Catalyst-free N-arylation using unactivated fluorobenzenes

Article abstract of DOI:10.1002/anie.201202149

Caught in a 'S_NAr'e: A one-step, high-yielding, catalyst-free method is described for N-arylation of azoles and indoles from unactivated monofluorobenzenes. This S_NAr reaction tolerates a wide range of substituents and can also generate halogenated N-aryl products. The reaction can also be performed simultaneously with or subsequent to a copper- or palladium-catalyzed cross-coupling reaction in the same pot. Copyright

Full text of DOI:10.1002/anie.201202149

Angewandte
Chemie
DOI: 10.1002/anie.201202149
Heterocycles
Catalyst-Free N-Arylation Using Unactivated Fluorobenzenes**
Frederik Diness* and David P. Fairlie*
N-arylation of heteroaromatic compounds is an extremely
tions such as copper-catalyzed Ullmann-type N-arylation or
important C N bond-forming reaction in organic synthesis,
palladium-catalyzed Buchwald–Hartwig coupling.[7] How-
ever, transition-metal-catalyzed N-arylation has some draw-
backs in industrial applications as it is expensive, oxygen
sensitive, and may leave toxic trace metal contaminants. In
addition, the synthesis of bromo- or iodo-substituted N-
arylated azole derivatives is difficult using metal-catalyzed
cross-coupling, which relies upon selective monosubstitution
of benzene rings having two or more iodo/bromo substitu-
ents.[8]
À
especially with N-arylated azole and indole derivatives
finding important uses (Scheme 1) as inhibitors of enzymes[1]
(e.g. COX-1,[1a] COX-2,[1b] PDE3,[1c] PDE5,[1d] topoisomera-
se II[1e]), inhibitors of ATP binding,[2] agonists or antagonists
of G protein-coupled and other receptors[3] (e.g. DA D-2,[3a] 5-
HT2,[3b] a1AR,[3a] CB1,[3b,c] Sigma s2,[3d] GABAA[3e]), modu-
lators of ion-channels,[4] as key components in LED produc-
tion,[5] and for creating organometallic catalysts.[6] N-arylated
azole and indole derivatives are also registered pharmaceut-
icals (e.g. celecoxib, midazolam, flumazenil, nilotinib, edar-
avone, alprazolam, sertindole; Figure 1) and insecticides or
fungicides (e.g. pyraclofos, pyraclostrobin).
Catalyst-free N-arylation has been effected by SNAr
substitution on highly electron-deficient fluorobenzene deriv-
atives having additional electron-withdrawing groups, such as
nitro, carbonyl, sulfonyl, nitrile, or fluoro,[9] but reported
methods give low yields for less activated fluorobenzene
derivatives and are not feasible for unactivated fluoroben-
zenes.[10] However, we find that under optimized reaction
conditions, in which the choices of base and solvent play key
roles, these reactions occur rapidly and with full conversion.
Herein we describe a simple, high yielding, catalyst-free N-
arylation reaction in which fluorine is displaced from
unactivated fluorobenzenes by azole and indole derivatives
(Scheme 1). This reaction also tolerates a wide range of
substituents on the azole or the fluorobenzene (including
bromo and iodo), thus making it a highly versatile and high
yielding synthetic method for N-arylation.
N-arylated azole and indole derivatives are most com-
monly synthesized from iodobenzene or bromobenzene
derivatives by transition-metal-catalyzed cross-coupling reac-
Scheme 1. Catalyst-free N-arylation using monofluorobenzenes.
N-arylation was initially optimized herein using 4-bromo-
fluorobenzene, which has been reported in numerous copper-
or palladium-catalyzed N-aryl cross-coupling reactions
involving the displacement of bromine.[11] Here, we instead
selectively displace fluorine with azole or indole derivatives in
dipolar aprotic solvents containing a simple inorganic base
(Tables 1 and 2). The reaction proved to be very robust, thus
tolerating a diverse range of inorganic bases, polar aprotic
solvents, and reaction temperatures. However, it was found
that the N-(4-bromophenyl)-benzimidazole product (1) was
prone to undergoing additional transformations. To prevent
ongoing reactions, conditions had to be optimized to achieve
full conversion, short reaction times, and high yields. Mon-
itoring crude reaction mixtures by HPLC and LCMS enabled
rapid identification of reaction progress and product forma-
tion (see Supporting Information). As a base, potassium
phosphate was superior to a range of other potassium bases,
with carbonate giving poor conversion, and hydroxide and
especially tert-butoxide giving good conversion but with
substantial amounts of by-products (Table 1 and Supporting
Information). The corresponding sodium salts had similar
reactivity, and lithium salts followed the same trends but with
lower conversion (see Supporting Information). Cesium
carbonate was superior to other carbonate salts, and reactions
were a little faster than that using potassium phosphate. DMF
or DMA were most effective and efficient for product
Figure 1. Examples of N-arylated registered pharmaceuticals.
