Palladium-Catalyzed Carbonylative Homocoupling of Aryl Iodides for the Synthesis of Symmetrical Diaryl Ketones with Formic Acid

Article abstract of DOI:10.1002/cctc.201701185

A convenient method for the palladium-catalyzed carbonylative homocoupling of aryl iodides was developed. With formic acid as the CO source, various symmetrical diaryl ketones were synthesized in moderate to good yield in the presence of a palladium catalyst.

Full text of DOI:10.1002/cctc.201701185

Accepted Article
Title: Palladium-Catalyzed Carbonylative Homo-coupling of Aryl
Iodides for the Synthesis of Symmetrical Diaryl Ketones with
Formic Acid
Authors: Xiao-Feng Wu, Fu-Peng Wu, Jin-Bao Peng, and Xinxin Qi
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10.1002/cctc.201701185
ChemCatChem
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Palladium-Catalyzed Carbonylative Homo-coupling of Aryl Iodides for
the Synthesis of Symmetrical Diaryl Ketones with Formic Acid
Fu-Peng Wu, Jin-Bao Peng,* Xinxin Qi, and Xiao-Feng Wu*[a]
Abstract: A convenient palladium-catalyzed carbonylative homo-
coupling of aryl iodides was developed. With formic acid as the CO
source, various symmetrical diaryl ketones were synthesized in
moderate to good yield in the presence of palladium catalyst.
carbonylation reactions. Since oxidative carbonylative coupling
reaction of organometallics usually requires pre-preparation of
the high reactive organometallic reagent, reductive carbonylation
of the easily available aryl halides turned out to be a more
economic and valuable strategy for the synthesis of symmetric
ketones. In 2003, Larhed and co-worker developed a Co2(CO)8-
mediated and microwave-irradiated carbonylation of aryl iodides
for the synthesis of symmetric ketones.8 Later, Iranpoor’s group
reported a microwave-free Cr(CO)6 mediated carbonylative
homo-coupling reaction of aryl iodides.9 Despite high efficiency,
the main drawback of these protocols is that it introduces
(sub)stoichiometric metal residuals into the reaction system.
Considering the importance of the symmetrical diaryl ketones in
organic synthesis and the general lackage of the benchtop-
friendly synthesis method, developing a practical gaseous CO-
free carbonylative homo-coupling reaction is of great interest.
Recently, we have developed a series of carbonylative coupling
reactions employing formic acid as the CO source.10,11 With our
continuous interest in developing palladium catalyzed
Diaryl ketones are important structure motifs in natural products,
pharmaceuticals, materials and fine chemicals.1 As an
ubiquitous synthetic intermediate, the synthesis of diaryl ketone
have attracted great attention from the organic chemists.
Typically, diaryl ketones are prepared by Friedel-Crafts acylation
of arene.2 However, this method usually suffers the low regio-
selectivity, narrow substrate scope as well as the requirement of
excess Lewis acid to catalyze the reaction. In this aspect,
transition metal catalyzed carbonylative coupling reaction3
serves as
a
versatile and straightforward method for
constructing polyfunctionalized ketones since it not only retains
the advantage of high chemoselectivity of the cross-coupling
reactions, but also excluded the usage of carboxylic acid
derivatives as the materials. Generally, transition metal
catalyzed carbonylative coupling reaction can be classified into
three categories: i) carbonylative cross-coupling reaction of
carbonylation reaction, we herein present
a
convenient
carbonylative homo-coupling reactions of aryl halides with formic
acid as both the CO source and the reductant.
organic halides R-X with
a
nucleophilic organometallic
compounds R’-m.4 This strategy was widely studied and was
comparably more mature, both symmetrical and unsymmetrical
diaryl ketones could be synthesized using this method. ii)
carbonylative homo-coupling reaction of organometallic
nucleophiles R’-m in the presence of oxidizing regents.5 Usually,
Cu2+ and O2 were used as the oxidant. iii) carbonylative homo-
coupling of aryl electrophiles R-X (or Ar2I+) under reductive
conditions with Zn and In as the reducing regent.6 However,
most of these protocols used gaseous CO as the carbonyl
source. Although gaseous CO has been abundantly used in
industry, the highly toxic and odorless character and the
requirement of special high pressure equipment has restricted
the wider application of this reaction in synthetic chemistry.
