Catalytic Enantioselective α-Fluorination of 2-Acyl Imidazoles via Iridium Complexes

Article abstract of DOI:10.1002/asia.201601306

The first highly enantioselective α-fluorination of 2-acyl imidazoles utilizing iridium catalysis has been accomplished. This transformation features mild conditions and a remarkably broad substrate scope, providing an efficient and highly enantioselective approach to obtain a wide range of fluorine-containing 2-acyl imidazoles which are found in a variety of bioactive compounds and prodrugs. A large scale synthesis has also been tested to demonstrate the potential utility of this fluorination method.

Full text of DOI:10.1002/asia.201601306

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Catalytic Enantioselective α-fluorination of 2-acyl imidazoles via
Iridium Complexes
Authors: Guo-Qiang Xu, Hui Liang, Jie Fang, Zhi-Long Jia, Jian-Qiang
Chen, and Peng-Fei Xu
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10.1002/asia.201601306
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COMMUNICATION
Catalytic Enantioselective α-fluorination of 2-acyl imidazoles via
Iridium Complexes
Guo-Qiang Xu, Hui Liang, Jie Fang, Zhi-Long Jia, Jian-Qiang Chen and Peng-Fei Xu*[a]
Abstract: The first highly enantioselective α-fluorination of 2-acyl
imidazoles utilizing iridium catalysis has been accomplished. This
transformation features mild conditions and a remarkably broad
substrate scope, providing an efficient and highly enantioselective
approach to obtain a wide range of fluorine-containing 2-acyl
imidazoles which are found in a variety of bioactive compounds and
found in a variety of bioactive compounds and prodrugs18.
Meggers and co-workers19 have accomplished a series of
valuable transformations and significant modifications upon this
biologically active skeleton. However, to the best of our
knowledge, there is still no effective method to enantioselectively
introduce fluorine atom into this valuable 2-acyl imidazole so far,
the biggest obstacle of which is that the corresponding chiral
fluorine products are very easy to racemize due to their
enolization17. Based on the development of asymmetric catalytic
method for the construction of drug molecules containing
trifluoromethyl20 and diverse complex chiral scaffolds21, herein,
we report the first example of highly enantioselective mono-
fluorination of 2-acyl imidazole derivatives utilizing a chiral
iridium complex (see scheme 1-c).
prodrugs.
A large scale synthesis has also been tested to
demonstrate the potential utility of this fluorination method.
Fluorine plays a conspicuous and increasingly important role
in pharmaceuticals1, 2, agrochemicals3, materials4 and tracers for
positron emission tomography5, due to its unique effect on the
properties of organic molecules6. Regrettably, to date only a few
organic compounds possessing this special atom have been
found in nature.7 Therefore, the preparation of various
organofluorine compounds is one of the most significant tasks of
synthetic organic chemistry, and the mono-fluorination is a
simple and direct way to introduce fluorine atom into various
useful and bioactive compounds. Recently, major advances
have been made in the field of the fluorination chemistry.8
Hintermann and Togni developed the first enantioselective
catalytic fluorination of α-branched β-ketoesters via titanium
catalysis.9 Later, several laboratories have established a variety
of elegant systems for the catalytic asymmetric fluorination
reactions of carbonyl compounds via palladium catalysis,10
nickel catalysis,11 copper catalysis12 and other transition-metal
catalysis13. Notably, MacMillan,14 Barbas15 and Jørgensen16
group developed the highly enantioselective α-fluorination of
aldehydes and ketones using organocatalysis(see scheme 1-a).
However, the enantioselective introduction of mono-fluorine
atom into highly activated carbonyl compounds which have no
branched chain in the α-position of carbonyl, such as 2-
phenylacyl imidazole, unbranched β-ketoesters, α-aryl acetic
acid derivatives, is still a big challenge, because the enolate
form of corresponding fluorination compounds is relatively
stable17. Sodeoka and co-workers reported the enantioselective
fluorination of α-aryl acetic acid derivatives catalyzed by a chiral
nickel complex,11a but the enantioselectivity of this reaction is still
not very ideal, and the best enantiomer excess value is only up
to 88% (see scheme 1-b). In view of this limitation, the design
and development of new mono-fluorination reaction with higher
enantioselectivity and better efficiency is one of the major goals
for fluorine chemists.
Scheme 1. Asymmetric Fluorination of activated carbonyl compounds
Initially, we investigated the reaction of 2-phenylacetyl-1-
methylimidazole 1a with commercially available 1-chloromethyl-
4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebis (tetrafluoroborate)
(Selectfluor)22 in the presence of the enantiomerically pure
iridium complex Δ-Ir (2 mol%) under nitrogen atmosphere.
