Rhodium-catalyzed synthesis of unsymmetrical di(aryl/heteroaryl)methanes using aryl/heteroarylmethyl ketones via CO-C bond cleavage

Article abstract of DOI:10.1039/c4cc00816b

RhH(PPh₃)₄ and 1,2-bis(diphenylphosphino)benzene catalyze the reaction of aryl/heteroarylmethyl ketones and aryl heteroaryl ethers giving unsymmetrical diarylmethanes containing one or two heteroarenes in high yields. The reaction do

Full text of DOI:10.1039/c4cc00816b

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Rhodium-catalyzed synthesis of unsymmetrical
di(aryl/heteroaryl)methanes using aryl/
heteroarylmethyl ketones via CO–C bond
cleavage†
Cite this: Chem. Commun., 2014,
50, 4328
Received 30th January 2014,
Accepted 26th February 2014
Guangzhe Li, Mieko Arisawa* and Masahiko Yamaguchi*
DOI: 10.1039/c4cc00816b
www.rsc.org/chemcomm
RhH(PPh3)4 and 1,2-bis(diphenylphosphino)benzene catalyze the coupling of potassium 2-pyridylacetates or [2-benzoxa(thia)zolyl]acetates
reaction of aryl/heteroarylmethyl ketones and aryl heteroaryl ethers with aryl halides.9 These reactions entailed the C–C bond activation.
giving unsymmetrical diarylmethanes containing one or two hetero- Although these methods do not use stoichiometric organometallic
arenes in high yields. The reaction does not use alkali metal bases, reagents, they use stoichiometric inorganic bases. In addition, the
and therefore does not form large amounts of metal waste.
reactions have a limited scope in terms of the heteroaryl structure in
the product because of the limited availability of a heteroarylmethyl
The di(aryl/heteroaryl) structure Ar–Ar is an important scaffold for drugs component. Note that very few examples of the synthesis of
and functional organic materials, and the construction of its carbon di(heteroaryl)methane were reported using the conventional methods
framework has been extensively studied using the C–C coupling either by the stoichiometric metal reagent methods2b,d,e,4b,d or
reactions between two aryl sp2-carbons.1 In contrast, the di(aryl/hetero- nonstoichiometric methods.5,8,9
aryl)methane structure Ar–CH2–Ar, a carbon homolog, is much less
Previously, we reported rhodium-catalyzed acyl transfer reaction
common,2 although it can be another important scaffold for functional between benzyl ketones and thioesters/aryl esters, which entailed the
organic molecules, characterized by a more flexible structure possessing CO–C bond cleavage of unstrained acyclic ketones.10 The rhodium-
two rotating sp2-C/sp3-C bonds. This may be due to the lack of efficient catalyzed synthesis of unsymmetrical di(aryl/heteroaryl)methanes 3 by
and versatile synthetic methods for constructing this structure.
the reaction of aryl heteroaryl ethers 1 and aryl/heteroarylmethyl
The transition metal-catalyzed synthesis of di(aryl/heteroaryl)- ketones 2 is described in this study (Scheme 1). This reaction proceeds
methanes by the C–C bond formation between the sp2- and sp3- via the cleavage of the C–O bond of 1 and the CO–C bond of 2,
carbons is attractive, since various heteroaryl products can be obtained and C–C bond formation gives 3 containing one or two heteroaryl
by changing the substrate structure. Generally, nucleophilic aryl/hetero- groups. This method, unlike conventional methods, does not use any
arylmethylmetal reagents are reacted with aryl/heteroaryl compounds alkali metal base, and accordingly large amounts of metal waste
with halogen-leaving groups,3 and, alternatively, electrophilic arylmethyl are not formed. A wide range of electron-deficient/electron-rich
halides are reacted with metalated heteroarenes.4 Both methods require five/six-membered heteroaryl ethers 1 such as 2-benzoxazolyl,
the preparation of metalated heteroarenes or methylheteroarenes using 2-benzothiazolyl, 2-thiazolyl, 2-oxazolyl, 2-thienyl, 2-furyl, 2-pyridyl,
stoichiometric amounts of metal, bases, or reducing reagents. Methods 4-quinazolinyl, and 2-triazyl derivatives were employed. Heteroaryl-
not using such stoichiometric metal reagents are rare for the synthesis methyl groups containing 4-pyridyl, 2-benzothiazolyl, 2-thienyl, and
of di(aryl/heteroaryl)methanes. Miura, Ackermann, and Fagnou 2-furyl groups could be attached to the heteroarene cores. The broad
reported the Pd-catalyzed reaction of heterocycles and substituted scope of this reaction, which provides various diarylmethanes 3
benzyl derivatives such as benzyl carbonates,5 benzyl phosphates,6 having one or two heteroarenes, is due to the use of stable substrates
and benzyl chlorides7 in the presence of Cs2CO3, K2CO3, K3PO4, for both heteroaryl and aryl/heteroarylmethyl components.
