Synthesis of functionalized aryl fluorides using organolithium reagents in flow microreactors

Article abstract of DOI:10.1002/asia.201201191

Flow on: Flow microreactors enable the generation of aryl lithium compounds and subsequent electrophilic fluorination with NFSI and N-fluorosultam. The reaction can be successfully accomplished to synthesize various aryl fluorides involving an electron-withdrawing, an electron-donating, and a sterically hindered functional group in good yields. Copyright

Full text of DOI:10.1002/asia.201201191

COMMUNICATION
DOI: 10.1002/asia.201201191
Synthesis of Functionalized Aryl Fluorides Using Organolithium Reagents in
Flow Microreactors
Aiichiro Nagaki, Yuki Uesugi, Heejin Kim, and Jun-ichi Yoshida*[a]
The development of mild and selective methods for intro-
duction of fluorine atoms into organic molecules is an im-
portant objective because this element exerts unique influ-
ences upon physical, chemical, and biological properties.[1]
In fact, fluorinated aromatic groups enhance solubility, bio-
availability, and metabolic stability compared with non-
fluorinated analogues. Especially, functionalized aryl fluo-
rides have a vast array of biological activities (Scheme 1).[2]
trophilic fluorinating reagents are also useful for this pur-
pose.[6] Recently, significant progress in the use of aryl mag-
nesium compounds has been made by Beller and Knochel.[7]
However, the method suffers from low reactivity of aryl
metal reagents bearing electron-withdrawing substituents,
Figure 1. Flow microreactor system for halogen-lithium exchange of aryl
halides followed by fluorination of the resulting aryl lithium compounds.
Table 1. Fluorination of 4-methoxyphenyllithium and 4-nitrophenyllithi-
um in the flow microreactor system.[a]
R
Fluorinating
reagent
Solvent of
fluorinating
reagent
Concentration
of fluorinating
reagent [m]
T
[8C]
Yield
[%][b]
OMe
NFSI
CH2Cl2
Et2O
THF
THF
THF
THF
THF
THF
CH2Cl2
0.10
0.10
0.10
0.50
1.0
0
0
0
0
0
54
55
57
60
68
69
65
59
28
Scheme 1. Biologically active functionalized aryl fluorides.
1.0[c]
1.0[c]
1.0[c]
0.10
0
À28
À48
0
Typical methods for introducing fluorine atoms to aromatic
groups, such as direct fluorination, the Balz–Schiemann re-
action, the Halex reaction, and reaction of aryl iodides with
CuF2, require relatively harsh reaction conditions that are
incompatible with many functional groups.[3,4] Recently,
Buchwald and co-workers reported a novel method using
palladium-catalyzed reaction of aryl triflates with fluo-
rides.[5]
N-fluoro-
sultam
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0.10
0.10
0.50
1.0
0
0
0
0
0
À28
À48
À28
À28
À28
À28
77
78
81
85
81
81
81
42
50
62
34
1.0[c]
1.0
1.0
NO2
NFSI
0.10
1.0
Reactions of aryl metal reagents, such as aryl magnesium,
zinc, silicon, germanium, and boron compounds with elec-
1.0[c]
0.10
N-fluoro-
sultam
[a] Dr. A. Nagaki, Y. Uesugi, H. Kim, Prof. Dr. J.-i. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering
THF
THF
1.0
À28
À28
52
52
1.0[c]
Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax : (+81)75-383-2727
[a] The reactions were carried out using a solution of halobenzenes
(0.10m in THF) and a solution of lithiating reagents (0.48m in hexane)
unless otherwise stated. [b] The yields of the products were determined
by GC. [c] Concentration of halobenzene: 0.20m in THF, concentration
of lithiating reagent: 1.62m in hexane (nBuLi), 0.70m in cyclohexane and
Et2O (PhLi).
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201201191.
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www.chemasianj.org
Jun-ichi Yoshida et al.
and highly reactive fluorinating reagents such as elemental
fluorine, XeF2, and AcOF should often be used.[8] Such fluo-
rinating reagents are dangerous and are difficult to handle.
Aryl lithium compounds are more reactive than other aryl
metal species because the carbon–lithium bond has the high-
est ionic character among carbon–metal bonds.[9,10] There-
fore, the reactions of aryl lithium compounds with electro-
philic fluorinating reagents should serve as a power-
gave better yields than NSFI. The decrease of the concen-
tration of NSFI caused the formation of anisole (see the
Supporting Information for details). The effect of the tem-
perature was not significant, but 08C is better than À488C
in the case of NSFI, presumably because fluorination is not
fast (yield of anisole: 6% (08C), 7% (À288C), 16%
(À488C)). In the case of 4-nitrophenyllithium, the reaction
ful method for synthesizing aryl fluorides. However,
Table 2. Synthesis of functionalized aryl fluorides using organolithium chemistry in
flow microreactors.
this method suffers from the problem of incompati-
bility of electrophilic functional groups such as
cyano, nitro, alkoxycarbonyl, and ketone carbonyl
groups. Such functional groups react with aryl lithi-
um compounds very quickly, and therefore, aryl
lithium species bearing such functional groups are
difficult to use for fluorination.
Recently, we reported that aryl lithium com-