[*] Dr. F. Diness,[+] Prof. D. P. Fairlie
Division of Chemistry and Structural Biology
Institute for Molecular Bioscience, The University of Queensland
Brisbane, Queensland 4072 (Australia)
E-mail: d.fairlie@imb.uq.edu.au
[+] Current address: Department of Drug Design and Pharmacology,
University of Copenhagen
Universitetsparken 2, 2100 Copenhagen (Denmark)
E-mail: fdi@farma.ku.dk
[**] We acknowledge the Carlsberg Foundation (Denmark) for a post-
doctoral fellowship (to F.D.) and the Australian Research Council
and NHMRC for fellowships (to D.P.F.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202149.
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Table 1: Varying reaction conditions.[a]
Table 2: N-arylation of azoles or indoles with 4-fluorobromobenzene.[a]
Entry Base
Solvent
T [8C] t [h] Conv. [%][b] Yield [%][c]
Product
Cond. Yield
[%][b]
Product
Cond. Yield
[%][b]
1
2
3
4
5
6
7
8
K3PO4
KOH
KOtBu
KF
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
–
DMF
–
–
–
–
–
–
–
DMF
DMA
NMP
DMSO
1,4-dioxane
DMF
190
–
–
–
–
–
–
–
170
–
0.5
–
–
–
–
–
–
–
1
–
–
–
–
24
16
4
1
0.25
1
88
61
81
<5
<5
15
11
97
75
87
27
64
88
38
29
[d]
–
–
–
–
A
B
89
93
[d]
A
A
84
79
[d]
[d]
88
75
83
17
53
A
B
71
72
9
10
11
12
13
14
15
16
17
18
19
–
–
–
–
–
–
[d]
<1
–
A
B
91
88
K3PO4
140[e]
150[e]
170
190
210
170
90
>99
99
99
96
90
93
95
91
90
88
C
A
A
91
94
89
–
–
–
–
A
B
87
81
Cs2CO3 DMA
>99
[a] Reaction conditions: benzimidazole (0.5 mmol), 4-bromo-fluoro-
benzene (2 equiv), base (5 equiv), solvent (5 mL), microwave heating.
[b] Conversion of benzimidazole determined by HPLC (see Supporting
Information). [c] Yield of 1 determined by HPLC (see Supporting
Information). [d] Not assessed because of low coversion. [e] Conven-
tional heating instead of microwave. DMA=N,N’-dimethylacetamide,
DMF=N,N’-dimethylformamide, DMSO=dimethylsulfoxide,
NMP=N-methylpyrrolidone.
A
78
[a] Reaction conditions: azole (0.5 mmol), 4-bromo-fluorobenzene (2 equiv),
and either A) K3PO4 (5 equiv), DMF (5 mL), 1908C, 1 h, microwave, or
B) K3PO4 (5 equiv), DMF (5 mL), 1508C, 16 h, conventional heating, or
C) Cs2CO3 (5 equiv), DMA (5 mL), 1908C, 16 h, microwave; [b] Yield of
isolated product.
formation with minimal amounts of by-products, but DMSO
promoted by-product formation and NMP gave much slower
conversion. The reaction proceeded at 140–2108C, however
by-product formation increased slightly at the higher temper-
atures. The reaction was insensitive to one equivalent of
water, but was prevented in a 1:4 mixture of H2O/DMF as the
solvent mixture.
Lowering the energy barrier to formation of the inter-
mediate Meisenheimer sigma complex is known to be
important in facilitating SNAr reactions.[9a] It was found that
reaction rates were enhanced by adding excess potassium
phosphate, even changing from 2 to 5 equivalents had
a pronounced effect. It was also noted that the reaction rate
was slower with potassium tert-butoxide, which is quite
soluble and fully deprotonates benzimidazole under the
reaction conditions, than with potassium phosphate or
cesium carbonate. Thus, base not only deprotonates the
azole/indole derivative but also has additional effects on the
reaction rates.
Detailed LCMS and HPLC studies (see Supporting
Information) proved that nucleophilic attack proceeds pref-
erentially on the fluorine-substituted carbon atom of the
bromobenzene ring, thus leading to the desired product 1 with
no trace of N-(4-fluorophenyl)-benzimidazole observed.
However, small amounts of phenol derivatives and N,N-
dimethyl-bromo-aniline were also generated, presumably
through attack on 4-bromofluorobenzene by small amounts
of competing nucleophiles. Depending upon reaction con-
ditions, varying amounts of disubstituted and debrominated
products were also observed. It is proposed that substitution
of bromine occurs through benzyne formation, which then is
attacked by a second nucleophile (SNEA mechanism) to form
disubstituted dehalogenated benzene derivatives. This is
supported by recent reports using other bromo- and iodo-
benzene derivatives.[12] Nevertheless, the optimized reaction
conditions identified herein gave high yields of the desired N-
(4-bromophenyl)-benzimidazole (1; Table 1, Table 2).
The optimized reaction conditions were also applied in
the N-arylation of a range of substituted azole and indole
derivatives, thus successfully converting them into one major
product in good to excellent yields (Table 2). In general, N-
arylation was not affected by the nature of the substituents on
either azoles or indoles, thus giving products with electron-
withdrawing or electron-donating substituents (Table 2).
To extend the scope of N-arylation, 4-fluorobromoben-
zene was replaced with a series of other halogenated
fluorobenzenes. Gratifyingly, each reacted under the opti-
mized reaction conditions to give the corresponding N-phenyl
benzimidazole or pyrazole derivative in good to excellent
2
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Table 3: N-arylation of azoles with halogenated fluorobenzenes.[a]
Table 4: N-arylation of azoles with alkyl- and aryl-fluorobenzenes.[a]
Product
Cond. Yield
[%]
Product
Cond. Yield
[%]
Product
Cond. Yield
[%][b]
Product
Cond. Yield
[%][b]
A
B
98[b]
A
B
62[b]
73[c]
A
B
>99
E
E
99
95
>95[c]
A
B
93[b]
A
B
84[b]
91[c]
>95[c]
92
C
B
94[b]
82[c]
D
A
A
A
80[b]
B
>99
E
98
A
B
86[b]
90[c]
>99[b]
A
A
79[b]
91[b]
83[b]
C
>99
F
81
96
72[b]
D
98
A
[a] Reaction conditions: azole (0.5 mmol), fluorobenzene derivative
(2 equiv), K3PO4 (5 equiv), DMF (5 mL) and either A) 1908C, 1 h, micro-
wave, or B) 1508C, 24 h, heating block, or C) 1908C, 2 h, microwave, or
D) 1708C, 1 h, microwave. [b] Yield of isolated product. [c] Determined by
HPLC.
[a] Reaction conditions: azole (0.5 mmol), fluorobenzene derivative,
Cs2CO3 (2.5 mmol), DMA (5 mL), microwave and either A) 2.5 mmol,
1908C, 16 h, or B) 2.5 mmol, 2108C, 12 h, or C) 5 mmol, 2108C, 24 h, or
D) 1 mmol, 2108C, 12 h, or E) 1.0 mmol, 1908C, 16 h, or F) 1.0 mmol,
1908C, 12 h. [b] Yield of isolated product.
yields (Table 3). These findings are important because bromo-
and iodo-substituted N-phenyl azole derivatives are difficult
to synthesize by other methods. In general, replacement of
fluorine did not affect the the other halogen substituent, there
was no loss of chlorine, and only meta-substituted bromo and
iodo products showed significant loss of halogen. However,
these meta-substituted products were still obtained in good
yields under optimized reaction conditions. Interestingly, the
reaction with 2-bromo-4-fluoro-iodobenzene showed little
loss of halogen and gave full conversion at 1708C after 1 hour.
N-phenyl azole products with a bromo and an iodo substitu-
ent are very difficult to obtain through other methods with 3i
being, to our knowledge, the first example of this kind.
