Rhodium-catalyzed transformation of heteroaryl aryl ethers into heteroaryl fluorides

Article abstract of DOI:10.1039/c6cc05400e

A rhodium complex catalyzed the conversion of the C-O bond of heteroaryl aryl ethers to the C-F bond. The reaction of (4-chlorophenylthio)pentafluorobenzene with heteroaryl aryl ethers provided heteroaryl fluorides and heteroaryl (4-chlorophenylthio)tetrafluorophenyl ethers; this involved the cleavage of a single heteroaryl C-O bond under equilibrium conditions. The reaction of heteroaryl aryl ethers with 2-fluorobenzothiazole in which two heteroaryl and aryl C-O bonds were cleaved provided heteroaryl fluorides and aryl fluorides. The reactions were applicable to five-membered and six-membered heteroaryl aryl ethers and also to diaryl ethers possessing one or two electron-withdrawing groups.

Full text of DOI:10.1039/c6cc05400e

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Rhodium-Catalyzed Transformation of Heteroaryl Aryl
Ethers to Heteroaryl Fluorides
Received 00th January 20xx,
Accepted 00th January 20xx
Mieko Arisawa*, Saori Tanii, Takeru Tazawa, and Masahiko Yamaguchi*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A rhodium complex catalyzed the conversion of the C-O bond of small activation energies are energy-saving, and can be used to
heteroaryl aryl ethers to the C-F bond. The reaction of (4- control forward/backward reactions by shifting equilibrium.6
chlorophenylthio)pentafluorobenzene and heteroaryl aryl ethers Recently, we reported rhodium-catalyzed synthesis of
provided
heteroaryl
fluorides
and
heteroaryl
(4- unsymmetrical diarylmethanes using benzyl ketones and diaryl
chlorophenylthio)tetrafluorophenyl ethers; this involved the ethers.7 It was noted that the C-O bonds of diaryl ethers were cleaved
cleavage of a single heteroaryl C-O bond under an equilibrium by rhodium catalyst, and then related reactions were examined.
conditions. The reaction of heteroaryl aryl ethers and 2- Described here is the rhodium-catalyzed fluorination reaction of
fluorobenzothiazole in which two heteroaryl and aryl C-O bonds heteroaryl aryl ethers giving heteroaryl fluorides (Scheme 1). The
were cleaved provided heteroaryl fluorides and aryl fluorides. use of (4-chlorophenylthio)pentafluorobenzene as the fluorinating
The reactions were applicable to five-membered and six- reagent gave heteroaryl fluorides and diaryl ethers, where a single C-
membered heteroaryl aryl ethers and also to diaryl ethers O bond in the substrate was converted to the C-F bond. In addition,
possessing one or two electron-withdrawing groups.
the use of 2-fluorobenzothiazole provided heteroaryl fluorides and
aryl fluorides, where two C-O bonds were converted to the C-F
bonds. The rhodium catalyst activates the C-O bonds and transfers
fluorine atoms from heteroaryl/aryl fluorides. A wide range of
Various bioactive substances, agricultural chemicals, and
functional materials contain heteroaryl aryl ether structures,1 which
are synthesized from heteroaryl halides and aryloxy metals by
substitution reactions.2 To form strong C-O bonds, such high energy
methods are employed. Note also that the cleavage of heteroaryl aryl
ethers can be employed for the transformation and recovery/reuse of
such functional substances. The C-O bonds of diaryl ethers, however,
are strong and stable, and exhibit low chemical reactivity. In
particular, it is not facile to convert heteroaryl aryl ethers to
heteroaryl halides, the reverse reaction of the synthesis.
electron-deficient/electron-rich
five-membered/six-membered
heteroaryl aryl ethers with 2-benzothiazolyl, 2-thiazolyl, 2-oxazolyl,
2-furyl, 2-thienyl, 2-pyridyl, 4-quinazolinyl, and 2-triazyl groups
were fluorinated under rhodium-catalyzed conditions. This method
converts stable heteroaryl aryl ethers8 into heteroaryl and aryl
fluorides using organofluorides as fluorinating reagents.
