Selective transition metal-free aroylation of diarylmethanes with 2-acyl-imidazolium salts via acyl C–C bond cleavage

Article abstract of DOI:10.1016/j.tetlet.2020.152532

A highly chemoselective method is reported for the aroylation of simple diarylmethane derivatives via direct acyl C–C cleavage with 2-acyl-imidazolium salts under transition metal-free conditions. This represents a straightforward way to access a variety of sterically and electronically diverse 1,2,2-triarylethanones, a class of compounds with biological activities and various applications.

Full text of DOI:10.1016/j.tetlet.2020.152532

Journal Pre-proofs
Selective transition metal-free aroylation of diarylmethanes with 2-acyl-imi‐
dazolium salts via acyl C−C bond cleavage
Dong Zou, Li-She Gan, Fan Yang, Jia-Min Wang, Lin-Lin Li, Jie Li
PII:
DOI:
Reference:
S0040-4039(20)31025-X
https://doi.org/10.1016/j.tetlet.2020.152532
TETL 152532
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 August 2020
28 September 2020
1 October 2020
Please cite this article as: Zou, D., Gan, L-S., Yang, F., Wang, J-M., Li, L-L., Li, J., Selective transition metal-
free aroylation of diarylmethanes with 2-acyl-imidazolium salts via acyl C−C bond cleavage, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152532
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Selective transition metal-free aroylation of
diarylmethanes with 2-acyl-imidazolium salts
via acyl C−C bond cleavage
Leave this area blank for abstract info.
Dong Zou,a,§ Li-She Gan,b,§ Fan Yang,a Jia-Min Wang,a Lin-Lin Li,a and Jie Li*,a
O
I
O
Ar2
N
Ar2
Ar1
LiHMDS
DME, 80 oC
+
■
■
broad scope
transition metal-free
Ar1
■ operational-simplicity
■ high selectivity
N
Ar3
Ar3
43-93% yield
Ar1 = Aryl/Hetero-aryl
Ar2 = Aryl/Hetero-aryl
Ar3 = Aryl

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Selective transition metal-free aroylation of diarylmethanes with 2-acyl-imidazolium
salts via acyl C−C bond cleavage
Dong Zou,a,§ Li-She Gan,b,§ Fan Yang,a Jia-Min Wang,a Lin-Lin Li,a and Jie Li*,a
a Department of Pharmacy, School of Medicine, Zhejiang University City College, No. 48, Huzhou Road, Hangzhou 310015, PR China
b School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China.
§These authors contributed equally
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly chemoselective method is reported for the aroylation of simple diarylmethane
derivatives via direct acyl C–C cleavage with 2-acyl-imidazolium salts under transition metal-
free conditions. This represents a straightforward way to access a variety of sterically and
electronically diverse 1,2,2-triarylethanones, a class of compounds with biological activities and
various applications.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
1,2,2-Triarylethanones
Transition metal-free
Aroylation
2-Acyl-imidazolium salts
Diarylmethane
Introduction
conditions (Scheme 1B).15 Diarylmethane is weakly acidic.16 These
benzylic C−H bonds can be reversibly deprotonated under basic
Among the α-aryl carbonyl compounds, 1,2-diaryl- and 1,2,2-
triarylethanones have gained considerable attention because of their
widespread abundance in numerous bioactive compounds1 and
natural products.2 The most popular route for the synthesis of these
privileged carbonyl compounds utilizes the palladium-catalyzed α-
arylation of ketone enolates, an approach pioneered simultaneously
by Buchwald, Hartwig, and Miura in 1997 (Scheme 1A).3
Subsequently, this methodology has been expanded to involve
cheaper metals such as nickel,4 copper,5 and iron.6 To avoid the
employment of precious and toxic metals, Taillefer and co-workers
recently developed a transition metal-free method.7 However, the
substrate scope was limited and only aryl iodides worked well in
most cases.
reaction conditions (MN(SiMe3)2, M = Li, Na, K), and the resulting
carbanions act as nucleophiles in transition metal-involved17 or
transition metal-free transformations.18 For the current study, we
were interested in alternative strategies to prepare the same 1,2,2-
triarylethanones via the aroylation of diarylmethanes with 2-acyl-
imidazolium salts (Scheme 1C). There are several features of our
study that should be noted: (a) 2-acyl-imidazolium salts are easy to
prepare; (b) high functional group tolerance (ketones, halides,
esters); (c) expensive and toxic organometallic reagents are avoided.