pounds bearing such electrophilic functional groups
could be generated and used for reactions with
electrophiles by taking advantage of one of the
characteristic features of flow microreactors,[11–14]
that is, extremely short residence times, which
enable the use of such highly unstable aryl lithium
compounds before they decompose.[15] Therefore,
we envisioned that the flow microreactor method is
useful for fluorination. The higher reactivity of aryl
lithium species may obviate the need for dangerous
fluorinating agents. Herein, we report synthesis of
functionalized aryl fluorides using organolithium re-
agents in flow microreactors.
At first, we optimized the reaction conditions
using 4-methoxyphenyllithium and 4-nitrophenyl-
lithium as electron-rich and electron-deficient aryl
lithium species, respectively. A flow microreactor
system consisting of two T-shaped stainless-steel mi-
cromixers (M1 and M2) and two stainless-steel mi-
crotube reactors (R1 and R2; Figure 1) was used. 4-
Methoxyphenyllithium was generated by bromine–
lithium exchange of 4-methoxyphenyl bromide with
n-butyllithium, whereas 4-nitrophenyllithium was
generated by iodine–lithium exchange of 4-nitro-
phenyl iodide with phenyllithium. As fluorinating
reagents, we examined N-fluorobenzenesulfonimide
((PhSO2)2NF, NFSI) and 2-fluoro-3,3-dimethyl-2,3-
dihydro-1,2-benzisothiazole-1,1-dioxide
Aryl halide
T [8C]
RLi
Product
Yield[a] [%]
NFSI N-fluoro-
sultam
À28
À28
À28
PhLi
83
56
PhLi
62
52
nBuLi
79[b]
52
À28
À28
nBuLi
nBuLi
64[b]
58
67
62[b,c]
À28
PhLi
73
80
À28
À28
À48
PhLi
PhLi
PhLi
67
57
63
65
66
31
À48
PhLi
45
35
0
nBuLi
70[d]
51[e]
0
nBuLi
69[d]
81[e]
0
0
0
nBuLi
nBuLi
nBuLi
69[d]
78[b]
60[b,f]
85[e]
76
66
((C9H10SO2)NF, N-fluorosultam). The flow reac-
tions were carried out with various concentrations
of the fluorinating reagents, various solvents, and at
different temperatures (Table 1).
In the case of p-methoxyphenyllithium, dichloro-
methane, diethyl ether, and THF could be used as
solvent for fluorination with NSFI, although di-
chloromethane could not be used for fluorination
with N-fluorosultam. Hereafter we used THF as sol-
vent. The yield increased with an increase in the
concentration of NSFI, whereas such effect was not
0
nBuLi
82[d]
79[g]
0
0
nBuLi
nBuLi
66[d,h]
67[d,h]
82[e,h]
83[e,h]
[a] The yields of the products were determined by GC analysis using an internal stan-
dard. Reactions were carried out under the following conditions unless otherwise
stated. tR1 =0.017 s (NFSI), tR1 =0.018 s (N-fluorosultam). [b] tR1 =0.020 s. [c] Inner di-
ameter of micromixer M2 was 500 mm. [d] tR1 =2.3 s. [e] tR1 =2.1 s. [f] The yield of the
product was determined by 19F NMR spectroscopy. [g] tR1 =4.2 s. [h] Fluorinating re-
appreciable in the case of N-fluorosultam, which agent: 1.1 equiv.
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Jun-ichi Yoshida et al.
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should be carried out at À288C, because its decomposition
is very fast at higher temperatures. NFSI was slightly better
than N-fluorosultam as fluorinating reagent.
We next examined fluorination reactions with various
functionalized aryl lithium compounds. As shown in Table 2,
the reactions were successful, and aryl fluoride species bear-
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ortho, meta, and para positions were obtained in good
yields. Notably, selective monolithiation of dibromoben-
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in mixing efficiency. In addition, highly sterically hindered
mesityllithium could be fluorinated to give mesitylfluoride.
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trophilic fluorinating reagents.[17] Aryl lithium compounds
are more reactive than such basic functional groups and
react with fluorinating reagents faster. Therefore, fluorina-
tion could be achieved without protecting such functional
groups. Such transformations are very difficult to achieve by
the conventional methods.
In conclusion, we have developed a new method for syn-
thesizing functionalized aryl fluoride compounds based on
organolithium chemistry in flow microreactors. Highly reac-
tive unstable functionalized aryl lithium species are generat-
ed by taking advantage of short residence times and are al-
lowed to react with electrophilic fluorinating reagents such
as NFSI and N-fluorosultam. High reactivity of aryl lithium
compounds solved the problem associated with strong elec-
tron-withdrawing and electron-donating substituents on the
aromatic rings. Therefore, the method adds a new dimension
to synthesis of organofluorine compounds and opens new
possibilities in organofluorine chemistry.
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Keywords: fluorination
·
lithiation
·
microreactors
·
synthetic methods
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Received: December 17, 2012
Published online: February 7, 2013
Chem. Asian J. 2013, 8, 705 – 708
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim