis of the reaction system under
optimized reaction conditions confirmed that the concentrations of
transition metals, such as Pd, Ru, Ni, and Cu were below the
detection limit of the instrument. These results suggest that the
catalytic reaction is based on transition metal-free process.
With the optimal conditions in hand, we examined a variety of
aryl iodides to undergo carbonylative coupling with phenylboronic
acid 2a (Scheme 2). Generally, a wide-range of aryl iodides could be
coupled to provide 3 in good to excellent yields with high selectivity.
A variety of electron-withdrawing groups such as trifluoromethyl,
nitro, acetyl, chloro and fluoro on the benzene ring were well
Table 1 Transition-metal-free carbonylative Suzuki reaction of 1a with 2aa
O
I
(HO)2B
CsOH.H2O (5 equiv)
base, acid, solvent
+
CHCl3 +
F3C
F3C
additive,
120 °C
1a
2a
3aa
Entry
Additive
Base
Acid
Solvent
Yield[%]b
1
-
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
PivOHe
PivOHe
PivOHe
PivOHe
PivOHf
PivOH
PivOHg
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
DMSO
42
45
69
65
78
82
80
76
44
70
56
68
62
27
12
-
2
NaIc
NaI
NaId
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
3
4
5
6
7
I
(HO)2B
O
8
CH3COOH
CF3COOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
NaI (1 equiv)
R1
+
CHCl3
+
CsOH.H2O (5 equiv)
Na2CO3 (2 equiv)
PivOH (0.75 equiv)
Glycol (2 mL), 120oC
R1
9
0.25 mmol 3 equiv
1.5 equiv
2a
1
3
10
11
12
13
14
15
16
17
18
19
20
21
22h
K3PO4
O
O
O
O
NaHCO3
NaOAc
PivOK
F3C
O2N
Cl
O
3ca
a
3aa
3ba
3da
, 24 h, 88%
, 24 h, 85%
O
, 24 h, 85%
, 24 h, 49%, 65%
O
O
Cl
O
DIPEA
F
Cl
Cl
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
F
F
a
3ga
, 24 h, 46%, 90%
3ea
3fa
3ja
3ha
, 24 h, 93%
, 24 h, 92%
O
, 24 h, 93%
O
Acetonitrile
Toluene
Glycol
-
O
O
13
85
83
58
86
O
O
O
3ia
3ka
, 24 h, 91%
O
, 24 h, 72%
O
, 24 h, 87%
O
PEG-200
PEG-600
Glycol
a
3la
, 48 h, 75%
O
O
HOOC
aReaction conditions (unless otherwise stated): 1a (0.25 mmol), 2a (0.375
mmol, 1.5 equiv.), NaI (0.25 mmol, 1 equiv), base (0.5 mmol, 2 equiv.), acid
(0.1875 mmol, 0.75 equiv), CsOH·H2O (1.25 mmol, 5 equiv.), CHCl3 (0.75
mmol, 3 equiv.), solvent (2.0 mL), 120 °C, and 24 h. b Yields were determined
by GC analysis using hexadecane as an internal standard. c NaI (0.125 mmol,
a
a
a
b
3ma
3na
, 48 h, 82%
3oa
, 48 h, 81%
, 48 h, 94%
O
3pa
, 48 h, 60%
O
O
O
N
S
3ra
a
a
a
3qa
, 48 h, 81%
, 48 h, 67%
3sa
, 48 h, 80%
d
e
f
0.5 equiv). NaI (0.375 mmol, 1.5 equiv). PivOH (0.375 mmol, 1.5 equiv).
Scheme 2 Transition-metal-free carbonylative Suzuki reaction of aryl iodides
1 with phenylboronic 2a. a Na2CO3 (0.75 mmol). b Na2CO3 (1 mmol).
PivOH (0.25 mmol, 1 equiv). PivOH (0.125 mmol, 0.5 equiv). h CO (1 atm)
g
instead of CHCl3-CsOH.H2O.
2 | J. Name., 2012, 00, 1-3
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O
Br
+
(HO)2B
NaI (1 equiv)
CsOH
tolerated (3aa-3ha). The reactions also worked smoothly with aryl
iodides having electron-donating groups, such as tert-butyl, m-
methyl and trimethoxy, on the aryl ring to afford the desired
products (3ja-3la). Gratifyingly, highly sterically hindered 2-iodo-
1,3,5-trimethylbenzene (1m) and 1-iodo-2-isopropylbenzene (1n)
did not hamper the transformation by increasing the amount of
Na2CO3 to 3 equiv. and furnished the corresponding products in
excellent yields, which is scarcely reported in carbonylative Suzuki
coupling (3ma-3na). Notably, highly reactive carboxylic group can
be tolerated and led to the desired ketone (3pa) in 60% yield. To
our delight, switching from the simple aryl group to heteroaryl and
naphthyl iodides still provided the products 3qa-3sa with pleasing
results in the presence of 3 equiv of Na2CO3. Unfortunately, 1-
bromo-4-nitrobenzene was poorly reactive and gave the desired
product in only 29% yield [eqn (1)]; 1-Chloro-4-nitrobenzene when
tested failed to give the desired product.