Considering the problem of safety and benchtop-friendly
manipulation, various caronylation reactions based on CO
surrogate had been developed in the past two decades.7 Metal
carbonyls, DMF, chloroform, formic acid and its derivatives were
all investigated and successively applied in various
Scheme 1. Carbonylative Coupling for the Synthesis of Diaryl Ketones.
[a]
Mr. F.-P. Wu, Dr. J.-B. Peng, Dr. X. Qi, Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou,
Zhejiang 310018, People’s Republic of China; Prof. Dr. X.-F. Wu,
Institution Leibniz-Institut für Katalyse e.V. an der, Institution
Universität Rostock, Albert-Einstein-Straße 29a, Rostock 18059,
Germany
Initially, we evaluated the feasibility of the carbonylative
homo-coupling reaction by employing iodobenzene as the model
substrate. To our delight, heating a solution of iodobenzene and
formic acid in the presence of [(cinnamyl)PdCl]2, PPh3 and
sodium formate at 120 oC, with DCC as the activator, the desired
product benzophenone was obtained in 48% (Table 1, entry 1).
E-mail: pengjb_05@zstu.edu.cn; xiao-feng.wu@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201701185
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Meanwhile, the direct homo-coupling product biphenyl was
detected as one of the byproducts. We then optimized the
reaction parameters and selected results were shown in Table 1.
First, we examined different phosphine ligands, electron-rich
triarylphosphine were successively proceeded the reaction but
gave decreased yields (Table 1, entries 2 and 3). However,
trialkylphosphine ligands were found not suitable for this reaction,
only trace amount of the desired product was detected when
PCy3 were used as the ligand (see details in SI). Fortunately, the
yield was increased to 51% when DPEphos was used as the
ligand (Table 1, entry 4). Compared to [(cinnamyl)PdCl]2, other
catalyst precursors such as Pd(OAc)2 and Pd(PPh3)4 gave the
product in trace and 23% yields, respectively (Table 1, entries 5
and 6). Then we tested the effect of the base and found that the
usage of sodium formate was essential to this reaction.
Combination of sodium formate with inorganic bases as co-
bases resulted in decreased yields, while the use of organic
base suppressed the reaction and no product was produced
(see details in SI). Screening of the solvent showed that THF is
the optimal solvent, other solvent such as toluene and acetone
gave decreased yields (see details in SI). On the other hand, the
reaction temperature played a crucial role in this transformation,
lower temperature was unfavorable. Thus, when the reactions
8
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
110
130
120
120
120
17
9
41
10c
11e
12c,f
68(63d)
50
66
aReaction condition: Iodobenzene (0.5 mmol), [Pd] (2 mol%), HCO2Na (1.0
mmol), DPEphos (2 mol%), HCO2H (1.0 mmol), DCC (1.0 mmol), THF (2 mL),
120 oC. 20h. bGC yield. cHCO2Na (1.5 mmol). dIsolated yield. eHCO2Na (2.0
mmol).
P(naphthalen-1-yl)3:
diphenylphosphino)phenyl] ether.
fP:Pd=4:1.
P(p-anisyl)3:
tris(p-methoxyphenyl)phosphine.
DPEphos: bis[(2-
tri-1-naphthylphosphine.
With the optimized reaction conditions in hand (Table 1,
entry 10), we turned our attention to evaluate the substrate
scope of the carbonylative homo-coupling reaction. As illustrated
in Table 2, various substituted aryl iodides were employed to
test the generality of the reaction. The steric effect of the
substituent at different position of the benzene ring has a
pronounced influence on the reaction yield. p-methyl
iodobenzene gave a higher yield than m-methyl iodobenzene,
while o-methyl iodobenzene was not able to undergo the homo-
coupling reaction and no desired product was detected (Table 2,
2b-2d). This might be resulted from the steric effect during the
transmetalation process. Both electron-donating and electron-
withdrawing group substituted aryl iodides were tolerated in the
transformation and gave the corresponding products in
moderate yields. Generally, substrates with electron-withdrawing
groups (Table 2, 2g-2l) gave higher yields than that of electron-
donating groups (Table 2, 2b-2f). It should be mentioned that
when m-methyl iodobenzene and p-tert-butyl iodobenzene were
subjected to the optimized reaction condition, only 43% and 22%
yields of the desired products were produced, respectively.