Excitingly, when MeOH/THF (4:1) was used as the reaction
solvent, the expected fluorinated product 2a was obtained in 87%
yield and 57% enantioselectivity (Table 1, entry 1). In an attempt
to improve the reaction efficiency and enantioselectivity, various
solvents were tested in the reaction, and the results showed that
the pure methanol was the best solvent, compared with THF,
MeCN, DMF, DCM, EtOH and i-PrOH in yield and
enantioselectivity (Table 1, entries 2-8). Although the fluorination
yield was close to be quantitative, the enantioselectivity of this
reaction was still unsatisfactory. Therefore, based on using
methanol as the optimal solvent, other factors which could affect
the reaction yield and enantiocontrol were evaluated. First, the
concentration of substrate 1a was gradually decreased from 0.2
mol/L to 0.025 mol/L (Table 1, entries 9-11), to our delight, the
2-Acyl imidazole is one of useful molecular scaffolds, which is
[a]
G.-Q. Xu, H. Liang, J. Fang, Z.-L. Jia, J,-Q. Chen, P.-F. Xu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University
Lanzhou 730000 (P.R. China)
Fax: (+86) 931-8915557
E-mail: xupf@lzu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201601306
Chemistry - An Asian Journal
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results showed that the yield of fluorination was decreasing, but
the enantioselectivity was increasing at first and then started to
decrease. Considering both of the reaction yield and
enantiocontrol, the optimal concentration of 1a was 0.05mol/L
for this fluorination methodology. Next, the reaction temperature
However, both of the yields and enantioselectivities of the
reaction rapidly decreased when the amount of the catalyst was
increasing to 8 mol% and 15 mol% for this reaction (Table 1,
entries 18, 19). Additionally, adding Na2HPO4 or decreasing
Selectfluor’s amount had a negative effect on both of the yield
was also evaluated from 40 oC to -20 oC (Table 1, entries 12-15), and enantioselectivity (Table 1, entries 20, 21). As a summary,
o
the results indicated that the room temperature (20 C) was the
optimal temperature for the best enantiocontrol of this reaction.
To further optimize the reaction conditions, 4Å MS was added to
reaction system to examine the effect of water (Table 1, entries
16). Unfortunately, the enantioselectivity of the fluorinated
product was still unsatisfactory even though the quantitative
yield was obtained. When the amount of catalyst Δ-Ir was
increased to 4 mol%, to our delight, the fluorinated product 2a
was obtained in 96% yield with 92% enantioselectivity (Table 1,
entries 17).
using the iridium complex Δ-Ir as the chiral catalyst at 20 oC with
methanol as the solvent provided α-fluoro-1-(1-methyl-1H-
imidazol-2-yl)-2-phenylethan-1-one 2a in 96% yield and 92% ee
(Table 2, entry 1), which was established as the optimal protocol
for this α-fluorination methodology.
The substrate scope of this novel fluorination reaction was
extensively investigated with the catalyst Δ-Ir. Table 2 showed
that the reactions of a series of 2-acyl imidazoles with Selecfluor
(1.2 equiv.) in the presence of Δ-Ir (4 mol%) at room
o
temperature (20 C) provided the expected fluorination products
2 in good yields with excellent enantioselectivities. Interestingly,
the substituents on the imidazole ring had a significant influence
on the yield and enantioselectivity of this fluorination reaction.
For example, the product 2b was obtained in 81% yield with only
89% ee (entry 2), whereas, the substrate of N-phenyl substituent
on the imidazole ring could provide the corresponding product
2c in 97% yield and 99% excellent enantioselectivity (entry 3).
Table 1. Optimization of the reaction conditionsa
Table 2. Substrate scope of the asymmetric fluorination.
Entry
Solvent
Con.
(M)
Δ-Ir
(mol%)
T
Yield
(%)b
ee
(oC)
(%)c
1
2
MeOH/THF
MeOH
THF
0.2
0.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
4.0
8.0
15.0
4.0
4.0
20
20
20
20
20
20
20
20
20
20
20
40
30
0
87
Quant.
18
57
60
11
3
0.2
4
MeCN
DMF
0.2
55
Trace
13
10
46
50
66
75
72
65
59
50
/
5
0.2
64
6
DCM
0.2
23
7
EtOH
0.2
37
8
iPrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
0.2
41
9
0.1
87
10
11
12
13
14
15
16d
17
18
19
20e
21f
a
0.05
0.025
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
69
60
Quant.
83
32
-20
20
20
20
20
20
20
Trace
Quant.
96
46
92
88
90
8
78
73
41
64
77
Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol),
Selectfluor (0.12 mmol, 1.2equiv.) and Δ-Ir (0.004 mmol, 4 mol%) in MeOH (2
mL) at room temperature. Isolated yield. Determined by HPLC. 50mg 4A
MS. e 1.2 equiv. Na2HPO4 was added. f 1a:Selectfluor=1:1.
b
c
d
Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol),
Selectfluor (0.12 mmol, 1.2euiv.) and Δ-Ir (0.004mmol, 4 mol%) in MeOH (2
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10.1002/asia.201601306
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COMMUNICATION
b
c
d
mL) at room temperature. Isolated yield. Determined by HPLC. 1.2 euqiv
Na2HPO4 was added.
with the iridium catalyst (intermediate I), followed by
deprotonation to generate an electron-rich Z- iridium enolate
complex (intermediate II), in which the re-face of Z-enolate was
shielded by chiral iridium complex. Whereafter, the electrophilic
Selectfluor attacked on the si-face of Z-enolate to afford an
iridium-coordinated complex (intermediate III). Finally, the
iridium catalyst was regenerated and participated in the next
catalytic cycle, and the corresponding chiral product 2 was
obtained simultaneously.