Heteroaryl fluorides are generally prepared by the nucleophilic
aromatic fluorination of heteroarenes possessing leaving groups such
as chloro-, bromo-, nitro-, triflate-, trialkylammonium-, and
diazonium groups in the presence of nucleophilic fluorides such as
KF, AgF, CsF, and Bu4N+F-.3 The nucleophilic/oxidative C-H
fluorination of pyridine and pyrimidine derivatives employing AgF2
has recently been reported.4 Alternatively, heteroaryl fluorides were
synthesized by electrophilic fluorination.3a, 5 It was then considered
attractive to synthesize heteroaryl fluorides from heteroaryl aryl
ethers, which can be used for the synthesis and recovery/reuse of
such functional substances.
Scheme 1. The rhodium-catalyzed fluorination reaction of heteroaryl
aryl ethers
Heteroaryl fluorides were formed from heteroaryl aryl ethers.
When 4-(2-benzothiazolyloxy)benzonitrile 1a8 was reacted with (4-
chlorophenylthio)pentafluorobenzene 2a (1 equiv.) in the presence
We have been studying on the use of catalyzed equilibrium
reactions in organic synthesis, because equilibrium reactions with
of
RhH(dppBz)2
(10
mol%,
dppBz
=
1,2-
bis(diphenylphosphino)benzene) in refluxing chlorobenzene for 3 h,
2-fluorobenzothiazole 3a (42%) and 1-(4-chlorophenylthio)-4-(4-
cyanophenoxy)-2,3,5,6-tetrafluorobenzene 4a (43%)9 were obtained
with the recoveries of 1a (40%) and 2 (42%) (Scheme 2). The
RhH(dppBz)2 complex was synthesized in this study by the ligand
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exchange of RhH(PPh3)4 and dppBz (2 equiv).10 When RhH(PPh3)4
(10 mol%) and dppBz (20 mol%) were used in place of
RhH(dppBz)2, 3a (27%) and 4a (30%) were formed along with
F2PPh3 (100% based on PPh3).9a The liberated PPh3 trapped the
fluorine atoms of the substrate and the product, which reduced the
yield of 3a. No reaction occurred in the absence of the RhH(PPh3)4
or dppBz. To avoid such side reactions, RhH(dppBz)2 was used, in
which the phosphine ligand was not fluorinated. The fluorination
reaction of 2-(4-benzoylphenoxy)benzothiazole (40%) and 2-(4-
chlorophenoxy)benzothiazole (5%) with 2a was lower than that of
1a. This result may be due to the weaker C-O bond in the latter.
Cleavage of the benzothiazolyloxy C-O bond of 1a occurred, while
that of the 4-cyanophenoxy C-O bond did not.
The reverse reaction of 3a and 4a under the same reaction
conditions gave 1a and 2a in 43% and 42% yields, respectively
(Scheme 2), which indicated the equilibrium nature of the reaction.
When the molar ratio of 2a to 1a was changed from 1 to 4, the yield
of 3a increased to 67%, which was consistent with the reaction being
in equilibrium. Here, 2a is the fluorinating reagent of 1a in the
forward reaction, and 3a is the fluorinating reagent of 4a in the
reverse reaction. This result also indicated that the reaction could be
used to synthesize heteroaryl ether 1a from diaryl ether 4a, and
alternatively, 4a from 2a. From a synthetic standpoint, this method
for heteroaryl/aryl aryl ethers, unlike conventional methods, does not
use metal alkoxides or bases.
Table 1. Rhodium-catalyzed synthesis of heteroaryl fluorides.
