Regioselective electrophilic fluorination of rationally designed imidazole derivatives

Article abstract of DOI:10.1021/acs.joc.5b02592

We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorination with N-fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6-tetramethylpiperidine. Aided b

Full text of DOI:10.1021/acs.joc.5b02592

Note
pubs.acs.org/joc
Regioselective Electrophilic Fluorination of Rationally Designed
Imidazole Derivatives
Klaus Albertshofer* and Neelakandha S. Mani
Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: We report the regioselective and direct functionalization of
rationally designed imidazole derivatives through electrophilic fluorina-
tion with N-fluorobenzenesulfonimide enabled via in situ deprotonation
with lithium 2,2,6,6-tetramethylpiperidine. Aided by a controlled
protecting group switch, we were able to effectively target both the
reactive 5- as well as the difficult to target 4-position of these molecules,
leading to a series of fluorinated polysubstituted imidazoles in gram scale.
he incorporation of fluorine or fluorine-containing
to-handle reagents7h,i,8 and show very limited substrate scope.7i
Tfunctional groups at specific positions within pharmaceuti- In order to address this unmet synthetic need, we envisioned a
reaction allowing for the efficient and regioselective incorpo-
ration of fluorine at selected positions within the imidazole
moiety, utilizing nontoxic reaction partners. Encouraged by
earlier work on electrophilic fluorination7 as well as our own
efforts on functionalization of imidazole analogs, demonstrating
that 2-chloroimidazoles can be readily alkylated at position C5
via directed metalation,9 we hypothesized that 5-fluoroimida-
zoles can be obtained under similar conditions and potentially
isomerized via controlled protecting group migration to their 4-
fluoro equivalents (Scheme 1). Weinreb and Lovely showed
cally relevant target molecules plays an increasingly important
role in modern drug development.1 This is due to the dramatic
biological as well as chemical effects fluorine introduction offers
such as increased metabolic stability, improved cellular
permeability, and alteration of pKa values of functionalities in
close proximity.2 Fluorinated molecules also play a major role
in molecular imaging technologies such as positron emission
tomography (PET).3 Copious fluoroimidazole-containing
target molecules display biologically interesting activities over
a wide range of disease areas such as oncology, infectious
diseases, or dermatology.4
However, few processes are applicable for the fluorination of
heterocyclic systems such as imidazoles.7 The first synthesis of
fluorinated imidazole analogs was described in a seminal paper
by the group of Kirk in the year 1971 via a Balz−Schiemann
process5 to obtain ethyl 4-fluoroimidazole-5-carboxylates in
38% yield.8a Since that time several other strategies have
evolved to get access to these molecules including the
construction from already fluorinated building blocks such as
bistrifluoromethyl-substituted 1,3-azoles via a [4 + 1] cyclo-
addition reaction.7a−c
Scheme 1. Regioselective Fluorination of Rationally
Designed Imidazole Derivatives
Fluoroimidazoles can also be obtained by Halex-type
processes6 through the displacement of leaving groups
including halides7d−g or trimethyltin7h with nucleophilic
fluorination reagents such as spray dried potassium fluoride
to obtain 2-fluoro-1-methyl-1H-imidazole-4,5-dicarbonitrile in
82% yield.7g Another synthetic strategy to prepare fluorine-
substituted imidazoles involves the use of electrophilic
fluorinating reagents. The group of Hay took advantage of
the fact that a 2-lithio imidazole readily reacts with gaseous
perchloryl fluoride at −78 °C to form N-methyl-2-fluoroimi-
dazole in 55% yield.7i Recently Jiang et al. reported the direct
fluorination of N-methyl-imidazole-2-carboxylates with select-
fluor in acetonitrile.7j Despite these excellent efforts, the direct
fluorination of imidazoles is extremely underdeveloped,7k,l and
most reported procedures rely on extremely toxic and difficult-
that 5-alkyl- as well as 5-iodo-substituted imidazole analogs
equipped with N1-protecting groups such as benzyloxymethyl
(BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM) readily
undergo isomerization via protecting group migration under
thermodynamic conditions, aided by the addition of catalytic
amounts of BOM-Cl and SEM-Cl, respectively.10
In an initial attempt to investigate the direct fluorination of
substituted imidazole derivatives, we selected 2-chloro-1-
(ethoxymethyl)-1H-imidazole 1a as model substrate with N-
fluorobenzenesulfonimide (NFSI) 2 as electrophilic fluorinat-
ing reagent2b,11 and tetrahydrofuran (THF) as polar aprotic
solvent (Table 1). The introduction of chlorine at position C2
Received: November 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02592
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The Journal of Organic Chemistry
Note
a
quenched the lithiated imidazole with NFSI 2 at the same
temperature (transfer via cannula). Under these conditions the
desired product 3a was obtained in 55% yield (entry 7). After
LTMP was identified as an optimal metalating reagent in this
system, we focused our attention on the optimization of
reaction conditions and investigated previously disclosed
electrophilic fluorinating reagents including 2-fluoro-3,3-
dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide, N-fluoro-
pyridinium salts as well as selectfluor (see Supporting
Information).2b,11 Unfortunately none of the probed reagents
provided the desired 5-fluoroimidazole 3a in satisfactory yields.
On the other hand, lowering the amount of LTMP to 1 equiv
and decreasing the time of the transformation to 5 min resulted
in no loss of reaction yield. With optimized reaction conditions
at hand, we investigated various protecting groups in order to
identify a removable N1-protecting group, that also can act as
ortho-directing group during the metalation process (Scheme
2). Initially we investigated various linear and branched ether
Table 1. Effect of Different Bases on the Fluorination of 4a
b
entry
1
base
temp (°C)
time (h) yield
−
−
20
20
24
24
24
24
1
−
−
−
c
2
d
3
e
TMP2Zn2MgCl2·LiCl
TMPMgCl·LiCl
n-BuLi
20
4
−78 to 20
−78
−78
−
5
6
7
53
51
55
LDA
1
LTMP
−78
1
a
Reaction conditions unless noted otherwise: 1a (2.49 mmol, 1 equiv),
2 (2.74 mmol, 1.6 equiv), base (4.98 mmol, 2 equiv), THF (22 mL).
Percent conversion determined by H NMR of the crude reaction
mixture. 1a (0.31 mmol, 1 equiv), selectfluor used for fluorination
(0.93 mmol, 3 equiv), acetonitrile (1.8 mL). 1a (1.25 mmol, 1 equiv),
2 (3.74 mmol, 3 equiv), THF (8 mL), base (0.88 mmol, 0.7 equiv).
1a (1.25 mmol, 1 equiv), 2 (2.5 mmol, 2 equiv), base (1.88 mmol, 1.5
b
1
c
d
Scheme 2. Evaluation of Various Imidazole Protecting
a b
,
Groups
e
equiv), THF (8 mL).
provides an electron-deficient functionality acting also as a
cleavable protecting group,12 potentially facilitating the direct
fluorination at C5.
Imidazoles equipped with alkyloxymethyl ethers have
previously been described as excellent reaction partners in
transformations involving lithiation, potentially acting as ortho-
directing groups.13 Initial attempts to directly introduce fluorine
at C5 in the absence of a strong base were unsuccessful (entries
1−2).
