A safe and efficient synthetic route to a 2,5-dimethyl-1-aryl-1H-imidazole intermediate

Article abstract of DOI:10.1021/op100335q

An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1H-imidazoles (6) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters

Full text of DOI:10.1021/op100335q

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pubs.acs.org/OPRD
A Safe and Efficient Synthetic Route to a 2,5-Dimethyl-1-aryl-1H-
imidazole Intermediate
Ana C. Barrios Sosa,* R. Thomas Williamson, Ryan Conway, Ashish Shankar, Rosline Sumpter, and
Thomas Cleary
Pharmaceutical Technical Development Actives (PTDA-FL), Roche Carolina Inc., 6173 East Old Marion Highway, Florence,
South Carolina 29506-9330, United States
S Supporting Information
b
Scheme 1. Existing route to ester 5
ABSTRACT: An optimized route to an iodo-imidazole
intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-
aryl-1H-imidazoles (6) was devised. Important data for the
optimization work was obtained by carrying out a DOE
study to gain understanding of the parameters that affect the
key intramolecular cyclization to build the imidazole ring.
Additional information on the reaction mechanism of this
step was obtained by carrying out a flow NMR experiment.
In order to complete the proof of concept, the iodo-
imidazole intermediate was converted to two ethynyl imi-
dazoles (6a, b) using metal-catalyzed reactions.
1. INTRODUCTION
1-(4-Fluorophenyl)-2,5-dimethyl-1H-imidazole-4-carboxylic
acid ethyl ester (5) is a key intermediate in the synthesis of 1-(4-
fluorophenyl)-2,5-dimethyl-4-arylethynyl-1H-imidazoles (6), which
have been shown to play an important role in the treatment of
exemplified in Scheme 2 with the synthesis of ethynyl imidazole
10 from precursor 9.1b One of the main concerns of this route is
metabotropic glutamate receptor-mediated disorders, such as
anxiety and chronic or acute pain.1 The current synthesis of
the low yields associated with the formation of diiodo-imidazole
intermediate 5 (Scheme 1)2 relies on the reaction of 3-oxo-butyric
acid ethyl ester (1) with sodium nitrite to form its hydroxyimino
derivative 2. Subsequent treatment of 2 with 4-fluoroaniline (3)
and catalytic amounts of pyridinium p-toluenesulphonate (PPTS)
furnishes the desired 4-fluorophenylimino intermediate 4. Forma-
tion of the imidazole ring (5) is then achieved via a one-pot metal-
catalyzed reduction and cyclization step using triethylorthoacetate,
hydrogen, and Pd(C).3
8 and iodo-imidazole 9.1b In addition, low selectivity in the
introduction of the methyl group at C5 in compounds such as
8 can lead to reduced yields in the synthesis of 5-methyl-iodo-
imidazole intermediates. In order to circumvent these problems a
different approach to the synthesis of this type of iodo-imidazole
was sought, which could in turn facilitate the overall synthesis of
ethynyl imidazoles.
Although intermediate 5 can be obtained in good yield and
purity through this route, the scalability of the process is affected
by potential safety hazards. Studies have shown that the addition
of sodium nitrite in the formation of 2 is highly exothermic,
exhibiting an adiabatic temperature rise of 96 °C. In addition,
accelerating rate calorimetry studies (ARC) performed on con-
centrated samples of intermediates 2 and 4 showed accelerating
self-heat and gas generation rates with increasing temperature
and rapid runaway. This type of behavior could be of particular
concern when residual amounts of 2 and 4 accumulate around
the vessel walls during the reaction.4 The potential safety hazards
associated with the route described above prompted us to re-
evaluate an alternate approach to the synthesis of 4-arylethynyl-
1H-imidazoles (6) where the ethynyl functionality is intro-
duced via metal catalyzed coupling reactions.1a,1b This route is
2. RESULTS AND DISCUSSION
As we searched for a suitable way to build the imidazole ring
we were intrigued by a report from Eloy et al. on the synthesis of
imidazoles from acetamidic esters and propargylamine.5 In order
to assess the feasibility of constructing the desired imidazole ring
in this fashion, 4-fluoroaniline (3) was reacted with triethy-
lorthoacetate to provide acetamidic ester 11 and its reaction with
propargylamine (12) was investigated (Scheme 3). Formation
of intermediate 14 was expected to proceed via an intramolec-
ular cyclization of intermediate 13. Subsequent iodination of
imidazole 14 could then lead to iodo-imidazole 15 (Scheme 3).