Entry Substrates 1
Yield of 3/%
1
2
3
4
5
1a R = H
3a 67
3b 60
3c 60
3d 55
3e 60
1b R = 6-Me
1c R = 6-iPr
1d R = 5-Me
1e R = 5,6-diMeO
6
7
8
9
1f R = 4-Ph
3f 65
3g 58
3h 50
3i 78
1g R = 4-ClC6H4
1h R = 4-MeOC6H4
1i R = 4,5-diPh
1j
3j 32
10
11
12
1k X = O, R = CH3CO
1l X = S, R = PhCO
3k 40
3l 26
13
14
15
16
17
1m R = MeO
3m 96
89
56
36
3n 68
R = MeO, Ar = 4-ClC6H4
R = MeO, Ar = Ph
R = MeO, Ar = 4-Tolyl
1n R = H
18
19
20
1o
1p
1q
3o 98
3p 96
3q 95
Scheme 2. Rhodium-catalyzed equilibrium fluorination
21
22
1r
1s
3r 99
3s 60
It was confirmed that the resulting diaryl ether 4a was not
fluorinated by 2a at the 4-cyanophenyl C-O bond (Scheme 3). In the
presence of RhH(dppBz)2 (10 mol%), the reaction of 4a and 2a gave
trace amounts of 5a and bis(tetrafluorophenyl) ether 9. Therefore, 2a
converted a single heteroaryl C-O bond in 1a, and not the aryl C-O
bond.
23
24
1t R = 2-CF3-4-CN
1u R = 3-CF3-4-CN
3t 99
3u 96
Entries 1-12, 4 equiv. of 2a were used. Entries 13-24, 2 equiv. of
2a were used.
The fluorination reaction using 2a (4 equiv.) was examined with
various five-membered heteroaryl aryl ethers (Table 1). Those with
1,3-benzothiazolyl, 1,3-oxazolyl, and 1,3-thiazolyl ethers with 4-
cyanophenoxy groups were converted to the fluorinated 1,3-azoles
3a-3j in good yields (entries 1–10). 2-Furyl and 2-thienyl 4-
cyanophenyl ethers also gave the corresponding products 3k and 3l
(enties 11 and 12).
Scheme 3. No fluorination of diaryl ether 4a by 2a
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The fluorination of six-membered heteroaryl aryl ethers using 2a
(2 equiv.) proceeded in high yields. The heteroaryl aryl ethers with
4-cyanophenoxy groups containing 4-quinazolinyl, 2-quinoxalinyl,
2-quinolinyl, 2-triazyl, 2-pyrimidyl, and 3-pyridazyl groups reacted
with 2a, and the corresponding heteroaryl fluorides 3m-3s were
obtained in quantitative yields (entries 13, 17–22). The fluorination
of 6,7-dimethoxy-4-quinazolinyl aryl ethers with 4-(4-
cyanophenoxy) (96%), 4-(4-chlorophenoxy) (89%), 4-phenoxy
(56%), and 4-(4-tolylphenoxy) (36%) groups also proceeded (entries
13–16). Diaryl ethers with 4-cyanophenoxy groups also provided the
aryl fluorides 3t and 3u, in which two electron-withdrawing groups
were attached (entries 23 and 24). The C-O bond cleavage reaction
using 2a showed broad applicability to heteroaryl aryl ethers and
diaryl ethers giving heteroaryl and aryl fluorides.
A possible mechanism of the fluorination reaction follows taking
into account of equilibrium nature of the reaction, (Figure 1).
Oxidative addition of Het1–OAr and Het2–F to the rhodium(I)
complex provides fluororhodium(V) intermediate, and reductive
elimination forms Het1–F and Het2–OAr with the regeneration of the
Scheme 4. Rhodium-catalyzed fluorination of heteroaryl and aryl C-
O bonds in heteroaryl aryl ethers
rhodium(I) catalyst.6,
It is considered that rhodium fluoride
11
complex can exhibit notable chemical reactivity. Bi(heteroaryl)
Het1–Het2 cannot form from the intermediate because of
thermodynamically unfavourable nature of ArOF.