Various substrates with bulky, electron-donating, and electron-
withdrawing groups on the phenyl ring could be smoothly
converted into the corresponding α-fluorination product in good
yields and excellent enantioselectivities. For instance, the
substrate with fluoro-substituent on para-position of phenyl ring
was smoothly converted into the corresponding fluorination
product 2d with 96% yield and 96% ee (entry 4), which contains
two fluorine atoms at different positions of 2-phenylacyl
imidazole. Similarly, other halo-substituent products, such as 2e
and 2f, also could be acquired in 92% yield with 92% ee and in
93% yield with 96% ee, respectively (entries 5, 6). In addition,
phenyl groups with meta- or ortho-chloro substituents had a
negative effect on the yields and enantioselectivities (entry 7: 2g,
86%, 93% ee, entry 8: 2h, 86%, 90% ee). Remarkably, the
introduction of electron-donating substituents on the 4-position
of phenyl ring enabled highly efficient fluorination with excellent
enantiocontrol (entry 9, 2i, 95%, 97% ee, entry 12, 2l, 92%, 99%
ee, entry 13, 2m, 93%, 97% ee,). Interestingly, the position of
electron-donating groups on the phenyl ring seemingly had no
influence on this asymmetric fluorination (entry 10, 2j, 97%, 97%
ee, entry 11, 2k, 97%, 97% ee). The conjugated substrate which
had two phenyl rings could also be efficiently converted to the
corresponding product (entry 14, 2n, 88%, 94% ee). Substrates
with di-substituents on the phenyl ring could also participate in
this transformation with excellent enantioselectivities (entry 15:
2o, 84%, 96% ee, entry 16: 2p, 82%, 99% ee). Moreover, 2-acyl
imidazole substrates with a naphthyl (2q) or thiophenyl (2r)
moiety were successfully fluorinated (entry 17: 2q, 90%, 96% ee,
entry 18: 2r, 91%, 98% ee). More surprisingly, this
enantioselective fluorination method also worked with aliphatic
group (entry 19: 2s, 92%, 98% ee; entry 20: 2t, 64%, 94% ee;
entry 21: 2u, 60%, 90% ee; entry 22: 2v, 63%, 82% ee),
however, the enantioselectivity of products was decreased with
the growth of the carbon chain. Importantly, this methodology
also was applicable to the asymmetric fluoration of 2-acyl
quinoline(entry 23: 2w, 89%, 77% ee), but the ee value of
product was moderate.
Scheme 3. Proposed mechanism for the enantioselective fluorination reaction
In summary, a highly enantioselective α-fluorination of 2-acyl
imidozales utilizing an electrophilic fluorine reagent (Selectfluor)
and the chiral iridium catalyst has been established. Various 2-
acyl imidozales could be smoothly fluorinated to provide the
corresponding fluorine-containing compounds in high yields with
excellent enantioselectivities under mild conditions. A large
scale synthesis was also tested to demonstrate the potential
utility of this fluorination method. This methodology can serve as
an efficient tool for the direct introduction of valuable carbon-
fluorine stereocenter into highly activated carbonyl compounds.
The bioactivity tests of these organofluorine compounds are
ongoing in our laboratory.
Acknowledgements
Scheme 2 Large scale synthesis and the X-ray crystal structure of compound
2c
We are grateful to the NSFC (21202070, 21302075, 21372105
and 21572087), the International S&T Cooperation Program of
China (2013DFR70580), and the “111” program from MOE of P.
R. China.
To demonstrate the potential utility of this enantioselective
fluorination methodology, we also tested a large scale synthesis
of 2c (Scheme 2). The reaction proceeded smoothly to afford
the fluorinated product 2c with a slight decrease in yield and ee
value (87%, 95% ee). The absolute configuration of the product
2c was determined to be S configuration by using X-ray
crystallographic analysis.23
A plausible catalytic cycle for this enantioselective fluorination
reaction was outlined in Scheme 3. Generally, the catalytic cycle
was initiated by bidentate coordination of the 2-acyl imidazole
Keywords: asymmetric catalysis• fluorination • iridium catalysis
• 2-acyl imidazoles
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G.-Q. Xu, H. Liang, J. Fang, Z.-L. Jia, J.-Q. Chen,
P.-F. Xu*
Page No. – Page No.
Catalytic Enantioselective α-fluorination of 2-
acyl imidazoles via Iridium Complexes
The first highly enantioselective α-fluorination of 2-acyl imidazoles utilizing
iridium catalysis has been accomplished. This transformation features mild
conditions and a remarkably broad substrate scope, providing an efficient
and highly enantioselective approach to obtain a wide range of fluorine-
containing 2-acyl imidazoles which are found in a variety of bioactive
compounds and prodrugs.
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