Inspired by the work of Knochel and others on directed
metalation of aromatic as well as heteroaromatic ring systems
and subsequent trapping with electrophiles,14 we envisioned to
selectively metalate imidazole 1a at position C5 to facilitate the
fluorination reaction at this position (entries 3−8). Direct
zincation of 1a with base complex (TMP)2Zn·2MgCl2·2LiCl
did not provide the desired product 3a after 24 h at room
temperature (entry 3). This is likely due to incomplete zinc
incorporation as evidenced by iodination experiments. We then
focused our attention on (TMP)MgCl·LiCl, which was added
to a solution of starting material 1a in THF at 0 °C. After 1 h at
room temperature, the reaction mixture was cooled to −78 °C
and subsequently reacted with 2 as a solution in THF. The
reaction was allowed to slowly warm back up to room
temperature. However, the transformation did not provide 3a
as product. The incorporation of other halides such as chlorine
or bromine at position C5 through the same reaction
conditions in the presence of TMPMgCl·LiCl resulted in
haloimidazoles in yields of up to 76%. After failed attempts to
fluorinate imidazole species 1a at ambient temperatures, we
treated the starting material with n-butyllithium (n-BuLi) at
−78 °C followed by transfer of a precooled solution of NFSI 2
in THF (−78 °C) via a cannula. To our delight, the desired
product 3a was obtained in moderate yields (53%; entry 5). To
further optimize the transformation, we exposed 1a to the less
nucleophilic base lithium diisopropylamide (LDA) under
similar reaction conditions (entry 6). Unfortunately the
reaction did not result in improved fluorine incorporation. In
a subsequent attempt we treated 1a with in situ generated
lithium 2,2,6,6-tetramethylpiperidine (LTMP) at −78 °C and
a
Reaction conditions unless noted otherwise: 1a (2.49 mmol, 1 equiv),
2 (2.74 mmol, 1.6 equiv), LTMP (2.49 mmol, 1 equiv), THF (22 mL).
Reaction yield based on isolation of 3. 1a (9.25 mmol, 1 equiv), 5
b
c
(14.80 mmol, 1.6 equiv), LTMP (9.25 mmol, 1 equiv), THF (81 mL).
derivatives, similar to those disclosed in the context of base-
mediated electrophilic derivatization of imidazoles or pyrazoles
(compounds 3b and 3c).10,15 Imidazole derivative 1b equipped
with a 2-(trimethylsilyl)ethoxymethyl ether (SEM) provided
the desired fluoroimidazole 3b in 21% yield. If branched
ethoxyethyl derived imidazole 1c was used, 44% of the desired
product 3c was obtained.
N,N-dimethylsulfamoyl protection is frequently utilized in
the context of alkylation reactions of imidazole structures.16
When applied under our reaction conditions, the desired 5-
fluoroimidazole 3d was obtained in 54% yield.
Both benzyl as well as phenyl-substituted substrates did not
allow for the efficient introduction of fluorine (3e and 3f). This
might be explained due to the poor ortho-directing capabilities
of these two functionalities. After we demonstrated that
ethoxymethyl ether-substituted imidazole 1a allowed for the
highest incorporation of fluorine at position C5 in milligram
and gram scale, we evaluated the generality of the developed
methodology (Scheme 3).
Initially we focused on various substituents at position C4 on
the imidazole ring system. Sterically more demanding
functionalities such as methyl or phenyl are well tolerated
under the probed reaction conditions, whereas electron-
B
DOI: 10.1021/acs.joc.5b02592
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The Journal of Organic Chemistry
Note
a b
,
ab
,
Scheme 3. Scope of the Reaction
Scheme 4. Controlled Protecting Group Migration
a
a
Reaction conditions unless noted otherwise: 4a (2.49 mmol, 1 equiv),
2 (2.74 mmol, 1.6 equiv), LTMP (2.49 mmol, 1 equiv), THF (22 mL).
Reaction yield based on isolation of 5.
Reaction conditions unless noted otherwise: 5 (0.20 mmol, 1 equiv),
b
AcOH (0.013 mmol, 0.06 equiv), acetonitrile (0.25 mL). Reaction
yield based on isolation of 6. 5a (2.8 mmol, 1 equiv), AcOH (0.013
b
c
d
mmol, 0.06 equiv), acetonitrile (0.25 mL). Reaction time 4 h.
e
Reaction time 24 h.
withdrawing halogens in the para position of the aryl
substituent resulted in a significant loss of reaction yield
(5d). 4-methyl-functionalized imidazole 4a provided the
desired product 5a in 62% yield. If phenyl-substituted electron
neutral imidazole 4b was applied in the reaction, product 5b
was isolated in an increased yield of 61% compared to the
parent compound 3a (Scheme 2). Incorporation of electro-
negative halogen substituents in the para position of the phenyl
ring resulted in successive loss of reaction yield (5c: 55%; 5d:
36%). Electronic effects might in part contribute to proto
demetalation, evidenced by the recovery of unreacted starting
materials, even though great care was taken to exclude moisture
from the system. To further evaluate the scope of the reaction,
we investigated various functional groups to replace chlorine at
position C2 (5e−g). We were delighted to find that 2-aryl
derived imidazoles provided the desired fluorinated products in
yields of up to 71%. Even though simple electron neutral 2-
phenyl-imidazole 4e afforded 5e only in 20% yield, 4-
chlorophenyl as well as 4-fluorophenyl analogs were success-
fully converted to fluorinated products 5f (71%) and 5g (61%).
Overall, the obtained reaction yields (5a−g) are rather
substrate specific and do not necessarily follow electronic
factors. Even though products functionalized at C4 (5a−e)
seem to suggest that electronegative substituents are disfavored,
compounds 5e−g equipped with aryl-substituents at position
C2 demonstrate that a fluorine in the para position is tolerated,
whereas more electron neutral phenyl provided only low yields.
Finally we investigated if the obtained 5-fluoroimidazoles can
be converted to otherwise difficult to obtain 4-fluoro analogs,
via a simple controlled protecting group migration (Scheme 4).
And indeed, we were delighted to find that imidazole
derivatives equipped with various C2 substituents ranging
from chlorine to aryl as well as aromatic C4 substituents
undergo the protecting group migration. If compound 3a was
dissolved in acetonitrile in the presence of a catalytic amount of
acetic acid (AcOH) followed by heating to 80 °C for 1 h, the
desired product 6a was obtained in almost quantitative yield.
3a also converts to the corresponding 4-fluoroimidazole
under neat conditions at 40 °C after 2.5 h. 4-chlorophenyl-5-
fluoroimidazole 5c was converted to 6b in 83% yield, however,
an increased reaction time of 4h was necessary to complete the
reaction, suggesting that steric factors have an influence on the
yield of the reaction. Similarly, compounds 5f and 5g were
converted to the desired 4-fluoroimidazole analogs 6c and 6d
after 4h. The longer reaction time of products 6c and 6d,
lacking the 2-chloro substituent compared to the more
electron-deficient 6a, suggests the possibility that electronic
factors also contribute to the outcome of the reaction. In
Scheme 5 a possible intermolecular mechanism for this
transformation is depicted involving an acid-catalyzed SN2-
type reaction, similar to previously suggested mechanisms
involving protecting group migrations in imidazole species.10
Bisethoxymethyl-substituted imidazolium salt 8 is formed via
nucleophilic attack of nitrogen N3 embedded in fluoroimida-
zole 3a, on protonated imidazole 7. In a subsequent step, 8
collapses to form two 4-fluoro-substituted products 6a. Other
reaction mechanisms including SN1-type processes, however,
cannot be ruled out completely.
We have demonstrated that a diverse set of complex
polysubstituted fluorinated imidazole derivatives can be
efficiently obtained through a LTMP enabled process with
NFSI as electrophilic fluorinating reagent. Aryl- and halide- as
well as alkyl-substituted starting materials were good substrates
in the disclosed transformation. Via a protecting group
migration from nitrogen N1 to N3 both 5- as well as the
otherwise difficult to obtain 4-substituted imidazoles are
accessible through this strategy in an atom economic manner.
The newly developed technology might also provide a valuable
tool for the direct fluorination of other five- and six-membered
heterocyclic systems such as pyrazoles as well as pyrimidines.
Research efforts in this context are ongoing.
EXPERIMENTAL SECTION
■
General Methods. Reagents were purchased from commercial
sources and used without further purification unless otherwise noted.
1H NMR (400, 500, 600 MHz), 13C NMR (101, 126, 150 MHz), and
19F (400, 500, 600 MHz) spectra were acquired on 400 and 500 as
well as 600 NMR spectrometers. Chemical shifts (δ) are reported in
parts per million downfield from tetramethylsilane as internal standard.
Spin multiplets are reported as s (singlet), d (doublet), t (triplet), q
(quartet), and m (multiplet). Coupling constants (J) are reported in
hertz (Hz). High-resolution mass spectra were recorded using a uTOF
C
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The Journal of Organic Chemistry
Note
Scheme 5. Plausible Mechanism for the Protecting Group Migration
spectrometer in electrospray mode, coupled with an HPLC, and
internally calibrated with sodium formate.
a post-acquisition software package was used to obtain high mass
accuracy).
General Procedure for the Fluorination of Imidazole
Derivatives (A). To freshly distilled 2,2,6,6-tetramethylpiperidine
(TMP) under nitrogen in a three-neck round-bottom flask equipped
with a Schlenck line is added THF and cooled to −78 °C. n-BuLi
(2.5M, hexanes) is slowly added to the solution at the same
temperature, and the reaction is stirred for 30 min at −78 °C. The
protected imidazole derivative is dissolved in THF and slowly added to
the reaction mixture containing LTMP (temperature should be kept
below −70 °C). After 10 min, NFSI, dissolved in THF and precooled
to −78 °C, is transferred to the reaction mixture via a cannula (−78
°C). After 5 min at the same temperature, the reaction is quenched
with water and saturated NH4Cl at −78 °C and allowed to warm to
room temperature. The reaction mixture was extracted with DCM, and
the organic fractions were combined and dried over Na2SO4. After the
solvents were removed by evaporation under reduced pressure, the
crude reaction product was subjected to silica gel purification.
General Procedure for the Controlled Protecting Group
Migration (B). 5-Fluoroimidazole 5 was dissolved in acetonitrile and
5 mol % of acetic acid. The reaction vessel was sealed and heated to 80
°C until complete isomerization to 4-fluoroimidazole 6, as indicated by
1H NMR of the crude reaction mixture. A solution of saturated sodium
2-Chloro-1-(1-ethoxyethyl)-5-fluoro-1H-imidazole (3c). Synthe-
sized according to General Procedure A. Compound 3c isomerizes
to 2-chloro-1-(1-ethoxyethyl)-4-fluoro-1H-imidazole during workup.
2-Chloro-1-(1-ethoxyethyl)-1H-imidazole (435 mg, 2.49 mmol) (1c)
dissolved in 4 mL THF was added slowly to a reaction mixture
containing TMP (420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49
mmol) in 9 mL THF at −78 °C. After 30 min at the same
temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF and
precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (hexanes: EtOAc, 8:2), and 3c was
1
obtained in 44% yield (211 mg, 1.10 mmol). H NMR (400 MHz,
CDCl3) δ 6.56 (d, J = 8.1 Hz, 1H), 5.51−5.46 (m, 1H), 3.42 (dd, J =
18.9, 7.0 Hz, 2H), 1.57 (d, J = 5.9 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 155.6 (d, J = 239.74 Hz), 124.5 (d, J =
19.8 Hz), 95.6, 83.3, 64.5, 22.6, 14.8.19F NMR (376 MHz, CDCl3) δ
−131.8 (d, J = 8.1 Hz). HRMS calcd for C7H10ClFN2O [M + H]+
193.0538, found 193.0540.
2-Chloro-5-fluoro-N,N-dimethyl-1H-imidazole-1-sulfonamide
(3d). Synthesized according to General Procedure A. 2-Chloro-N,N-
dimethyl-1H-imidazole-1-sulfonamide (1d) (522 mg, 2.49 mmol)
dissolved in 4 mL THF was added slowly to a reaction mixture
containing TMP (420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49
mmol) in 9 mL THF at −78 °C. After 30 min at the same
temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF and
precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (DCM: ether, 93:7), and 3d was
carbonate (Na2CO3) was added, and the reaction product was
extracted with DCM.
2-Chloro-1-(ethoxymethyl)-5-fluoro-1H-imidazole (3a). Synthe-
sized according to General Procedure A. 2-chloro-1-(ethoxymethyl)-
1H-imidazole (1a) (400 mg, 2.49 mmol) dissolved in 4 mL THF was
added slowly to a reaction mixture containing TMP (420 μL, 2.49
mmol) and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF at −78 °C.
After 30 min at the same temperature NFSI (1.26g, 3.99 mmol)
dissolved in 9 mL THF and precooled to −78 °C is transferred to the
reaction mixture via a cannula. After 5 min, the reaction mixture was
subjected to aqueous workup and silica gel purification (hexanes:
EtOAc, 8:2) and 3a was obtained in 55% yield (245 mg, 1.37 mmol).
1H NMR (600 MHz, CDCl3) δ 6.46 (d, J = 7.4 Hz, 1H), 5.24 (d, J =
0.8 Hz, 2H), 3.57 (dd, J = 7.1, 0.8 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 147.8 (d, J = 276 Hz), 125.5 (d, J =
1
obtained in 54% yield (306 mg, 1.34 mmol). H NMR (600 MHz,
MeOD) δ 6.64 (d, J = 7.9 Hz, 1H), 2.95 (s, 6H). 13C NMR (151
MHz, MeOD) δ 156.6 (d, J = 236.9 Hz), 125.6 (d, J = 19.6 Hz), 97.7
(d, J = 36.2 Hz), 39.8.19F NMR (376 MHz, MeOD) δ-138.1 (d, J =
10.5 Hz). HRMS calcd for C5H7ClFN3O2S [M + H]+ 228.0004, found
228.0005.
1-Benzyl-2-chloro-5-fluoro-1H-imidazole (3e). Synthesized ac-
cording to General Procedure A. 1-benzyl-2-chloro-1H-imidazole
(1e) (480 mg, 2.49 mmol) dissolved in 4 mL THF was added slowly
to a reaction mixture containing TMP (420 μL, 2.49 mmol) and n-
BuLi (996 μL, 2.49 mmol) in 9 mL THF at −78 °C. After 30 min at
the same temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL
THF and precooled to −78 °C is transferred to the reaction mixture
via a cannula. After 5 min, the reaction mixture was subjected to
aqueous workup, and 3e was obtained in trace amount.
2-Chloro-5-fluoro-1-phenyl-1H-imidazole (3f). Synthesized ac-
cording to General Procedure A. 2-Chloro-1-phenyl-1H-imidazole
(1f) (445 mg, 2.49 mmol) dissolved in 4 mL THF was added slowly to
a reaction mixture containing TMP (420 μL, 2.49 mmol) and n-BuLi
(996 μL, 2.49 mmol) in 9 mL THF at −78 °C. After 30 min at the
same temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF
and precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (hexanes: EtOAc, 9:1), and 3f was
obtained in trace amount.
10.0 Hz), 105.4, 72.4, 65.2, 14.8. 19F NMR (376 MHz, CDCl3) δ
−146.9 (d, J = 7.2 Hz). HRMS calcd for C6H8ClFN2O [M + H]+
179.0382, found 179.0393.
2-Chloro-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imida-
zole (3b). Synthesized according to General Procedure A. 2-chloro-
((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1b) (580 mg, 2.49
mmol) dissolved in 4 mL THF was added slowly to a reaction mixture
containing TMP (420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49
mmol) in 9 mL THF at −78 °C. After 30 min at the same
temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF and
precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (hexanes: EtOAc, 8:2), and 3b was
1
obtained in 21% yield (131 mg, 0.52 mmol). H NMR (400 MHz,
CDCl3) δ 6.46 (d, J = 7.5 Hz, 1H), 5.25−5.20 (m, 1H), 3.62−3.58 (m,
1H), 0.95−0.91 (m, 1H), 0.00 (s, 7H). 13C NMR (151 MHz, CDCl3)
δ 149.2 (d, J = 276.0 Hz), 126.9−125.3 (m), 106.7 (d, J = 7.9 Hz),
73.4, 68.6, 19.2, −0.6. 19F NMR (376 MHz, CDCl3) δ −146.9 (d, J =
7.6 Hz). HRMS calcd for C9H16ClFN2OSi [M] 250.0705, found
250.0700 (3b was analyzed by GCMS with quadrupole mass analyzer;
2-Chloro-1-(ethoxymethyl)-5-fluoro-4-methyl-1H-imidazole (5a).
Synthesized according to General Procedure A. 2-Chloro-1-(ethox-
ymethyl)-4-methyl-1H-imidazole (4a) (435 mg, 2.49 mmol) dissolved
D
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Note
in 4 mL THF was added slowly to a reaction mixture containing TMP
(420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF
at −78 °C. After 30 min at the same temperature, NFSI (1.26g, 3.99
mmol) dissolved in 9 mL THF and precooled to −78 °C is transferred
to the reaction mixture via a cannula. After 5 min, the reaction mixture
was subjected to aqueous workup and silica gel purification (hexanes:
EtOAc, 9:1), and 5a was obtained in 62% yield (296 mg, 1.54 mmol).
1H NMR (400 MHz, CDCl3) δ 5.19 (d, J = 0.8 Hz, 2H), 3.59−3.53
(m, 2H), 2.11 (d, J = 1.8 Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 143.9 (d, J = 272.6 Hz), 123.6 (d, J = 11.5 Hz),
113.2 (d, J = 6.8 Hz), 72.33, 65.0, 14.7, 10.5 (d, J = 4.0 Hz). 19F NMR
(376 MHz, CDCl3) δ −152.2. HRMS calcd for C7H10ClFN2O [M +
H]+ 193.0538, found 193.0539.
2-Chloro-1-(ethoxymethyl)-5-fluoro-4-phenyl-1H-imidazole (5b).
Synthesized according to General Procedure A. 2-Chloro-1-(ethox-
ymethyl)-4-phenyl-1H-imidazole (4b) (590 mg, 2.49 mmol) dissolved
in 4 mL THF was added slowly to a reaction mixture containing TMP
(420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF
at −78 °C. After 30 min at the same temperature, NFSI (1.26g, 3.99
mmol) dissolved in 9 mL THF and precooled to −78 °C is transferred
to the reaction mixture via a cannula. After 5 min, the reaction mixture
was subjected to aqueous workup and silica gel purification (hexanes:
EtOAc, 9:1), and 5b was obtained in 61% yield (350 mg, 1.37 mmol).
1H NMR (400 MHz, CDCl3) δ 7.80−7.71 (m, 2H), 7.40 (t, J = 7.7
and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF at −78 °C. After 30
min at the same temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9
mL THF and precooled to −78 °C is transferred to the reaction
mixture via a cannula. After 5 min, the reaction mixture was subjected
to aqueous workup and silica gel purification (DCM:ether:hexanes,
93:7:100), and 5e was obtained in 20% yield (110 mg, 0.45 mmol). 1H
NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 8.1, 1.6 Hz, 2H), 7.48−7.40
(m, 2H), 6.65 (d, J = 7.7 Hz, 1H), 5.22 (d, J = 1.2 Hz, 2H), 3.64 (dd, J
= 7.1, 1.3 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 149.1 (d, J = 273.5 Hz), 141.8 (d, J = 5.7 Hz), 130.2, 129.2,
128.9,, 105.3 (d, J = 8.0 Hz), 72.2, 64.9, 15.0. 19F NMR (376 MHz,
CDCl3) δ −150.9 (d, J = 8.0 Hz). HRMS calcd for C12H13FN2O [M +
H]+ 221.1085, found 221.1089.
2-(4-Chlorophenyl)-1-(ethoxymethyl)-5-fluoro-1H-imidazole (5f).
Synthesized according to General Procedure A. 2-(4-Chlorophenyl)-1-
(ethoxymethyl)-1H-imidazole (4f) (590 mg, 2.49 mmol) dissolved in
4 mL THF was added slowly to a reaction mixture containing TMP
(420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF
at −78 °C. After 30 min at the same temperature, NFSI (1.26g, 3.99
mmol) dissolved in 9 mL THF and precooled to −78 °C is transferred
to the reaction mixture via a cannula. After 5 min, the reaction mixture
was subjected to aqueous workup and silica gel purification
(DCM:ether:hexanes, 93:7:100), and 5f was obtained in 71% yield
(450 mg, 1.77 mmol). 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 8.6
Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.20 (d, J
= 1.2 Hz, 2H), 3.67 (qd, J = 7.0, 1.3 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 149.0 (d, J = 274.1 Hz), 140.6 (d, J =
5.8 Hz), 135.3, 129.6, 129.0, 128.4, 105.3 (d, J = 7.6 Hz), 72.0, 64.9,
14.9. 19F NMR (376 MHz, CDCl3) δ −150.5 (d, J = 7.8 Hz). HRMS
calcd for C12H12ClFN2O [M + H]+ 255.0695, found 255.0692.
1-(Ethoxymethyl)-5-fluoro-2-(4-fluorophenyl)-1H-imidazole (5g).
Synthesized according to General Procedure A. 1-(Ethoxymethyl)-2-
(4-fluorophenyl)-1H-imidazole (4g) (549 mg, 2.49 mmol) dissolved
in 4 mL THF was added slowly to a reaction mixture containing TMP
(420 μL, 2.49 mmol) and n-BuLi (996 μL, 2.49 mmol) in 9 mL THF
at −78 °C. After 30 min at the same temperature, NFSI (1.26g, 3.99
mmol) dissolved in 9 mL THF and precooled to −78 °C is transferred
to the reaction mixture via a cannula. After 5 min, the reaction mixture
was subjected to aqueous workup and silica gel purification
(DCM:ether:hexanes, 93:7:100), and 5g was obtained in 62% yield
Hz, 2H), 7.27−7.24 (m, 1H), 5.29 (d, J = 0.9 Hz, 2H), 3.65−3.59 (m,
2H), 1.24 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 143.7
(d, J = 280.7 Hz), 131.0 (d, J = 5.4 Hz), 128.8, 127.2, 125.2 (d, J = 4.4
Hz), 117.7 (d, J = 1.7 Hz), 72.8, 65.4, 14.9. 19F NMR (376 MHz,
CDCl3) δ −144.2. HRMS calcd for C12H12ClFN2O [M + H]+
255.0695, found 255.0690.
2-Chloro-4-(4-chlorophenyl)-1-(ethoxymethyl)-5-fluoro-1H-imi-
dazole (5c). Synthesized according to General Procedure A. 2-Chloro-
4-(4-chlorophenyl)-1-(ethoxymethyl)-1H-imidazole (4c) (675 mg,
2.49 mmol) dissolved in 4 mL THF was added slowly to a reaction
mixture containing TMP (420 μL, 2.49 mmol) and n-BuLi (996 μL,
2.49 mmol) in 9 mL THF at −78 °C. After 30 min at the same
temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF and
precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (hexanes: EtOAc, 9:1), and 5c was
1
1
(362 mg, 1.52 mmol). H NMR (400 MHz, CDCl3) δ 7.81 (dd, J =
obtained in 55% yield (395 mg, 1.37 mmol). H NMR (400 MHz,
8.7, 5.5 Hz, 2H), 7.19−7.11 (m, 2H), 6.641 (d, J = 7.6 Hz, 1H), 5.20
(s, 2H), 3.67 (qd, J = 7.0, 1.4 Hz, 2H), 1.27 (t, J = 8 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 163.3 (d, J = 249.4 Hz), 148.8 (d, J =
273.6 Hz), 140.8 (d, J = 5.7 Hz), 130.4 (d, J = 8.3 Hz), 126.1 (d, J =
3.2 Hz), 115.9 (d, J = 21.1 Hz), 105.0 (d, J = 8.0 Hz), 72.0, 64.8, 14.9.
19F NMR (376 MHz, CDCl3) δ −111.7, −150.9 (d, J = 9.1 Hz).
HRMS calcd for C12H12F2N2O [M + H]+ 239.0990, found 239.0989.
2-Chloro-1-(ethoxymethyl)-4-fluoro-1H-imidazole (6a). Synthe-
sized according to General Procedure B. 2-Chloro-1-(ethoxymethyl)-
5-fluoro-1H-imidazole (3a) (500 mg, 2.80 mmol) was reacted in the
presence of acetonitrile (3.5 mL) and of acetic acid (8 μL, 0.14 mmol)
at 80 °C for 1 h. After aqueous work up with saturated sodium
carbonate (Na2CO3) and extraction with DCM, followed by silica gel
purification, 6a was obtained in quantitative yield (500 mg, 2.80
mmol). 3a also isomerizes to 6a if stored under neat conditions at 40
CDCl3) δ 7.71−7.67 (m, 2H), 7.38−7.34 (m, 2H), 5.29 (d, J = 0.9 Hz,
2H), 3.65−3.59 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 143.7 (d, J = 281.0 Hz), 132.8, 129.6 (d, J = 5.6 Hz),
129.5, 126.4 (d, J = 4.4 Hz), 125.4 (d, J = 11.1 Hz), 116.8 (d, J = 2.0
Hz), 72.8, 65.4, 14.9. 19F NMR (376 MHz, CDCl3) δ −143.6. HRMS
calcd for C12H11Cl2FN2O [M + H]+ 289.0305, found 289.0314.
2-Chloro-1-(ethoxymethyl)-5-fluoro-4-(4-fluorophenyl)-1H-imi-
dazole (5d). Synthesized according to General Procedure A. 2-Chloro-
1-(ethoxymethyl)-4-(4-fluorophenyl)-1H-imidazole (4d) (634 mg,
2.49 mmol) dissolved in 4 mL THF was added slowly to a reaction
mixture containing TMP (420 μL, 2.49 mmol) and n-BuLi (996 μL,
2.49 mmol) in 9 mL THF at −78 °C. After 30 min at the same
temperature, NFSI (1.26g, 3.99 mmol) dissolved in 9 mL THF and
precooled to −78 °C is transferred to the reaction mixture via a
cannula. After 5 min, the reaction mixture was subjected to aqueous
workup and silica gel purification (hexanes: EtOAc, 9:1), and 5d was
1
°C for 2.5 h. H NMR (400 MHz, CDCl3) 6.58 (d, J = 8.0 Hz, 1H),
1
obtained in 39% yield (244 mg, 0.90 mmol). H NMR (400 MHz,
5.24 (d, J = 1.2 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 155.2 (d, J = 239.7 Hz), 126.0
(d, J = 19.3 Hz), 99.5 (d, J = 36.2 Hz), 75.9, 65.0, 14.8. 19F NMR (376
MHz, CDCl3) δ −132.6 (d, J = 8.1 Hz). HRMS calcd for
C6H8ClFN2O [M + H]+ 179.0382, found 179.0382.
CDCl3) δ 7.72 (dd, J = 8.4, 5.4 Hz, 2H), 7.09 (t, J = 8.7 Hz, 2H), 5.28
(d, J = 0.9 Hz, 2H), 3.65−3.59 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 162.0 (d, J = 246.2 Hz), 143.3 (d, J =
279.9 Hz), 133.8, 129.3, 128.5 (d, J = 5.1 Hz), 128.0, 127.3(dd, J = 5.5,
3.2 Hz), 127.08 (dd, J = 8.0, 4.4 Hz), 125.4 (d, J = 11.3 Hz), 117.1(d, J
= 2.0 Hz), 115.7 (d, J = 21.6 Hz), 72.8, 65.4, 14.9. 19F NMR (376
MHz, CDCl3) δ −114.8, −145.0. HRMS calcd for C12H11ClF2N2O [M
+ H]+ 273.0601, found 273.0612.
1-(Ethoxymethyl)-5-fluoro-2-phenyl-1H-imidazole (5e). Synthe-
sized according to General Procedure A. 1-(Ethoxymethyl)-2-phenyl-
1H-imidazole (4e) (504 mg, 2.49) dissolved in 4 mL THF was added
slowly to a reaction mixture containing TMP (420 μL, 2.49 mmol)
2-Chloro-5-(4-chlorophenyl)-1-(ethoxymethyl)-4-fluoro-1H-imi-
dazole (6b). Synthesized according to General Procedure B. 2-Chloro-
4-(4-chlorophenyl)-1-(ethoxymethyl)-5-fluoro-1H-imidazole 5c (80
mg, 0.28 mmol) was reacted in the presence of acetonitrile (0.55
mL) and acetic acid (0.8 μL, 0.014 mmol) at 80 °C for 4 h. After
aqueous work up with saturated sodium carbonate (Na2CO3) and
extraction with DCM, followed by silica gel purification, 6b was
obtained in yield 83% yield (66 mg, 0.23 mmol). 1H NMR (500 MHz,
E
DOI: 10.1021/acs.joc.5b02592
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The Journal of Organic Chemistry
Note
CDCl3) δ 7.53−7.47 (m, 2H), 7.46−7.40 (m, 2H), 5.23 (d, J = 1.2 Hz,
2H), 3.63 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 152.0 (d, J = 242.4 Hz), 134.6, 130.3 (d, J = 2.4 Hz),
129.4, 127.3 (d, J = 20.0 Hz), 125.2 (d, J = 4.7 Hz), 112.6 (d, J = 29.5
Hz), 73.8, 65.0, 15.1. 19F NMR (376 MHz, CDCl3) δ −134.5. HRMS
calcd for C12H11Cl2FN2O [M + H]+ 289.0305, found 289.0319.
2-(4-Chlorophenyl)-1-(ethoxymethyl)-4-fluoro-1H-imidazole (6c).
Synthesized according to General Procedure B. 2-(4-Chlorophenyl)-1-
(ethoxymethyl)-5-fluoro-1H-imidazole 5f (50 mg, 0.21 mmol) was
reacted in the presence of acetonitrile (0.42 mL) and acetic acid (0.7
μL, 0.013 mmol) at 80 °C for 24 h. After aqueous work up with
saturated sodium carbonate (Na2CO3) and extraction with DCM,
followed by silica gel purification, 6c was obtained in yield 90% yield
After aqueous work up, the crude reaction mixture was subject to silica
gel chromatography (hexanes: EtOAc; 8:2), and 1c was obtained in
89% yield (1.51g, 8.65 mmol). 1H NMR (400 MHz, CDCl3) δ 7.09 (d,
J = 1.6 Hz, 1H), 7.00 (dd, J = 1.5, 0.6 Hz, 1H), 5.51 (q, J = 5.9 Hz,
1H), 3.50−3.27 (m,, 2H), 1.60 (d, J = 5.9 Hz, 3H), 1.17 (t, J = 7.0 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 130., 129.0, 116., 82.7, 64.2,
22.6, 14.7. HRMS calcd for C7H11ClN2O [M] 174.0554, found
174.0529 (1c was analyzed by GCMS with quadrupole mass analyzer;
a postacquisition software package was used to obtain high mass
accuracy).
2-Chloro-N,N-dimethyl-1H-imidazole-1-sulfonamide (1d).17 NaH
(60% dispersion in mineral oil) (1.56g; 39.02 mmol) and 2-chloro-1H-
imidazole (1.0 g; 9.75 mmol) in THF at 0 °C were reacted for 30 min.
Dimethylsulfamoyl chloride (1.68g; 11.71 mmol) was added at 0 °C,
and the mixture was allowed to continue for 3 h at room temperature.
After aqueous work up, the crude reaction mixture was subject to silica
gel chromatography (hexanes: EtOAc; 6:4), and 1d was obtained in
55% yield (1.12g, 5.34 mmol). Analysis data are in accordance with
previously disclosed substrate.
1
(45 mg, 0.19 mmol). H NMR (400 MHz, CDCl3) δ 7.78−7.65 (m,
2H), 7.50−7.36 (m, 2H), 6.64 (d, J = 8.2 Hz, 1H), 5.20 (d, J = 1.2 Hz,
2H), 3.59 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 156.7 (d, J = 235.1 Hz), 141.2 (d, J = 15.1 Hz), 135.6,
130.2, 129.1, 127.9, 100.0 (d, J = 37.7 Hz), 76.3, 64.9, 15.0. 19F NMR
(376 MHz, CDCl3) δ −135.7 (d, J = 8.2 Hz). HRMS calcd for
C12H12ClFN2O [M + H]+ 255.0695, found 255.0698.
1-Benzyl-2-chloro-1H-imidazole (1e).19 1-Benzyl-1H-imidazole
(7.91g; 50 mmol) was dissolved in 50 mL THF and reacted with
TMPMgCl·LiCl (1 M THF/toluene) (75 mL; 75 mmol) and
hexachloroethane (13.02g; 55 mmol) dissolved in 55 mL THF.
After aqueous workup, the crude product was subjected to silica gel
purification (hexanes: EtOAc 9:1), and product 1e was obtained in
71.5% (6.89g, 35.77 mmol). Analysis data are in accordance with
previously disclosed substrate.
2-Chloro-phenyl-1H-imidazole (1f). To 1-pheny-1H-limidazole
(3g, 20.81 mmol) dissolved in THF (12 mL), n-BuLi (2.5 M in
hexanes) (9.16gml, 22.89 mmol) was added at −78 °C. After 30 min
hexachloroethane (4.93g, 20.81 mmol) in THF (12 mL) was added
dropwise via a dropping funnel at −78 °C. The reaction mixture was
stirred for 15 min and then quenched with saturated aqueous
ammonium chloride (20 mL). After extraction with ethyl acetate (125
mL), the organic layer was separated, washed with water and brine,
and dried over anhydrous sodium sulfate. After filtration, the solvents
were evaporated under reduced pressure, and the resulting crude
product was subjected to silica gel purification (8:2 hexanes:EtOAc).
1f was obtained in 84.7% yield (3.18g, 17.63 mmol). Analysis data are
in accordance with previously disclosed substrate.
1-(Ethoxymethyl)-4-fluoro-2-(4-fluorophenyl)-1H-imidazole (6d).
Synthesized according to General Procedure B. 1-(Ethoxymethyl)-5-
fluoro-2-(4-fluorophenyl)-1H-imidazole 5g (50 mg, 0.21 mmol) was
reacted in the presence of acetonitrile (0.42 mL) and acetic acid (0.7
μL, 0.013 mmol) at 80 °C for 24 h. After aqueous work up with
saturated sodium carbonate (Na2CO3) and extraction with DCM,
followed by silica gel purification, 6d was obtained in 90% yield (45
mg, 0.19 mmol). 1H NMR (400 MHz, CDCl3) δ 7.82−7.68 (m, 2H),
7.22−7.07 (m, 2H), 6.68−6.59 (d, J = 8.2 Hz, 1H), 5.2 (d, J = 1.2 Hz,
2H), 3.59 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 163.5 (d, J = 249.9 Hz), 156.6 (d, J = 235.0 Hz),
141.4 (d, J = 15.2 Hz), 131.0, 130.0, 125.6 (d, J = 3.3 Hz), 116.0,
115.9, 99.6 (d, J = 37.8 Hz), 76.3, 64.9, 15.0. 19F NMR (376 MHz,
CDCl3) δ −111.3, −136.0 (d, J = 9.3 Hz). HRMS calcd for
C12H12F2N2O [M + H]+ 239.0990, found 239.0986.
2-Chloro-1-(ethoxymethyl)-1H-imidazole (1a).17,19 1H-imidazole
(10 g, 146.89 mmol) in THF (140 mL) was reacted with NaH (60%
dispersion in oil) (23.5 g, 0.588 mol) and chloromethyl ethyl ether
(16.66g, 0.176 mol) for 3 h at room temperature. After aqueous
workup with chloroform and NH4Cl, the reaction mixture was
subjected to silica gel purification (9.5:0.5 chloroform/methanol), and
1-(ethoxymethyl)-1H-imidazole was obtained in 84% yield (15.71g,
0.123 mol). 1-(Ethoxymethyl)-1H-imidazole (7.7 g, 60.80 mmol) was
dissolved in 60 mL THF and treated with TMPMgCl·LiCl (91.2 mL,
91.20 mmol) and hexachloroethane dissolved in 55 mL THF (15.83g,
66.88 mmol) at −25 °C. After aqueous workup, the crude product was
subjected to silica gel purification (8:2 hexanes:ethyl acetate), and (1a)
was obtained in 71% yield (7.34g, 31.93 mmol). 1H NMR (400 MHz,
CDCl3) δ 7.05 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 5.28 (s,
2H), 3.51 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 132.3, 128.8, 121.0, 75.4, 64.6, 14.7. HRMS calcd for
C6H9ClN2O [M + H]+ 161.0476, found 161.0477.
2-Chloro-1-(ethoxymethyl)-4-methyl-1H-imidazole (4a). (1:1 re-
gioisomeric mixture with 2-chloro-1-(ethoxymethyl)-5-methyl-1H-
imidazole.)17 NaH (60% dispersion in mineral oil) (9.74g, 244
mmol) was reacted with 4-methyl-1H-imidazole (5g, 60.90 mmol) in
THF (70 mL) and chloromethyl ethyl ether (6.91g, 73.08 mmol) for 3
h at room temperature. After aqueous work up (NH4Cl; chloroform),
the crude product was purified by silica gel purification (9.5:0.5
chloroform/methanol), and an inseparable 1:1 mixture of 1-
(ethoxymethyl)-4-methyl-1H-imidazole and 1-(ethoxymethyl)-5-
methyl-1H-imidazole was obtained (5.9 g, 41.67 mmol, 64% yield).
To the regioisomeric mixture (5.78g, 41.24 mmol) dissolved in THF
(25 mL), n-BuLi (2.5 M in hexanes) (9.16gml, 22.89 mmol) was
added at −78 °C. After 30 min, hexachloroethane (4.93g, 20.81 mmol)
in THF (12 mL) was added dropwise at −78 °C. After 15 min, the
reaction was quenched with saturated aqueous ammonium chloride
(20 mL) and extracted with ethyl acetate (125 mL). The organic layer
was dried over anhydrous sodium sulfate. The crude product obtained
after evaporation of solvents was subjected to silica gel purification
(8:2 hexanes:EtOAc). 4a was obtained in 89% yield (6.6 g, 36.67
2-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole
(1b).17 NaH (60% dispersion in mineral oil) (1.56 g; 39.02 mmol) and
2-chloro-1H-imidazole (1.0 g; 9.75 mmol) in THF at 0 °C were
reacted for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (1.95g;
11.71 mmol) was added at 0 °C, and the mixture was allowed to
continue for 3 h at room temperature. After aqueous work up, the
crude reaction mixture was subject to silica gel chromatography
(hexanes: EtOAc; 8:2), and 1b was obtained in 97% yield (2.21g, 9.49
mmol). 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 1.5 Hz, 1H), 7.00
(d, J = 1.5 Hz, 1H), 5.27 (s, 2H), 3.56−3.51 (m, 2H), 0.94−0.89 (m,
2H), 0.00 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 132.4, 128.9,
121.1, 75.2, 66.7, 17.8, −1.3. HRMS calcd for C9H17ClN2OSi [M +
H]+ 233.0871, found 233.0865.
1
mmol). H NMR (500 MHz, CDCl3) δ 6.78−6.73 (m, 1H), 6.72−
6.67 (m, 1H), 5.25 (s, 2H), 5.21 (s, 2H), 3.50 (q, J = 7.0 Hz, 4H),
2.29−2.23 (m, 3H), 2.21−2.15 (m, 3H), 1.24−1.15 (m,, 6H). 13C
NMR (151 MHz, CDCl3) δ 138.0, 131.5, 131.0, 129.9, 126.0, 117.3,
75.2, 73.1, 64.5, 64.2, 14.9, 14.8, 13.9, 10.0. HRMS calcd for
C7H11ClN2O [M + H]+ 175.0633, found 175.0626.
2-Chloro-1-(1-ethoxyethyl)-1H-imidazole (1c).17 NaH (60% dis-
persion in mineral oil) (1.56g; 39.02 mmol) and 2-chloro-1H-
imidazole (1.0 g; 9.75 mmol) in THF at 0 °C were reacted for 30 min.
1-Chloro-1-ethoxyethane18 (1.27g; 11.71 mmol) was added at 0 °C,
and the mixture was allowed to continue for 3 h at room temperature.
2-Chloro-1-(ethoxymethyl)-4-phenyl-1H-imidazole (4b).17 NaH
(60% dispersion in mineral oil) (5.55g, 138 mmol) was reacted with 4-
phenyl-1H-imidazole (5g, 34.68 mmol) in THF (70 mL) and
chloromethyl ethyl ether (3.93g, 41.62 mmol) for 3 h at room
temperature. After aqueous work up (NH4Cl; chloroform), the crude
F
DOI: 10.1021/acs.joc.5b02592
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The Journal of Organic Chemistry
Note
product was purified by silica gel purification (9.5:0.5 chloroform/
methanol), and 1-(ethoxymethyl)-4-phenyl-1H-imidazole was ob-
tained in 61% yield (4.3 g, 21.26 mmol). 1-(Ethoxymethyl)-4-
phenyl-1H-imidazole (2.58g, 12.76 mmol) was dissolved in 8 ml THF
and treated with n-BuLi (2.5 M in hexanes) (5.61 mL, 14.03 mmol) at
−78 °C. After 30 min, hexachloroethane (3.02 g, 12.76 mmol) in THF
(8 mL) was added dropwise at −78 °C. After 15 min, the reaction was
quenched with saturated aqueous ammonium chloride (20 mL) and
extracted with ethyl acetate (125 mL). The organic layer was dried
over anhydrous sodium sulfate. The crude product obtained after
evaporation of solvents was subjected to silica gel purification (8:2
hexanes:EtOAc). 4b was obtained in 63% yield (1.9 g, 8.03 mmol). 1H
NMR (400 MHz, MeOD) δ 7.72−7.68 (m, 2H), 7.67 (s, 1H), 7.40−
7.33 (m, 2H), 7.28−7.22 (m, 1H), 5.39 (s, 2H), 3.59 (q, J = 7.0 Hz,
2H), 1.19 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 141.1, 1325,
132.4, 128.8, 127.7, 124.8, 116.2, 75.8, 64.9, 14.9. HRMS calcd for
C12H13ClN2O [M + H]+ 237.0789, found 237.0792.