Fortunately, the yields could be improved by increasing the
reaction temperature to 130 oC (Table 2, 2c and 2f). Interestingly,
the fluoro- and chloro-substituted iodobenzene were well
tolerated in this transformation (Table 2, 2g and 2h).12
Furthermore, heterocyclic aryl iodides such as 3-iodothiophene
and 6-iodoquinoline also underwent the reaction smoothly and
delivered the desired ketones in 74% and 78% yields,
respectively (Table 2, 2m and 2n). However, in the case of
bromobenzen and 4-bromobenzotrifluoride, no or very low
conversion of substrates were observed.
o
o
were performed at 110 C and 100 C, the yields decreased to
17% and trace, respectively (Table 1, entries 7 and 8).
Surprisingly, when the temperature was risen to 130 oC, the
o
yield was decreased compared to that of 120 C (Table 1, entry
9 vs 1). This might be resulted from the preference of reversed
decarbonylation of the acyl-palladium complex at high
temperature. Finally, the equivalent of sodium formate also
seems to be an important factor to this reaction. Increasing the
amount of sodium formate to 3.0 equivalent improved the yield
to 68% (Table 1, entry 10). However, 4 equivalent sodium
formate gave a decreased yield of 50% (Table 1, entry 11).
Increasing the ratio of P:Pd didn’t affect the reaction much
(Table 1, entry 12).
Table 1. Optimizing the reaction condition.a
Temp.
(oC)
Yield
(%)b
Entry
Catalyst
Ligand
1
2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
PPh3
120
120
48
17
With these homo-coupling results in hand, we were
interested in the application of this method in the carbonylative
cross-coupling reaction. Unfortunately, when a mixed substrate
(0.5 mmol iodobenzene 1a and 0.5 mmol p-ethyl iodobenzene
1e) were subjected to the optimized condition, a mixture of
homo- and cross-coupling products were generated with poor
selectivity (Scheme 2, eq. 1). Considering that the difference of
electronic properties on the substrates might play an important
role in the reaction selectivity, a mixture of 1e and 1i was
employed in the standard condition. However, there was no
P(p-anisyl)3
P(naphthalen-1-
yl)3
3
[(cinnamyl)PdCl]2
120
23
4
5
6
7
[(cinnamyl)PdCl]2
Pd(OAc)2
DPEphos
DPEphos
DPEphos
DPEphos
120
120
120
100
51
trace
23
Pd(PPh3)4
[(cinnamyl)PdCl]2
trace
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significant improvement of the selectivity of homo- and cross-
products (Scheme 2, eq. 2).
Table 2. Substrate Scope of the Carbonylative Homo-Coupling Reaction.a
aReaction condition: Iodobenzene (0.5 mmol), [(cinnamyl)PdCl]2 (1 mol%), HCO2Na (1.5 mmol), DPEphos (2 mol%), HCO2H (1.0 mmol), DCC (1.0 mmol), THF (2
mL), 120 oC. 20h. b130 oC. c30h.
Scheme 2. Carbonylative Cross-Coupling.
Scheme 3. Control Reactions for Exploring the Mechanism.
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To gain a better understanding of the reaction pathway, a
set of supporting experiments were carried out (Scheme 3). First,
sodium formate was essential for this reaction, when the
reaction was performed with gaseous CO with NaOAc as the
base, no carbonylation product was detected (Scheme 3, eq. 1).
It was known that the decarboxylation of anhydrides would
generate the ketone under thermal condition. However, when
acid anhydride was subjected to the optimized condition, no
decarboxylated product was detected (Scheme 3, eq. 2).
Besides, when a mixture of p-iodobenzonitrile 1j and benzoic
acid was used in this reaction, only homo-coupling product 2j
was produced and no cross-product 2aj was observed (Scheme
3, eq. 3). These excluded the possibility of the anhydride
formation/decarboxylation pathway. Additionally, the presence of
aldehyde in the reaction also didn’t afford the cross-coupling
product (Scheme 3 eq. 4).