t-BuOLi, or NaOAc. Oshima and Yorimitsu reported a 2-pyridylmethyl
transfer reaction from 2,4-dimethyl-3-(pyridin-2-ylmethyl)pentan-3-ol to
aryl halides in the presence of Cs2CO3.8 Liu reported the decarboxylative
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aoba, Sendai, 980-8578, Japan.
E-mail: arisawa@m.tohoku.ac.jp, yama@m.tohoku.ac.jp; Fax: +81-22-795-6811;
Tel: +81-22-795-6812
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1
c4cc00816b
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Table 1 Rhodium-catalyzed aryl/heteroarylmethylation of phenyl 2-benz-
oxazolyl ethers
Entry
R
Ar/HetAr
Yield of 3/%
Scheme 2
1
H
Ph
77a, 41b, 57c, 23d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
H
H
H
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-EtO2CC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
p-NCC6H4
4-Pyridyl
51
45
the CO–C bond.10 Although the mechanism of C–O bond cleavage is
not clear, oxidative addition of 2 to a low-valent rhodium complex is
assumed (Scheme 2). It may also be noteworthy that the reaction gave
3 and 4 but not heteroaryl ketones 5 and aryl aryl/heteroarylmethyl
ethers 6, the other mode of the C–O/C–C metathesis reaction. It may
be governed by the thermodynamic stability of the products.
80, 50e
72
H
90, 73e
90
4-Me
5-Me
5-Cl
5-Ph
6-Me
6-Cl
H
H
H
H
85
74
61
89
78
83
70
70
The reaction was applicable to various 1,3-azoles other
than benzoxazoles (Table 2). The p-cyanophenylmethylation of
2-benzothiazoyl ethers proceeded in a higher yield using the
2-(p-chlorophenoxy) derivative (75%) than using the 2-phenoxy
derivative (26%). Benzothiazoles bearing 5-chloro or 5-methoxy
substituents could be transformed into the corresponding products 3c
and 3d in high yields, respectively. p-Chlorophenyl ethers containing
1,3-oxazolyl, 1,3-thiazolyl, and 1,3,4-oxadiazolyl groups reacted with aryl/
heteroarylmethyl ketones, and the corresponding products 3e–3k were
2-Benzothiazolyl
2-Thienyl
2-Furyl
36
a
b
Phenyl benzoate 4a was also obtained in 76% yield. p-Chlorophenyl
c
2-benzoxazolyl ether was used. p-Methoxyphenyl 2-benzoxazolyl ether
was used. Phenyl 2-benzoxazolyl thioether was used. Octyl p-cyano-
phenylmethyl ketone was used.
d
e
When phenyl 2-benzoxazolyl ether 1a was reacted with benzyl obtained. p-Chlorophenyl 2-furyl ether and 2-thienyl ether also gave the
phenyl ketone 2a (3 equiv.) in the presence of RhH(PPh3)4 (10 mol%) aryl/heteroarylmethylation products 3l–3p. The reaction was applied
and 1,2-bis(diphenylphosphino)benzene (dppBz, 20 mol%) in refluxing to the synthesis of the N-heterocyclic six-membered ring compounds
chlorobenzene for 6 h, 2-benzylbenzoxazole 3a and phenyl benzoate 4a 3q–3z containing 2-pyridyl, 4-quinazolinyl, and 2-triazyl groups. The
were obtained in 77% and 76% yields, respectively (Table 1, entry 1). No broad applicability of the rhodium-catalyzed reaction enabled the
reaction occurred in the absence of the rhodium complex or dppBz. synthesis of various di(aryl/heteroaryl)methanes.