However, numerous efforts to form the desired imidazole 14 in
Received: December 18, 2010
Published: February 02, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of 4-arylethynyl-1H-imidazoles from
Scheme 5. Synthesis of imidazole 14 from amidine 18
iodoimidazole 9
Scheme 3. Synthesis of imidazoles from acetamidic esters
Scheme 4. Hydrolysis product of compound 16
Figure 1. Surface plots. (A) Percentage of product 14 (a) as a function
of temperature (b) and equivalents of 12 (c). (B) Percentage of starting
material 18 (a) as a function of temperature (b) and equivalents of 12
(c). Compounds 14 and 18 were measured by GC analysis. Tempera-
tures were measured in °C.
toluene and MeTHF from 11 were unsuccessful. The use of
catalysts such as TsOH, ZnCl2, and Pd(OAc)2 did not result
in increased formation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-
imidazole 14. Attempts to detect intermediate 13 by stan-
dard analytical tools were unsuccessful, presumably due to its
instability.
dimethylacetal (Scheme 5). Reaction of 18 with propargylamine
(12) in acetic acid led to the successful formation of imidazole 14
(Scheme 5).
Failure to produce compound 14 led us to believe that the
harsh reaction conditions needed to react precursor 11 with
propargylamine (12) were resulting in the decomposition of pre-
cursor 11. In an attempt to favor formation of intermediate 13,
the reactivity of precursor 11 was modified. Initial attempts
focused on replacing acetamidic ester 11 with the more reactive
N-(4-fluorophenyl)acetimidoyl chloride (16).6 Compound 16,
however, was found to be unstable and hydrolyzed readily to
N-(4-fluorophenyl)acetamide (17) during its reaction with 12
(Scheme 4). Careful drying did not improve the result.
A recent report by Díaz et al. describes the synthesis of
amidines through an amine-exchange reaction under mild con-
ditions.7 In order to test this approach, the synthesis of com-
pound 14 from N0-(4-fluorophenyl)-N,N-dimethylacetamidine
(18) was attempted next. Intermediate 18 was produced
quantitatively from 4-fluoroaniline (3) and dimethylacetamide
With these results in hand, a DOE study using a fractional
factorial design was carried out to gain more understanding on
the impact of variables such as reaction temperature, reaction
time, and equivalents of propargylamine (12) on the formation
of product 14. The effects of these variables were monitored by
measuring the percentages of imidazole 14, 4-fluoroaniline (3),
and starting material (18) by GC analysis. The study consisted of
11 runs with 3 center points.
Surface plots were generated to view the levels of product (14)
(Figure 1A) and starting material (18) (Figure 1B) as a function
of temperature and equivalents of propargylamine (12). Of
particular interest was the curvature observed in the levels of
product 14 as the equivalents of propargylamine (12) were
increased. As shown in Figure 1A, the percentage of product
increased as expected when the amount of propargyalmine (12)
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Figure 2. Setup for the study of the reaction of derivative 18 to generate
imidazole 14 using flow NMR. A mixture of compound 18 and com-
pound 12 were stirred in a vessel (b), and acetic acid was dosed over
time. The mixture was cycled through the flow cell (a) as the reaction
progressed and 1H NMR spectra were acquired.
was elevated to 1.25 equiv. However, additional amounts of pro-
pargylamine (12) led to lower levels of imidazole 14. Interest-
ingly, the starting material (18) was consumed under these latter
conditions (Figure 1B). This nonlinear relationship between
product (14) levels and amounts of propargylamine (12) sug-
gested that the desired reaction path can become less favored
when increasing amounts of propargylamine (12) are used in the
system. The consumption of the starting material (18) indicated
the existence of a side reaction.