Scheme 1. Representative methods for the synthesis of 1,2,2-
triarylethanones.
On the other hand, the development of new methods for the
cleavage and formation of C−C bonds remains challenging.8 Over
the past decades, a series of groundbreaking transition metal-
involved strategies have been developed in this area.9 Of these, acyl
C(O)−C bond cleavage has attracted significant interest in organic
synthesis.10 From an acylation viewpoint, there have been numerous
advances in the transition metal-catalyzed cross-coupling reactions
of amides and aromatic esters via C(O)−N and C(O)−C cleavage.11,12
Apart from cleaving the more polarized C(O)−N and C(O)−C bonds,
reactions proceeding via direct activation of the less polarized acyl
C(O)−C bond are scarce and remains a challenge to date.13 To
facilitate C−C bond cleavage, the conversion of various functional
groups into their salts represents an alternative strategy due to their
improved leaving ability. Accordingly, several groups have utilized
2-acyl-imidazolium salts for amidation and esterification via acyl
C(O)−C bond cleavage.14 In this context, we were curious if 2-acyl-
imidazolium salts could be employed with other nucleophiles.
Recently, we reported the synthesis of 1,2,2-triarylethanones via the
aroylation of diarylmethanes with amides under metal-free
A.
Transition metal-catalyzed arylation of deoxybenzoins
O
O
Ar'
X
M
catalyst
base
Ar
Ar'
+
R
Ar
R
X = Br, Cl, I
B.
Aroylation of diarylmethanes with amides under metal free conditions
O
O
O
Ar2
Ar3
or
Ar2
Ar3
MHMDS
DME, 80 o
Boc
Ar1
N
Ar1
N
+
Ar1
C
Bn
M = K, Na, Li
C.
This work
O
I
O
Ar2
N
Ar2
Ar1
LiHMDS
DME, 80 o
+
Ar1
C
N
Ar3
Ar3
■
■
■
■ operational-simplicity
broad scope
transition metal-free
high selectivity

2
Tetrahedron
O
O
I
Ar2
Ar1
H
Ar2
N
LiN(SiMe3)2 (3 equiv.)
DME, 80 o
+
Ar1
C
N
Results and Discussion
3aa-3ar
2a-2r
1a
We commenced our exploration by examining the model reaction
of 2-benzoyl-1,3-dimethyl-1H-imidazol-3-ium iodide 1a with 4-
benzylpyridine 2a in THF using NaN(SiMe3)2 as a base. After
heating at 80 oC for 12 h, the desired product 3aa was formed in 48%
isolated yield. The screening of five bases indicated that silyl amide
bases were suitable for this transformation (Entries 1−3), with
LiHMDS the most promising (78% yield). Other bases, such as
NaOtBu and KOtBu, failed to give the product (Entries 4−5). Various
solvents (DME, THF, CPME (cyclopentyl methyl ether), 1,4-dioxane
and toluene) were next explored, where DME was found to be the
best choice, and toluene also provided an acceptable yield (Entries
6−9). The temperature dramatically affected the yields; only 44%
yield was observed when the reaction temperature was lowered to 60
oC, and no product was observed at 40 oC (Entries 10−11).
O
O
O
O
N
N
N
N
c
d
3aa
3ad
88%
92%
3ab
3ac
92%
80%
tBu
OMe
F
O
O
O
O
N
N
N
N
d,e
3af
3ag
3ah
75%
82%
83%
3ae
93%
F
CN
O
O
O
O
O
O
O
Table 1. Optimization of the reaction conditions.a
N
c
c
d
c,d
3ai
3aj
3ak
3al
53%
55%
52%
43%
O
I
O
N
O
3 equiv base
solvent, 80 o
+
O
O
O
N
C
O
O
N
N
O
1a
2a
3aa
Entry
Base
Solvent
THF
Yield 3aa b
Temp. (°C)
d,e
3an
3ao
3ap 90%
56%
63%
3am
68%
1
NaHMDS
KHMDS
LiHMDS
NaOtBu
80
80
80
80
80
80
80
80
80
60
40
48
Br
2
THF
39
O
O
3
THF
76
4
THF
0
5
KOtBu
THF
0
d,e
d,e
3aq
3ar
83%
85%
6
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
1,4-dioxane
toluene
DME
trace
70
aReagents and conditions: 1a (0.1 mmol), diarylmethane (0.1 mmol),
7
b
LiHMDS (0.3 mmol), DME (0.1 M), 80 °C, 12 h. Isolated yield.
cKHMDS (3 equiv.). NaHMDS (3 equiv.). Reaction conducted in
d
e
8
88
THF.
9
CPME
DME
trace
44
10
11
The scope of the aroylation with respect to the 2-acyl-
imidazolium salts was next investigated with 4-benzylpyridine 2a.
Replacement of the phenyl group in 2-acyl-imidazolium salt 1a with
4-biphenyl and 2-naphthyl groups worked well in this
transformation, affording the corresponding products 3ba and 3ca in
75% and 85% yield, respectively. 2-Acyl-imidazolium salts bearing
alkyl substituents at the meta- and para-positions gave the desired
products 3da, 3ea and 3fa in 72−92% yield. Moreover, substrates
possessing electronically varied substituents (2g, 2h, 2i, 2j), as well
as steric hindrance (2k), were all well-tolerated. In particular, 2-acyl-
imidazolium salts possessing halides (1g and 1h) gave the expected
products in good yields (72−83%) with the carbon-halide bond
remaining intact. Further functionalization of these products could be
achieved through cross-coupling strategies. Furthermore,
heterocyclic 2-acyl-imidazolium salts possessing furan and
thiophene groups were both compatible, giving 3la and 3ma in 63%
and 52% yield respectively.
DME
trace
aReagents and conditions: 1a (0.1 mmol), 2a (0.1 mmol), base
(0.3 mmol), solvent (1 mL), 12 h. bIsolated yield.
After establishing the optimal reaction conditions, we next
examined the scope of the diarylmethanes in this transformation. As
shown in Table 2, substrates bearing electronically-diverse
substituents on the phenyl group of 4-benzylpyridine (2-Me, 3-Me,
4-Me, 4-tBu, 4-OMe, 4-F) gave the desired products (3ab, 3ac, 3ad,
3ae, 3af, 3ag) in 82−93% yield. Notably, the sterically-hindered
substrate 2b was tolerated in this protocol, affording the desired
product in high yield (92%). Perhaps most attractive feature of this
approach is the facile aroylation of diarylmethanes with privileged
heterocyclic motifs, including both electron-deficient heterocycles,
such as pyridine (2i), and electron-rich heterocycles, such as furan
(2j, 2k, 2l, 2m), as well as benzofuran (2o). Additionally, both
fluorene (2p, 2q) and benzofluorene (2r) proved to be suitable
substrates, with the desired products isolated in 83−90% yield.
To determine the practicality of this aroylation method, the
reaction using 2-acyl-imidazolium salt 1a with 4-benzylpyridine was
performed on a 4 mmol scale. The expected product was isolated in
75% yield (0.82 g).
Table 3. Scope of the 2-acyl-imidazolium salts.a,b
Table 2. Scope of the diarylmethane.a,b

3
O
Miyase, T.; Warashina, T.; Noguchi, H. J. Nat. Prod. 2005, 68, 361; (d)
O
I
Ar3
Lu, T. M.; Kuo, D. H.; Ko, H. H.; Ng, L. T. J. Agric. Food Chem. 2010,
58, 10027.
LiN(SiMe3)2 (3 equiv.)
DME, 80 o
N
Ar3
+
C
N
N
[3] (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108;
(b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382;
(c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int.
Ed. 1997, 36, 1740; (d) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.;
Nomura, M. Tetrahedron Lett. 1999, 40, 5345.
N
1a-1m
2a
3aa-3ma
O
O
O
O
[4] Takise, R.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed.
2014, 53, 6791.
[5] Danoun, G.; Tlili, A.; Monnier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2012, 51, 12815.
Ph
N
N
N
N
3aa
3ba
3ca 80%
3da
88%
88%
75%
[6] Chen, T.; Li, Y. F.; An, Y.; Zhang, F. M. Org. Lett. 2016, 18, 4754.
[7] Drapeau, M. P.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier, T.;
Taillefer, M. Angew. Chem. Int. Ed. 2015, 54, 10587.
O
O
O
O
[8] Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410.
tBu
F
Cl
[9] For reviews on C−C bond cleavage, see: (a) Ruhland, K. Eur. J. Org.
Chem. 2012, 2683; (b) Murakami, M.; Matsuda, T. Chem. Commun. 2011,
47, 1100; (c) Bonesi, S. M.; Fagnoni, M. Chem. Eur. J. 2010, 16, 13572;
(d) Winter, C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 2460; (e)
Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222; (f)
Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835; (g) Jun, C. H.
Chem. Soc. Rev. 2004, 33, 610; (h) Tobisu, M.; Chatani, N. Chem. Soc.
Rev. 2008, 37, 300; (i) Crabtree, R. H. Nature 2000, 408, 415; (j)
Murakami, M.; Ito, Y.; In Activation of Unreactive Bonds and Organic
Synthesis; Murai, S., Ed., Springer: Berlin, 1999; p 97.
N
N
N
N
c
c
3ga
3ha
83%
72%
3ea
3fa
72%
92%
O
O
OMe O
O
O
F3C
MeO
N
N
N
N
e
d,e
d,e
3ia
82%
3la
63%
3ja
3ka
93%
91%
[10] (a) Deng, L.; Xu, T.; Li, H.; Dong, G. J. Am. Chem. Soc. 2016, 138,
369; (b) Zhang, J.; Wu, D.; Chen, X.; Liu, Y.; Xu, Z. J. Org. Chem. 2014,
79, 4799; (c) Zhou, W.; Fan, W.; Jiang, Q.; Liang, Y. F.; Jiao, N. Org.
Lett. 2015, 17, 2542.
O
S
[11] For reviews on transition metal-catalyzed C−N and C−O bond
cleavage, see: (a) Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev.
2017, 46, 5864; (b) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413;
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(d) Liu, C. W.; Szostak, M. Org. Biomol. Chem. 2018, 16, 7998.
[12] For representative examples, see: (a) Hie, L.; Fine Nathel, N. F.;Shah,
T. K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N.
K. Nature 2015, 524, 79; (b) Weires, N. A.; Baker, E. L.; Garg, N. K.
Nature Chem. 2016, 6, 75; (c) Meng, G.; Szostak, M. Angew. Chem. Int.
Ed. 2015, 54, 14518; (d) Shi, S.; Meng, G.; Szostak, M. Angew. Chem.
Int. Ed. 2016, 55, 6959; (e) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami,
K. J. Am. Chem. Soc. 2012, 134, 13573; (f) Halima, T. B.; Zhang, W. Y.;
Yalaoui, I.; Hong, X.; Yang, Y. F.; Houk, K. N.; Newman, S. G. J. Am.
Chem. Soc. 2017, 139, 1311; (g) Meng, G.; Shi, S.; Lalancette, R.;
Szostak, R.; Szostak, M. J. Am. Chem. Soc. 2018, 140, 727; (h)
Chatupheeraphat, A.; Liao, H. H.; Srimontree, W.; Guo, L.; Minenkov, Y.;
Poater, A.; Cavallo, L.; Rueping, M. J. Am. Chem. Soc. 2018, 140, 3742.