When the molar ratio 2a/1a was changed from 3 to 2, the yields of 3a
Note that 3v equilibrated with the enol form 3v0 (3v : 3v0 =
and 4a decreased to 43% and 43%, respectively. p-Chlorophenyl and 1 : 1.6), and recrystallization from CHCl3 gave pure 3v0 in 70%
p-methoxyphenyl 2-benzoxazolyl ethers reacted to form 3a in moderate isolated yield (Scheme 3). Such enolization of diheteroaryl-
yields. The yield of 3a decreased using phenyl 2-benzoxazolyl thioether; methane has not yet been reported.11
2-ethoxy-, 2-methylthio-, 2-chlorobenzoxazole, and benzoxazole did not
The reaction was applied to a 2-aryl cyclic ketone giving a
react under the given conditions: the leaving ability appears to be (heteroaryl)arylmethane with an alkyl substituent at the benzylic
not directly related to the yield of 3a. Substituted benzyl ketones with position (Scheme 4). The reaction of phenyl 2-benzoxazolyl ether 1a
either p-electron-donating or p-electron-withdrawing groups gave aryl with 2-( p-cyanophenyl)cyclopentanone 7b gave 1-(2-benzoxazolyl)-1-
2-benzylbenzoxazoles (entries 2–6). Octyl p-cyanophenylmethyl ketone ( p-cyanophenyl)pentanoic phenyl ester 8b in 60% yield.
underwent p-cyanophenylmethylation (entries 4 and 6). Benzoxazolyl
In summary, RhH(PPh3)4 and dppBz catalyze the aryl/
ethers bearing methyl, phenyl, or chloro substituents on the benzene heteroarylmethylation of aryl heteroaryl ethers 1 using aryl/
ring could be reacted to form p-cyanobenzyloxazole derivatives in high heteroarylmethyl ketones 2, and various di(aryl/heteroaryl)-
yields (entries 7–12). The reaction was also applicable to heteroaryl- methanes 3 are produced from such a reaction. The reaction
methyl ketones containing 4-pyridylmethyl, 2-benzothiazolylmethyl, entails the C–O bond cleavage of 1 and the CO–C bond cleavage
2-thienylmethyl, and 2-furylmethyl groups (entries 13–16). This of 2 with concomitant C–C bond formation. The broad applic-
method can transfer heteroarylmethyl groups to aryl heteroaryl ability of this method is due to the use of stable substrates for
ethers, giving various unsymmetrical di(heteroaryl)methanes. both heteroaryl and heteroarylmethyl components. Also note
Note that heteroatom chelation is not critical for the CO–C that the chelation of the metal catalyst with the heteroarene is
bond cleavage, as indicated by the reaction of the substituted not required for the cleavage of the CO–C bond in the substrates.
benzyl and 4-pyridylmethyl ketones.
The nonuse of an alkali metal base is another advantage of
The rhodium catalyst activates the C–O bond of phenyl this reaction. This catalytic process provides a straightforward
heteroaryl ethers 1 and the CO–C bond of aryl/heteroarylmethyl synthetic method for unsymmetrical diarylmethanes with one or
ketones 2 providing product 3 with the concomitant formation two heteroaryl groups, which are interesting for both medicinal
of aryl esters 4. As noted before, the catalysis can directly cleave and material applications.
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Table 2 Rhodium-catalyzed aryl/heteroarylmethylation of aryl heteroaryl
ethers
This work was supported by a Grant-in-Aid for Scientific
Research (No. 21229001), and Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
M. A. expresses her appreciation for the financial support from
the Grant-in-Aid for Scientific Research (No. 22689001 and
25109503), and also from the Asahi Glass Foundation.
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Scheme 3
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Scheme 4
4330 | Chem. Commun., 2014, 50, 4328--4330
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