On the basis of the above experimental results, a plausible
mechanism was proposed in Scheme 4. The catalytic cycle
starts with the oxidative addition of the in-situ generated Pd0 with
aryl iodide 1 to give the corresponding aryl-palladium complex 3.
Subsequently, coordination and insertion of 3 with one molecule
of carbon monoxide, which was generated in-situ from the
reaction of formic acid and DCC, forms an acyl-palladium
intermediate 4. Then, a transmetalation between 3 and 4
generates the acyl-palladium intermediate 5 and PdI2. Finally,
reductive elimination of 5 delivers the product 2 and regenerate
the active Pd0 species for the next catalytic cycle. On the other
hand, PdI2 would be reduced by sodium formate to give the
active Pd0.
In conclusion, a novel palladium catalyzed carbonylative
homo-coupling reaction for the synthesis of symmetrical diaryl
ketone has been developed. This method uses formic acid as
the CO source, various (hetero)aryl iodides were conveniently
transformed into the corresponding ketones in moderate to good
yields.
Experimental Section
[(cinnamyl)PdCl]2 (1 mol %), DPEphos (2 mol%), NaOOCH (1.5 mmol),
DCC (1.0 mmol), were transferred into an oven-dried tube which was
filled with nitrogen. THF (2.0 mL) and iodobenzene (0.5 mmol) were
added to the reaction tube. After formic acid (1.0 mmol) was added, the
tube was sealed and the mixture was stirred at 120 °C for 24 h. After the
reaction finished, the reaction system was cooled to room temperature
and the reaction mixture was filtered and concentrated under vacuum.
The crude product was purified by column chromatography on silica gel
column using EtOAc/petroleum ether (1/200 to 1/50) to give the desired
product.
Scheme 4. Plausible Reaction Mechanism
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R. F. W. Jackson, D. Turner, M. H. Block, J. Chem. Soc., Perkin Trans.
1 1997, 865-870; d) K. Kobayashi, Y. Nishimura, F.-X. Gao, K. Gotoh,
Y. Nishihara, K. Takagi, J. Org. Chem. 2011, 76, 1949-1952; e) L. Ren,
N. Jiao, Chem. Asian J. 2014, 9, 2411-2414.
Acknowledgements
The authors thank the financial supports from NSFC (21472174,
21602201, 21602204), education department of Zhejiang
Province (Y201636555),
(16062095-Y) and Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020002).
[6]
[7]
a) M. Uchiyama, T. Suzuki, Y. Yamazaki, Chem. Lett. 1983, 1201-1202;
b) J.-J. Brunet, A. E. Zaizi, J. Organomet. Chem. 1995, 486, 275-277;
c) T. Zhou, Z.-C. Chen, Synth. Commun. 2002, 32, 3431-3435; d) A.
Rérat, C. Michon, F. Agbossou-Niedercorn, C. Gosmini, Eur. J. Org.
Chem. 2016, 4554-4560.
Zhejiang Sci-Tech University
For selected reviews on carbonylation using CO surrogates, see: a) T.
Morimoto, K. Kakiuchi, Angew. Chem. Int. Ed. 2004, 43, 5580-5588; b)
L. R. Odell, F. Russo, M. Larhed, Synlett 2012, 685-698; c) H. Konishi,
K. Manabe, Synlett 2014, 1971-1986; d) L. Wu, Q. Liu, R. Jackstell, M.
Beller, Angew. Chem. Int. Ed. 2014, 53, 6310-6320; e) P. Gautam, B. M.
Bhanage, Catal. Sci. Technol. 2015, 5, 4663-4702; f) B. Sam, B. Breit,
M. J. Krische, Angew. Chem. Int. Ed. 2015, 54, 3267-3274; g) S. D.
Friis, A. T. Lindhardt, T. Skrydstrup, Acc. Chem. Res. 2016, 49, 594-
605; h) J.-B. Peng, X. Qi, X.-F. Wu, Synlett 2017, 28, 175–194.
P.-A. Enquist, P. Nilsson, M. Larhed, Org. Lett. 2003, 5, 4875-4878.