Additional details on the nature of the side reaction could not
be derived from the data, because the effect of the variables was
measured directly by the formation of product 14 without the
detection of intermediate 13. For this reason, we began to con-
sider other analytical approaches for the detection of this inter-
mediate during the reaction. In recent years flow NMR has
become a useful tool for reaction monitoring.8 This inline moni-
toring technique relies on cycling the reaction mixture through a
Figure 3. 1H NMR spectra acquired with a flow probe for the reaction
of 18 with compound 12 to give intermediate 13. A reaction mixture
consisting of compound 18, propargylamine (12) and acetonitrile is
cycled through the probe. The addition of acetic acid leads to the
formation of intermediate 13. This is evident by the disappearance of
the N,N-dimethyl peak as intermediate 13 is formed.
1
flow probe as the reaction takes place. H NMR spectra are
acquired periodically over time to collect information as the reac-
tion progresses, thus circumventing the need of sample collection
and preparation. Figure 2 shows a simplified diagram of the flow
NMR setup used to study the reaction of 18 to imidazole 14.
For the flow NMR experiment, compound 18 and propargy-
lamine (12) were mixed at 0-4 °C in a vessel. Acetonitrile was
used as a solvent to thin the mixture and facilitate the pumping of
1
the solution through the flow probe. H NMR spectra were
acquired periodically, and acetic acid was added. The data col-
lected showed that the formation of N-(4-fluorophenyl)-N0-
prop-2-ynyl acetamidine 13 occurred rapidly and cleanly. This
was evident by the sudden disappearance of the N,N-dimethyl
peak (Figure 3) as the reaction intermediate (13) formed.
The reaction mixture was subsequently heated to 80 °C and
maintained at this temperature. Analysis of the spectra showed
that cyclization of 13 to the desired imidazole 14 was accom-
panied by the formation of a byproduct, which was identified as
2,5-dimethyl-1-prop-2-ynyl-1H-imidazole (20).7 A snapshot of
the reaction progress is shown in Figure 4.
The proposed mechanism for the formation of byproduct 20 is
shown in Scheme 6. It is believed that, as the temperature is
increased, propargylamine (12) reacts with intermediate 13,
forming 19 and displacing 4-fluoroaniline (3). Subsequent
intramolecular cyclization of intermediate 19 leads to the for-
mation of imidazole 20.
Since both reactions (the desired and side reaction) are acid
catalyzed, a study was initiated to investigate the effect of the acid
in the transformation of 18 to 14. As shown in Table 1, the use of
TFA (entry c) did not provide detectable levels of imidazoles 14
Figure 4. Snapshot of the reaction from 13 to imidazole 14. Key chemical
shifts are indicated for compounds 13, 14, and 3. Analysis of the 1H NMR
spectra shows the formation of imidazole 20 as a byproduct.
or 20, while the use of formic acid (entry b) produced only 18%
of imidazole 14. Surprisingly, reaction of 18 with propargylamine
(12) in hydrochloric acid (entry d) gave high levels of imidazole
14 as the sole imidazole product. In order to explain the selective
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Scheme 6. Proposed mechanism for the formation of imi-
dazoles 14 and 20
Scheme 7. Optimized synthesis to ethynyl imidazoles 6
bisulfite, and the desired product 15 was precipitated by addition
of aqueous sodium hydroxide. To complete the proof of con-
cept, iodo-imidazole 15 was reacted with two alkynes (21) using
Sonogashira coupling conditions. As seen in Scheme 6, the
desired 1-(4-fluorophenyl)-2,5-dimethyl-4-arylethynyl-1H-imi-
dazoles 6a, b were isolated in good yields.1a,1b
To assess the safety of the synthesis of 14 from 18 we looked at
the reaction enthalpy and associated adiabatic temperature rise
for the formation of 13 and its subsequent intramolecular cycli-
zation to 14. The reaction enthalpy was measured in a Super
CRC reaction microcalorimeter. The adiabatic temperature rise
was calculated to be 71.7 °C. This suggests that an accidental loss
of cooling would raise the batch temperature to ∼72 °C, which
lies within the specified reaction conditions. Additionally, ARC
studies were completed to determine the thermal stability of the
mixture. In contrast to the original route, the exotherm observed
did not show acceleration of self-heat rates or generation of
pressure at temperatures below 218 °C.12
Table 1. Effect of acid on the formation of imidazoles 14 and
20a
entry
acid
20 (%)b
14 (%)b
a
acetic acid
9.4
77.9
18.2
ND
93.1
b
c
formic acid
NDc
ND
ND
trifluoroacetic acid
d
hydrochloric acid
a Representative reaction conditions: amidine 18 was cooled to 0-4 °C,
acid and propargylamine (12) were added. The mixture was heated to
85 °C and held at this temperature for ∼5 h. A sample was collected and
treated with Na2CO3 (aq); the products were extracted with MTBE.
b Values measured by GC analysis in area %. c ND = not detected.
3. CONCLUSIONS
formation of imidazole 14, the effect of the acid on the amine
exchange step to generate 13, as well as on the subsequent
cyclization step, needs to be considered. It has been reported that
amine exchanges using strong acids are less effective, presumably
due to the strong acid-base interaction between the acid and
nucleophile.7 Nevertheless, it could be suggested that strongly
acidic conditions lead to an increase in the rate of cyclization of
13 to 14. As a result, the aminolysis of 13 to 19 is minimized, and
the formation of imidazole 20 is avoided.
The final workup involved the dilution of the reaction mixture
with methyl tert-butyl ether (MTBE) and extraction with aqu-
eous sodium carbonate and water, followed by concentration of
the organic phase. No agitation issues were observed during the
concentration of the solution, and the concentrate remained as a
stirable liquid upon cooling. Attempts to crystallize compound
14 in situ from aqueous and organic media were unsuccessful.
However, the reaction of 14 to 15 was easily telescoped by
diluting the concentrate (14) with methanol and sulfuric acid
(Scheme 7) and treating the solution with sodium periodate and
iodine.9,10 Interestingly, addition of iodine upfront followed by
heating of the reaction mixture to reflux gave an incomplete
reaction with starting material levels as high as 50%. In this case,
use of excess iodine and other solvents such as THF did not result
in an increase in product formation.11 This problem was cir-
cumvented by dosing a solution of iodine in methanol to the
mixture while the reaction mixture stirred at 60 °C. This type of
addition allowed the starting material (14) to be consumed over
time. Once cooled, the reaction was quenched with sodium
An optimized approach to the synthesis of 1-(4-fluorophe-
nyl)-2,5-dimethyl-4-arylethynyl-1H-imidazoles (6) from iodo-
imidazole 15 was devised starting from 4-fluoroaniline (3).
The route relies on the reaction of N0-(4-fluorophenyl)-N,N-
dimethylacetamidine 18 with propargylamine (12) to produce
acetamidine 13, which upon intramolecular cyclization furnished
the desired imidazole core (14). This route avoids the thermal
hazards associated with the synthesis of compounds 2 and 4 as
shown by thermal analysis data. Key parameters which affect the
formation of imidazole 14 were identified in a DOE study, while
flow NMR data provided mechanistic information for the
formation of 14. These studies helped to elucidate a side reaction,
which can be avoided by choosing the appropriate acid for the
reaction. Final synthesis of the key intermediate 1-(4-fluoro-
phenyl)-4-iodo-2,5-dimethyl-1H-imidazole (15) was achieved by
reaction of 1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazole (14)
with iodine and sodium periodate. To complete the proof of
concept two ethynyl imidazoles (6a, b) were synthesized from 15
using Sonogashira coupling conditions.
4. EXPERIMENTAL SECTION
General Methods. Statistical analysis of the DOE was carried
out using Modde 7 by Umetric Inc.
GC Analysis. GC analysis was performed on an Agilent 6890
gas chromatograph equipped with FID and an Optima 5-Amin
(Macherey-Nagel) column (30 m ꢀ 0.25 mm, 0.5 μm film
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thickness). Carrier gas/flow: helium/2.0 mL/min. Inlet tem-
perature: 200 °C; split ratio 20:1. Detector temperature: 300 °C;
H2 flow = 30 mL/min; air flow = 300 mL/min; makeup gas =
helium (30 mL/min). Injection volume: 2 μL. Gradient: 100-
300 at 10 °C/min.