The reaction of an aryl C-O bond to form a C-F bond was
examined using the benzothiazolyl aryl ethers 1a, 1v, and 1w with
different substituted aryl groups. The reaction of 3a (1 equiv) and 4-
(2-benzothiazolyloxy)benzonitrile 1a in the presence of
RhH(dppBz)2 (10 mol%) in refluxing chlorobenzene for 3 h gave 4-
fluorobenzonitrile 5a (99%) and 6 (99%) (Scheme 5). The cleavage
of the aryloxy C-O bond in 1v and 1w occurred using 3a and formed
4-fluorobenzophenone 5v (78%) and 3-chloro-4-fluorobenzonitrile
5w (99%), respectively, along with 6. The reaction of benzothiazolyl
4-chlorophenyl and phenyl ethers with 3a did not occur. It was
determined that the reaction of 6 and 5a did not give 1a and 3a in the
presence of RhH(dppBz)2 (10 mol%). The fluorination reaction is
irreversible, which may be due to the thermodynamically stable
nature of 6.
Figure 1. Possible mechanism.
Use of 2-fluorobenzothiazole 3a for the fluorinating reagent was
examined. It was found that both heteroaryl and aryl C-O bonds in
heteroaryl aryl ethers were cleaved and converted to the C-F bonds
(Scheme 4). The reaction of 3a (2 equiv) and 1f gave 2-fluoro-4-
phenyloxazole 3f (58%) and 4-fluorobenzonitrile 5a (67%), which
was accompanied by [2,3’(2’H)-benzothiazol]-2’-one 612 (56%).
Noted that two fluorine atoms of two moles of 3a were used to
convert two C-O bonds of 1f into two C-F bonds, and the oxygen
atom of 1f was captured by 3a, which resulted in the formation of
the dimeric compound 6. Oxazolone 7, the coupling product of 1f
and 3a, was not observed. The heteroaryl C-O bond of 1f should
initially be converted to the C-F bond, which would then be
followed by the fluorination of the aryl C-O bond. 4-[(4,5-
Diphenyloxazolyl)oxy]bezonitrile 1i was also fluorinated. The
fluorination of 4-[(5-acetyl-2-furanyl)oxy]benzonitrile 1k with 3a
gave
1-(5-fluoro-2-furanyl)ethanone
3k
(53%)
and
fluorobenzonitrile 5a (30%), which was accompanied by 6 (34%).
The fluorination of the 4-quinazolinyl 4-cyanophenyl ethers 1m and
1n provided the corresponding 4-quinazolinyl fluorides 3m and 3n
in high yields, which were accompanied by 5a and 6. 4-[2-
Quinoxalinyl]oxy] 1o and 4-[(2-pyrimidyl)oxy] 1r bezonitriles were
also fluorinated using 3a.13 Thus, the fluorination is applicable to 5-
membered and 6-membered heteroaryl aryl ethers, and the use of 3a
efficiently converted two C-O bonds of the heteroaryl aryl ethers to
C-F bonds.
Scheme 5. Rhodium-catalyzed fluorination of benzothiazolyl aryl
ethers
The initial C-O bond cleavage of heteroaryl aryl ethers occurred at
the heteroaryl C-O bond using 3a, which should be a weaker bond
compared with the aryl C-O bond (Scheme 6), and heteroaryl
fluorides and benzothiazolyl 4-cyanophenyl ether 1a were formed.
The second fluorination occurred at the 4-cyanophenoxy C-O bond
of 1a and gave the aryl fluoride 5a and 6 (Scheme 5). Because 1a
was not observed in the reaction of heteroaryl aryl ether with 3a, the
second fluorination of 1a by 3a may be faster than the initial
fluorination. The 2-fluorobenzothiazole 3a efficiently converted two
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C-O bonds of the heteroaryl aryl ethers to C-F bonds in irreversible Molecules (No.2408)” (JSPS KAKENHI Grant Number 15H00911),
reaction. Irreversibility is likely because of the high thermodynamic and the research grant of Astellas Foundation for Research on
stability of 6, compared with the hypothetical product Metabolic Disorders.
bis(benzothiazolyl) ether 8.14
Notes and references
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and P. J. Steel, Inorg. Chem. Commun. 1999, 2, 368-370.