Encouraged by the success with halogenated fluoroben-
zene derivatives, substituents other than a halogen were also
examined for effects on reactivity. A series of unactivated
fluorobenzenes were tested and no further transformation of
the product was observed despite the extended reaction times
(Table 4). Interestingly, even fluorobenzene reacted under
the conditions with full conversion and excellent product
yields (Table 4). To our knowledge, this is the first example of
a quantitative, catalyst-free, synthesis of N-phenyl derivatives
of any type of azole. Even the fluorotolyl derivatives, with an
electron-donating methyl group, underwent full conversion
within 24 hours albeit at higher temperatures. Fluorine-
substituted biphenyl and naphthyl derivatives also gave full
conversion to the desired products in excellent yields upon
isolation. Methoxy and thiophenyl substituents were
untouched even under prolonged reaction times (4i/4j and
4k). The electronic effect of the methoxy substituent had little
impact on regioselectivity, thus resulting in approximately 1:1
mixture of 4i/4j. In contrast, a bulky 3-thiophenyl group on
pyrazole leads to one product (4k; Table 4). Compounds 3b,
4a, 4b, and 4i are known inhibitors of ATP binding to the
platelet-derived growth factor receptors (PDGFRs),[2] which
are targets in cancer, vascular disorders, and fibrotic dis-
eases.[13] Previously 4i was synthesized in three steps by
a cross-coupling reaction.[2] We envisage that the present
methodology may be useful for developing new PDGFR
inhibitors.
Because of the high purity of the crude N-(4-bromo-
phenyl)-benzimidazole products, we envisaged that addi-
tional transformation by cross-coupling reactions could be
effected in the same pot without the need for an intervening
purification step. This was indeed the case, exemplified here
for Suzuki coupling, Sonogashira coupling, Ullmann-type
reactions, and a simple N-alkylation (Scheme 2). All these
reactions proceeded successfully to the desired products in
good yields and with no significant by-products. To explore
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result in halogenated N-aryl derivatives. This catalyst-free N-
arylation reaction is also compatible with metal-catalyzed
cross-coupling reactions performed in the same pot simulta-
neously with, or subsequent to, SNAr substitution of fluorine
in fluorobenzene derivatives. We predict that these new
methods may have wide synthetic utility across organic,
medicinal, agricultural, and polymer chemistry as well as in
materials science applications.
Experimental Section
General procedure for SNAr N-arylation using monofluorosubstituted
benzene: Base was added to a glass vial containing the azole/indole
derivative and the fluorobenzene derivative in dry solvent (5 mL).
The vial was sealed with a teflon cap and the mixture was heated by
microwave (0–250 W) or conventional heating while stirring. The
mixture was cooled to RT, treated with 10 mL H2O, and extracted
with diethyl ether (4 ꢀ 5 mL). The solvent was removed and the crude
reaction mixture was purified by vacuum liquid chromatography on
silica gel using a 0–100% gradient of petrol ether and EtOAc.
1
Other experimental procedures, HPLC chromatograms, and H
and 13C NMR spectra and data are provided in the Supporting
Information.
Scheme 2. Scope of one-pot reactions. [a] Yield of isolated product
(after 2 steps). [b] Determined by HPLC. [c] Trifluoroacetate salt after
purification.
Received: March 18, 2012
Revised: May 18, 2012
Published online: && &&, &&&&
the orthogonality of this reaction further, N-arylation by SNAr
substitution and transition-metal-catalyzed cross-coupling
reactions were conducted simultaneously in one pot
(Scheme 3). This gave the desired product in reasonable
yield, thus proving that N-arylation by SNAr substitution and
Keywords: aromatic substitution · cross-coupling ·
heterocycles · microwave chemistry · nucleophilic substitution
.
À
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4
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Communications
Heterocycles
Caught in a ’SNAr’e: A one-step, high-
yielding, catalyst-free method is de-
scribed for N-arylation of azoles and
indoles from unactivated monofluoro-
benzenes. This SNAr reaction tolerates
a wide range of substituents and can also
generate halogenated N-aryl products.
The reaction can also be performed
simultaneously with or subsequent to
a copper- or palladium-catalyzed cross-
coupling reaction in the same pot.
F. Diness,* D. P. Fairlie*
&&&& — &&&&
Catalyst-Free N-Arylation Using
Unactivated Fluorobenzenes
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!