E. Etemadi-Davan, N. Iranpoor, ChemistrySelect 2016, 1, 4300-4304.
Keywords: palladium • carbonylation • ketone • formic acid •
aryl iodide
[1]
a) G. R. Pettit, B. Toki, D. L. Herald, P. Verdier-Pinard, M. R. Boyd, E.
Hamel, R. K. Pettit, J. Med. Chem. 1998, 41, 1688-1695; b) D. R. Guay,
Pharmacother. 1999, 19, 6-20; c) M. Cueto, P. R. Jensen, C. Kauffman,
W. Fenical, E. Lobkovsky, J. Clardy, J. Nat. Prod. 2001, 64, 1444-1446;
d) D. Plazuk, A. Vessieres, E. A. Hillard, O. Buriez, E. Labbe, P. Pigeon,
M.-A. Plamont, C. Amatore, J. Zakrzewski, G. Jaouen, J. Med. Chem.
2009, 52, 4964-4967; e) S. K. Vooturi, C. M. Cheung, M. J. Rybak, S. M.
Firestine, J. Med. Chem. 2009, 52, 5020-5031; f) J. R. Luque-Ortega, P.
Reuther, L. Rivas, C. Dardonville, J. Med. Chem. 2010, 53, 1788-1798;
g) A. Ghinet, A. Tourteau, B. Rigo, V. Stocker, M. Leman, A. Farce, J.
Dubois, P. Gautret, Bioorg. Med. Chem. 2013, 21, 2932-2940.
a) G. Sartori, R. Maggi, Chem. Rev. 2006, 106, 1077-1104; b) G.
Sartori, R. Maggi, Chem. Rev. 2011, 111, PR181-PR214.
[8]
[9]
[10] a) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. 2003, 5, 4269-4272;
b) J. Hou, J.-H. Xie, Q.-L. Zhou, Angew. Chem. Int. Ed. 2015, 54, 6302-
6305.
[11] a) X. Qi, L.-B. Jiang, C.-L. Li, R. Li, X.-F. Wu, Chem. Asian J. 2015, 10,
1870-1873; b) X. Qi, C.-L. Li, L.-B. Jiang, W.-Q. Zhang, X.-F. Wu, Catal.
Sci. Technol. 2016, 6, 3099-3107; c) J.-B. Peng, F.-P. Wu, C.-L. Li, X.
Qi, X.-F. Wu, Eur. J. Org. Chem. 2017, 1434-1437; d) F.-P. Wu, J.-B.
Peng, L.-S. Meng, X. Qi, X.-F. Wu, ChemCatChem 2017, DOI:
[2]
[3]
For selected reviews, see: a) D. Milstein, Acc. Chem. Res. 1988, 21,
428-434; b) K. Khumtaveeporn, H. Alper, Acc. Chem. Res. 1995, 28,
414-422; c) R. Skoda-Foldes, L. Kollar, Curr. Org. Chem. 2002, 6,
1097-1119; d) A. Brennführer, H. Neumann, M. Beller, Angew. Chem.
Int. Ed. 2009, 48, 4114-4133.
10.1002/cctc.201700517.
[12] When 1-bromo-4-iodobenzene was used as the substrate in this
reaction, a mixture of homo-coupling products with major reduced
product
were
obtained.
[4]
[5]
a) M. Beller, Applied Homogeneous Catalysis with Organometallic
Compounds, Vol. 1, 2nd ed., Wiley-VCH, Weinheim, 2002, pp. 145-
156; b) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40,
4986-5009; c) X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113,
1-35.
a) R. F. Heck, J. Am. Chem. Soc. 1968, 90, 5546-5548; b) K. Yasui, K.
Fugami, S. Tanaka, Y. Tamaru, J. Org. Chem. 1995, 60, 1365-1380; c)
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Fu-Peng Wu, Jin-Bao Peng,* Xinxin Qi,
and Xiao-Feng Wu*
Page No. – Page No.
Palladium-Catalyzed Carbonylative
Homo-coupling of Aryl Iodides for the
Synthesis of Symmetrical Diaryl Ketones
with Formic Acid
A convenient palladium-catalyzed carbonylative homo-coupling of aryl iodides has
been developed. By using formic acid as the CO source, various desired
symmetrical diaryl ketones can be produced in moderate to good yields.
This article is protected by copyright. All rights reserved.