2. For examples, a) Y. Zhang, G. Ni, C. Li, S. Xu, Z. Zhang and X. Xie,
Scheme 6. Rhodium-catalyzed cleavage of two heteroaryl and aryl
Tetrahedron, 2015, 71, 4927-4932; b) Q. Liu, Z. Lu, W. Ren, K. Shen,
C-O bonds using 3a
Y. Wang, Q. Xu, Chin. J. Chem. 2013, 31, 764-772; c) Q. Zhang, D.
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2006, 47, 5045-5048; e) Review R. Frlan and D. Kikelj, Synthesis,
In contrast, the (4-chlorophenylthio)pentafluorobenzene 2a
converted a single C-O bond of heteroaryl aryl ethers giving
heteroaryl fluorides and diaryl ether 4a under equilibrium
conditions (Scheme 7). It was determined that 2a did not
fluorinate 4a (Scheme 3). The rhodium-catalyzed fluorination
reactions are governed by the reactivity of the fluorinating
reagents 2a and 3a.I
2006, 14, 2271-2285; f) Review S. V. Ley and A. W. Thomas, Angew.
Chem. Int. Ed. 2003, 42, 5400-5449.
3. a) Review M. G. Campbell and T. Ritter, Chem. Rev., 2015, 115, 612-
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Fan, X. Li, J. Clemens, C. L. Horchler, N. C. Lim and G. Attardo, Org.
Lett., 2015, 17, 3726-3729; c) Halogen derivatives, H. Sun, S. G.
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Scheme 7. Rhodium-catalyzed cleavage of a single heteroaryl C-O 8. For examples, a) M. Tobisu, T. Takahira, T. Morioka and N. Chatani, J.
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Conclusions
9. The rhodium-catalyzed reaction generally proceeded at the p-position
In summary, the rhodium catalyst transferred fluorine atoms from
arylfluorides to heteroaryl aryl ethers, which provided various
heteroaryl and aryl fluorides. The rhodium catalyst converted of a C-
of
pentafluorobenzenes,
and
the
reactivity
of
arylthiopentafluorobenzene is comparatively high. a) M. Arisawa, T.
Suzuki, T. Ishikawa and M. Yamaguchi, J. Am. Chem. Soc., 2008, 130,
12214-12215; b) M. Arisawa, Y. Igarashi, H. Kobayashi, T. Yamada,
K. Bando, T. Ichikawa and M Yamaguchi, M. Tetrahedron, 2011, 67,
7846-7859.
O
bond
to
a
C-F
bonds
using
(4-
chlorophenylthio)pentafluorobenzene 2a under equilibrium. Use of
2-fluorobenzothiazole 3a converted two C-O bonds to the C-F bonds.
This method, which cleaves the C-O bonds of heteroaryl aryl ethers
and provides the C-F bonds, can be used for the synthesis and
recycle/reuse of functional heteroaryl aryl ethers.
10. The synthesis and characterization are described in SI.
11. a) S. A. Macgregor, T. Wondimagegn, Organometallics, 2007, 26,
1143-1149. b) V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc., 2004,
126, 3068-3069.
12. Y. Uchibori, M. Umeno and H. Yoshioka, Heterocycles, 1992, 34,
1507-1510.
13. The reaction data were included in SI.
Acknowledgements
14. Compound 8 was not known before. It was reported that 4-nitrophenyl-
4-pyridyl ether isomerized a N-(4-nitorophenyl)pyridone at 140°C in
the presence of a base. F. You and R. J. Twieg, Tetrahedron Lett., 1999,
40, 8759-8762.
This work was supported by 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 to the financial supports from a Grant-in-
Aid for Scientific Research on Innovative Areas “Stimuli-responsive
Chemical
Species
for
the
Creation
of
Functional
4 | J. Name., 2012, 00, 1-3
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