2-(4-Chlorophenyl)-1-(ethoxymethyl)-1H-imidazole (4f).17 2-(4-
Chlorophenyl)-1-(ethoxymethyl)-1H-imidazole (2g, 11.20 mmol) in
THF (40 mL) was reacted with NaH (60% dispersion in oil) (1.79g,
44.79 mmol) and chloromethyl ethyl ether (1.27g, 13.44 mmol) for 3
h at room temperature. After aqueous workup with chloroform and
NH4Cl, the reaction mixture was subjected to silica gel purification
(9.5:0.5 chloroform/methanol), and 4f was obtained in 84% yield
1
(2.21g, 9.34 mmol). H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.5
Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 6.2 Hz, 1H), 5.27 (s,
1H), 3.57 (q, J = 7.0 Hz, 1H), 1.24 (t, J = 7.0 Hz, 2H). 13C NMR (151
MHz, CDCl3) δ 147.6, 135.1, 130.2, 128.9, 128.8,128.8, 122.0, 75.8,
64.6, 14.9. HRMS calcd for C12H13ClN2O [M + H]+ 237.0789, found
237.0799.
1-(Ethoxymethyl)-2-(4-fluorophenyl)-1H-imidazole (4g).17 2-(4-
Fluorophenyl)-1-(ethoxymethyl)-1H-imidazole (1g, 6.17 mmol) in
THF (12 mL) was reacted with NaH (60% dispersion in oil) (0.99g,
24.67 mmol) and chloromethyl ethyl ether (0.7 g, 7.40 mmol) for 3 h
at room temperature. After aqueous workup with chloroform and
NH4Cl, the reaction mixture was subjected to silica gel purification
(9.5:0.5 chloroform/methanol), and 4g was obtained in 75% yield
2-Chloro-4-(4-chlorophenyl)-1-(ethoxymethyl)-1H-imidazole
(4c).17,19 4-(4-Chlorophenyl)-1H-imidazole (3g, 16.80 mmol) in THF
(36 mL) was reacted with NaH (60% dispersion in oil) (2.69g, 67.18
mmol) and chloromethyl ethyl ether (1.91g, 20.15 mmol) for 3 h at
room temperature. After aqueous workup with chloroform and
NH4Cl, the reaction mixture was subjected to silica gel purification
(9.5:0.5 chloroform/methanol), and 4-(4-chlorophenyl)-1-(ethoxy-
methyl)-1H-imidazole was obtained in 35% yield (1.4 g, 5.92
mmol). 4-(4-Chlorophenyl)-1-(ethoxymethyl)-1H-imidazole (1.4 g,
5.92 mmol) was dissolved in 6 mL THF and treated with TMPMgCl·
LiCl (1 M in THF/toluene) (8.87 mL, 8.87 mmol) for 0.5 h at 0 °C
and transferred via cannula to hexachloroethane (1.54g, 6.51 mmol)
dissolved in 5.5 mL THF at −25 °C. After aqueous workup, the crude
product was subjected to silica gel purification (8:2 hexanes:ethyl
1
(1.02g, 4.63 mmol). H NMR (400 MHz, CDCl3) δ 7.81−7.76 (m,,
1H), 7.18−7.11 (m, 2H), 5.26 (s, 1H), 3.57 (q, J = 7.0 Hz, 1H), 1.23
(t, J = 7.0 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 163.5 (d, J =
249.0 Hz), 147.8, 131.0, 130.9, 128.7, 126.5 (d, J = 3.4 Hz), 121.7,
115.8, 115.7, 75.9, 64.6, 15.0. HRMS calcd for C12H13FN2O [M + H]+
221.1085, found 221.1094.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02592.
1
acetate), and 4c was obtained in 63% yield (1.01g, 3.73 mmol). H
NMR (400 MHz, CDCl3) δ 7.73−7.60 (m, 1H), 7.41−7.23 (m, 2H),
5.30 (s, 1H), 3.55 (q, J = 7.0 Hz, 1H), 1.22 (t, J = 7.0 Hz, 2H). 13C
NMR (151 MHz, CDCl3) δ 140.3, 132.9, 132.7, 131.5, 128.8, 125.9,
116.2, 75.6, 64.8, 14.8. HRMS calcd for C12H12Cl2N2O [M + H]+
271.0399, found 271.0408.
Data regarding the evaluation of various fluorination
reagents, copies of 1H and 13C NMR spectra for
compounds 1a−c, 3a−d, 4a−g, 5a−g, and 6a−d, and
copies of 19F NMR spectra of compounds 3a−d, 5a−g,
and 6a−d (PDF)
2-Chloro-1-(ethoxymethyl)-4-(4-fluorophenyl)-1H-imidazole
(4d).17,19 4-(4-Fluorophenyl)-1H-imidazole (3g, 18.50 mmol) in THF
(36 mL) was reacted with NaH (60% dispersion in oil) (2.96g, 74.00
mmol) and chloromethyl ethyl ether (2.1 g, 22.20 mmol) for 3 h at
room temperature. After aqueous workup with chloroform and
NH4Cl, the reaction mixture was subjected to silica gel purification
(9.5:0.5 chloroform/methanol), and 4-(4-fluorophenyl)-1-(ethoxy-
methyl)-1H-imidazole was obtained in 43% yield (1.8 g, 7.95
mmol). 4-(4-Fluororophenyl)-1-(ethoxymethyl)-1H-imidazole (1.8 g,
7.95 mmol) was dissolved in 10 mL THF and treated with TMPMgCl·
LiCl (1 M in THF/toluene) (11.92 mL, 11.92 mmol) for 0.5 h at 0 °C
and transferred via cannula to hexachloroethane (5.64g, 23.84 mmol)
dissolved in 24 mL THF at −25 °C. After aqueous workup, the crude
product was subjected to silica gel purification (8:2 hexanes:ethyl
AUTHOR INFORMATION
Corresponding Author
*kalberts@its.jnj.com
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Dr. Jiejun Wu and Mrs.
Heather McAllister for analytical support.
1
acetate), and 4d was obtained in 73% yield (1.47g, 5.77 mmol). H
REFERENCES
NMR (400 MHz, CDCl3) δ 7.73−7.67 (m, 2H), 7.28 (s, 1H), 7.06 (t,
J = 8.7 Hz, 2H), 5.31 (s, 2H), 3.56 (d, J = 7.0 Hz, 2H), 1.22 (t, J = 7.0
Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 162.2 (d, J = 246.2 Hz),
140.7, 132.6, 129.2 (d, J = 3.0 Hz), 126.4 (d, J = 8.0 Hz), 115.7−115.5
(m), 75.6, 64.8, 14.8. HRMS calcd for C12H12ClFN2O [M + H]+
255.0695, found 255.0695.
■
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DOI: 10.1021/acs.joc.5b02592
J. Org. Chem. XXXX, XXX, XXX−XXX