[13] (a) Xia, Y.; Wang, J. C.; Dong, G. B. J. Am. Chem. Soc. 2018, 140,
5347; (b) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6,
1257; (c) Dennis, J. M.; Compagner, C. T.; Dorn, S. K.; Johnson, J. B.
Org. Lett. 2016, 18, 3334; (d) Wang, J. J.; Chen, W. Q.; Zuo, S. J.; Liu, L.;
Zhang, X. R.; Wang, J. H.; Angew. Chem. Int. Ed. 2012, 51, 12334.
[14] (a) Hoshimoto, Y.; Asada, T.; Hazra, S.; Kinoshita, T.; Sombut, P.;
Kumar, R.; Ohashi, M.; Ogoshi, S. Angew. Chem. Int. Ed. 2016, 55,
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738; (c) Ohta, S.; Hayakawa, S.; Moriwaki, H.; Tsuboi, S.; Okamoto, M.
Heterocycles. 1985, 23, 1759.
N
d
3ma
52%
aReagents and conditions: 2-acyl-imidazolium salt (0.1 mmol), 2a (0.1
mmol), LiHMDS (0.3 mmol), DME (0.1 M), 80°C, 12 h. bIsolated yield.
cKHMDS (3 equiv.). dNaHMDS (3 equiv.). eReaction conducted in THF.
Conclusion
In summary, a novel method was developed for the aroylation
of diarylmethanes with 2-acyl-imidazolium salts under transition
metal-free conditions. This protocol is distinct from metal-
catalyzed α-arylation methods. An attractive feature of this
method is its avoidance of the use of expensive and toxic metals.
Further studies toward the development of new approaches
involving the cleavage of C(O)−C bonds under transition metal-
free conditions are currently under way.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[15] Yang, F.; Zou, D.; Chen, S. G.; Wang, H.; Zhao, Y. C.; Zhao, L. Y.;
Li, L. L.; Li, J.; Walsh, P. J. Adv. Synth. Catal. 2020.
https://doi.org/10.1002/adsc.202000622
Acknowledgments
J.L. thanks the National Natural Science Foundation of China
(31670357) and Zhejiang Provincial Natural Science Foundation
of China (LY20C020003)
[16] Bordwell, F. G.; Acc. Chem. Res. 1988, 21, 456.
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H.; Robinson, J. R.; Schelter, E. J.; Walsh, P. J. J. Am. Chem. Soc. 2014,
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References and notes
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T. A.; Dixon, R. A. F. J. Med. Chem. 2001, 44, 1211; (e) Fokialakis, N.;
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K.; Du ,G.; Yang, G. Y.; Gao, X. M. J. Nat. Prod. 2013, 76, 1854; (b)
Elavarasan, S.; Gopalakrishnan, M.Chem. Sci. Rev., Lett. 2014, 2, 508; (c)
Monthakantirat, O.; De-Eknamkul, W.; Umehara, K.; Yoshinaga, Y.;
Supplementary Material
Supplementary data to this article can be found online at

4
Tetrahedron
The authors declare no conflict of interest,
financial or otherwise.
Graphical Abstract
To create your abstract, type over the instructions in
the template box below.
Fonts or abstract dimensions shou
Selective transition metal-free aroylation of
diarylmethanes with 2-acyl-imidazolium salts
via acyl C−C bond cleavage
Leave this area blank for abstract info.
Dong Zou,a,§ Li-She Gan,b,§ Fan Yang,a Jia-Min Wang,a Lin-Lin Li,a and Jie Li*,a
O
I
O
Ar2
N
Ar2
Ar1
LiHMDS
DME, 80 oC
+
■
■
broad scope
transition metal-free
Ar1
■ operational-simplicity
■ high selectivity
N
Ar3
Ar3
43-93% yield
Ar1 = Aryl/Hetero-aryl
Ar2 = Aryl/Hetero-aryl
Ar3 = Aryl
Highlights
1. Transition
metal-free
aroylation
of
diarylmethanes with 2-acyl-imidazoliums was
reported.
2. The method expands the application of 2-acyl-
imidazoliums in organic synthesis.
3. A series of 1,2,2-triarylethanones were prepared
using the method present in this study/