View Article Online
(1)
H O (5 equiDv)OI: 10.1039/C9GC00598F
CHCl3
+
2
O2N
Na2CO3 (2 equiv)
PivOH (0.75 equiv)
Glycol (2 mL), 120oC
0.25 mmol 3 equiv
1.5 equiv
2a
O2N
1b'
3ba,
24h, 29%
O
NaI (1 equiv)
CsOH.H2O (5 equiv)
I
(HO)2B
R3
R2
+
CHCl3
+
R2
R3
Na2CO3 (2 equiv)
3 equiv
1.5 equiv
0.25 mmol
PivOH (0.75 equiv)
1
2
3
o
Glycol (2 mL),
120 C
O
O
O
Cl
F
O
F3C
F3C
F
Cl
a
3ab
3ac
3dd
, 24 h, 48%, 85%
O
, 24 h, 81%
, 24 h, 84%
O
O
NO2
Cl
Cl
3de
3df
3tg
, 24 h, 73%
O
, 24 h, 68%
O
, 24 h, 70%
O
OH
OCF3
Next, to further confirm that the reactions are generally
applicable to various arylboronic acids, we examined the
carbonylative transformation of representative aryl iodides with a
broad range of arylboronic acids (Scheme 3). They could effectively
deliver biaryl ketones in 66–90% yields. It is worth noting that the
particularly valuable vinyl and hydroxyl groups remained intact in
the transformation (3tg-3th). Even sterically hindered o-tolylboronic
acid and (2-fluorophenyl)boronic acid provided the desired
products in 75% (3kj) and 77% (3kk) yields, respectively. In addition,
when 2-naphthylboronic acid was used in the transformation, the
corresponding product 3oc was produced in 76% yield.
3kj
3th
3ki
, 24 h, 75%
O
, 24 h, 83%
, 24 h, 90%
O
F
O
O
O
O
O
3kk
, 24 h, 77%
O
3om
, 24 h, 76%
3ol
, 24 h, 70%
O
O
Cl
3mo
3ln
, 24 h, 66%
b
, 48 h, 87%
O
Cl
O
Cl
Scheme 3 Transition-metal-free carbonylative Suzuki reaction of aryl iodides
1 with arylboronic acids 2. PEG-400 (2 mL) instead of Glycol (2 mL).
a
b
Na2CO3 (0.75 mmol).
To highlight the advantage of the protocol, a comparison of the
transition-metal free method with previously reported transition-
metal catalyzed carbonylative Suzuki reactions was investigated by
carbonylative cross coupling of 1m with 2a (Table 2; for details, see
the ESI). In our case, the reaction gave the desired product 3ma in
94% yield (entry 4). An efficient method of Pd-catalyzed
carbonylative Suzuki coupling using CO (1 atm) as carbonyl source
was employed to carbonylate 1m and resulted in moderate yield
(entry 1).6h Recently, two examples of Pd- and Fe- catalyzed
carbonylative Suzuki reactions using CHCl3 as CO precusor were
reported.16-17 They were used to test the carbonylation of 1m,
providing 3ma in 50% and 6% yields, respectively (entries 2-3).
These results showcase the utility of our protocol in organic
synthesis.
B(OH)2
NaI (1 equiv)
O
I
+
CHCl3
+
(2)
HO
CsOH.H2O (5 equiv)
Na2CO3 (4 equiv)
PivOH (0.75 equiv)
HO
O
O
Cl
Fenofibric acid
O
Cl
O
0.25 mmol
1t
3 equiv 1.5 equiv
3tn
, 48h, 72%
Glycol (2 mL), 120 o
C
2n
O
O
O
I
(HO)2B
+
O
O
NaI (1 equiv)
CsOH.H2O (5 equiv)
+
CHCl3
(3)
Na2CO3 (3 equiv)
PivOH (0.75 equiv)
Glycol (2 mL),120 o
O
O
naphthylphenstatin
, 48h, 64%
3 equiv
1.5 equiv
2p
0.25 mmol
C
3lp
1l
O
O
I
(HO)2B
O
O
13C
NaI (1 equiv)
+
13CHCl3
3 equiv
+
(4)
CsOH.H2O (5 equiv)
Na2CO3 (3 equiv)
PivOH (0.75 equiv)
O
O
O
13
1.5 equiv
2p
C-
3lp,
48h, 64%
0.25 mmol
Glycol (2 mL),120 o
C
1l
Furthermore, to amplify the applicability of the developed
carbonylative method, the pharmaceuticals Fenofibric acid (a
triglyceride and cholesterol regulator) and naphthyl phenstatin (a
tubulin polymerization and tumor cell growth activities inhibitor)26
were readily obtained in satisfying yields (3tn and 3lp) using this
protocol [eqn (2) and eqn (3)]. Much to our delight, the 13C-labeled
I
(HO)2B
NaI (1 equiv)
+
CHCl3
+
(5)
CsOH.H2O (5 equiv)
Na2CO3 (2 equiv)
PivOH (0.75 equiv)
O
O
3ua
observed by GC/MS
3 equiv
1.5 equiv
2a
0.25 mmol
1u
Glycol (2 mL),120 o
C
Ar-X
base
heat
O
Ar
Table 2. Comparison of catalyst systems
+
CO
O
X
Ar
Ar'
MOH
CHCl3
O
Reaction
system
Ar-X
Transition
Metal Free
Radical
(HO)2B
I
+
O
Carbonylation
1m
1a
3ma
yield (%)a
Ar
Ar'
Ar
Entry
Reaction system
Pd2(dba)3/CO
Ref.
1
2
3
4
6h
17
16
72
50
6
Pd(OAc)2/CHCl3
FeCl2/CHCl3
CHCl3
Ar'B(OH)2,base
This work
94
Scheme 4 Plausible reaction mechanism.
a Isolated yields after column chromatography are given.
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2012, 44, 315; (c) J. R. Luque-Ortega, P. Reuther, L. Rivas and
version could be prepared in an identical yield simply by using
commercially available 13C-labeled chloroform instead of
chloroform in the reaction conditions for 3lp [eqn (4)].
Recently, transition-metal-free carbonylations of aryl halides with
CO were proposed to involve a radical process.21 To gain further
insight of whether our transition-metal-free carbonylative
transformation is a free radical process, a radical probe 1-(allyloxy)-
2-iodobenzene (1u) was subjected to the normal conditions and
C. Dardonville, J. Med. Chem., 2010, 53, 1788; V(idew) AAr.ticLle. OOnnlinge,
DOI: 10.1039/C9GC00598F
A. H. Kamaruddin and S. Bhatia, Process Biochem., 2005, 40,
3526; (e) M. Cueto, P. R. Jensen, C. Kauffman, W. Fenical, E.
Lobkovsky and J. Clardy, J. Nat. Prod., 2001, 64, 1444.
E. J. Jeong, Y. Liu, H. Lin and M. Hu, Drug Metab. Dispos.,
2005, 33, 785.
A. T. Lindhardt, R. Simmonsen, R. H. Taaning, T. M. Gøgsig, G.
N. Nilsson, G. Stenhagen, C. S. Elmore and T. Skrydstrup, J.
Labelled Compd. Radiopharm., 2012, 55, 411.
2
3
only
afforded
a
cyclization
product,
3-methyl-2,3-
4
5
T. G. Kantor, Pharmacotherapy, 1986, 6, 93.
T. Ishiyama, H. Kizaki, N. Miyaura and A. Suzuki, Tetrahedron
Lett., 1993, 34, 7595.
dihydrobenzofuran (3ua) based on GC/MS analysis [eqn (5)],27
implying that aryl radical intermediate is present in the transition-
6
For selective examples of carbonylative Suzuki couplings of
aryl halides with CO, see: (a) H. Neumann, A. Brennführer
and M. Beller, Chem. Eur. J., 2008, 14, 3645; (b) P. Gautam,
M. Dhiman, V. Polshettiwar and B. M. Bhanage, Green
Chem., 2016, 18, 5890; (c) M. Z. Cai, J. Peng, W. Y. Hao and
G. D. Ding, Green Chem., 2011, 13, 190; (d) B. M. O’Keefe, N.
Simmons and S. F. Martin, Org. Lett., 2008, 10, 5301; (e) M. J.
Dai, B. Liang, C. H. Wang, Z. J. You, J. Xiang, G. B. Dong, J. H.
Chen and Z. Yang, Adv. Synth. Catal., 2004, 346, 1669; (f) Q.
Zhou, S. Wei and W. Han, J. Org. Chem., 2014, 79, 1454; (g)
P. Wójcik, M. Mart, S. Ulukanli and A. M. Trzeciak, RSC Adv.,
2016, 6, 36491; (h) H. Li, M. Yang, Y. Qi and J. Xue, Eur. J.
Org. Chem., 2011, 2662.
For selective reviews on transition-metal-catalyzed
carbonylations of aryl halides or aryl pseudohalides with CO,
see: (a) X.-F. Wu, H. Neumann and M. Beller, Chem. Soc.
Rev., 2011, 40, 4986; (b) A. Brennführer, H. Neumann and M.
Beller, Angew. Chem., Int. Ed., 2009, 48, 4114; (c) J.-B. Peng,
F.-P. Wu and X.-F. Wu, Chem. Rev., 2019, DOI:
10.1021/acs.chemrev.8b00068; (d) Y. Li, Y. Hu and X.-F. Wu,
Chem. Soc. Rev., 2018, 47, 172; (e) W. W. Fang, H. B. Zhu, Q.
Y. Deng, S. L. Liu, X. Yu. Liu, Y. J. Shen and T. Tu, Synthesis,
2014, 46, 1689; (f) R. Grigg and S. P. Mutton, Tetrahedron,
2010, 66, 5515.
For selected reviews on carbonylations using CO surrogates,
see: (a) J.-B. Peng, X. X. Qi and X.-F. Wu, Synlett, 2017, 28,
175; (b) S. D. Friis, A. T. Lindhardt and T. Skrydstrup, Acc.
Chem. Res., 2016, 49, 594; (c) P. Gautam and B. M. Bhanage,
Catal. Sci. Technol., 2015, 5, 4663; (d) L. P. Wu, Q. Liu, R.
Jackstell and M. Beller, Angew. Chem., Int. Ed., 2014, 53,
6310; (e) H. Konishi and K. Manabe, Synlett, 2014, 25, 1971;
(f) L. R. Odell, F. Russo and M. Larhed, Synlett, 2012, 23, 685;
(g) T. Morimoto and K. Kakiuchi, Angew. Chem., Int. Ed.,
2004, 43, 5580.
metal-free carbonylation process.21e,28 According to our
21, 22a
experimental results and previous studies,16,
we propose a
radical-chain reaction mechanism for this reaction (Scheme 4).
Initially, aryl halide thermally dissociates with the assistance of a
base21f,29 to give an aryl radical, which further reacts with CO (in situ
generated from chloroform and CsOH.H2O) to provide an acyl
radical intermediate.21c When the amount of CHCl3 was increased
from 3 equiv to 4 equiv, the yields were almost the same in 3 h
(23% and 25%, respectively), suggesting that in-situ CO generation
may be not the rate-determining step in the reaction. Then, the acyl
radical reacts with arylboronic acid under the assistance of a base
to afford a biaryl ketone radical anion.21b,21f Subsequently, SET
(single electron transfer) from the biaryl ketone radical anion to an
aryl halide gives the desired biarylketone product and regenerates a
reactive aryl radical, thus completing a radical chain.21b, 21f
In conclusion, we have developed a radical carbonylative Suzuki
coupling using stoichiometric CHCl3 instead of CO gas to deliver a
range of biaryl ketones in good to excellent yields with high
selectivities. Notably, this reaction was entirely transition-metal-
free and was utilizing CO precursor to avoid the drawbacks of
gaseous CO. This protocol provides an attractive alternative to
7
8
classical
metal-catalyzed
carbonylative
transformations.
Importantly, the method is applicable to isotope labeling of biaryl
ketones simply by using the commercially available 13C-labeled
chloroform. Moreover, the environmentally friendly and
operationally simple method was successfully applied to the
synthesis of the marketed pharmaceutical Fenofibric acid and a
potent inhibitor of the tumor growth, naphthyl phenstatin. Further
studies focused on the application to other carbonylation reactions
are on going in our laboratory, and will be reported in due course.
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.
9
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Conflicts of interest
There are no conflicts to declare.
Notes and references
1
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Green Chemistry
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Journal Name
COMMUNICATION
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This journal is © The Royal Society of Chemistry 20xx
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Green Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9GC00598F
Transition-metal-free carbonylation of aryl halides with
arylboronic acids by utilizing stoichiometric CHCl3 as the
carbon monoxide-precursor
Fangning Xu, Dan Li and Wei Han*
– Table of Contents Entry –
O
TM
NaI, base, PivOH
Glycol, 120 o
(HO)2B
X
CHCl3
+
+
Ar
Ar
R''
R'
Ar
Ar
R'
R''
3 equiv
C
X= I, Br
up to 94% yield
36 examples
A transition-metal-free, carbon monoxide-free, and general methodology for
carbonylative Suzuki coupling has been developed.