(15) (350 mg, 1.11 mmol), trimethyl(phenylethynyl)silane
(338 mg, 1.94 mmol), triphenylphosphine (58.1 mg, 0.221
mmol), copper(I) iodide (5.16 mg, 0.058 mmol), potassium
carbonate(765mg, 5.54mmol), bis(triphenylphosphine)palladium-
(II) chloride (40.4 mg, 0.058 mmol), NMP (1.0 mL) and metha-
nol (0.75 mL) were heated to 77 °C. The mixture was stirred
overnight at this temperature. The mixture was cooled to room
temperature, passed through a Celite bed, and added to ice. The
solids were filtered, and the desired product was recrystal-
lized from 10% ethyl acetate and 90% hexanes. The solids were
filtered and dried under vacuum at 60 °C overnight to give 1-(4-
fluorophenyl)-2,5-dimethyl-4-phenylethynyl-1H-imidazole (6a)
Flow NMR. Spectra were acquired on a Varian VNMRS
1
400 MHz spectrometer operating at a H frequency of 399.75
MHz. The probe was a Varian inverse detect 3 mm/60 μL triple
resonance (HCN) probe equipped with single-axis pulsed field
gradients. Solvent suppression was achieved using the WET
pulse sequence, and all data were acquired with no deuterium
lock. The reaction mixture was transferred from the reaction flask
to the flow probe and back in a single loop via a Hewlett-Packard
series 1050 HPLC pump operating at a flow rate of 1.0 mL/min.
An acquisition time of 2.318 s with a relaxation delay of 0.682 s
was used, and eight scans were acquired for each spectrum.
N0-(4-Fluorophenyl)-N,N-dimethylacetamidine (18). 4-
Fluoroaniline (24.12 g, 0.217 mmol) and (46.33 g, 347 mmol) of
N,N-dimethylacetamide dimethylacetal were heated to 85 °C
while stirring and were kept at this temperature overnight. The
mixture was cooled to room temperature to give the desired
product in 99% purity (a/a GC). MS m/z 180 [M]þ. The
mixture was used as is.
1
as a tan solid (230 mg, 72%). MS m/z 291 [M]þ. H NMR
(500 MHz, DMSOd6) δ 7.54-7.37 (m, 9H), 2.12 (s, 3H),
2.09 (s, 3H).
1-(4-Fluorophenyl)-2,5-dimethyl-4-o-tolylethynyl-1H-
imidazole (6b). Compound 6b was synthesized using the pro-
cedure described above for 6a. 1-(4-Fluorophenyl)-2,5-dimeth-
yl-4-o-tolylethynyl-1H-imidazole (6b) was isolated as a tan solid
1
(141 mg, 75%). MS m/z 305 [M]þ. H NMR (500 MHz,
DMSOd6) δ 7.56-7.38 (m, 5H), 7.25 (dddd J = 26.8, 15.3,
7.3 Hz, 3H), 2.43 (s, 3H), 2.11 (3H), 2.09 (s, 3H).
Flow NMR Experiment. N0-(4-Fluorophenyl)-N,N-dimethy-
lacetamidine (18) (1.0 g, 5.2 mmol) and propargylamine (12)
(0.409 g, 7.4 mmol) were added to acetonitrile (30 mL) at 0 °C.
Glacial acetic acid (1.0 g, 16.6 mmol) was then added to the
mixture over 2 min. After 10 min, the reaction was heated to 80 °C
and stirred for 3 h. Note: these solvents were not deuterated.
1-(4-Fluorophenyl)-2,5-dimethyl-1H-imidazole (14). N0-(4-
Fluorophenyl)-N,N-dimethylacetamidine (18) (101 g, 560 mmol)
was cooled to 0 °C and 36.5-38% hydrochloric acid (61.3 g,
1.68 mol) was added over 40 min. Propargylamine (12) (37.0 g,
673 mmol) was added to the mixture and the mixture was stirred
for 15 min. The reaction temperature was increased to 85 °C and
kept at this temperature for 5 h. The mixture was cooled to 25 °C
and MTBE (404 mL) and an aqueous solution of saturated sodium
bicarbonate (202 mL) were charged while stirring. The phases
were separated, and the aqueous phase was washed with MTBE
(404 mL). The combined organic phases were washed with water
(202 mL). The organic phase was separated, and the solvent was
distilled off to give 14 as an oil in 94% purity (a/a GC). MS m/z
190 [M]þ. 1H NMR (400 MHz, DMSOd6) δ 7.58-7.26 (m, 4H),
6.65 (s, 1H), 2.10 (s, 3H), 1.96 (s, 3H). The product was used as is
in the next step.
’ ASSOCIATED CONTENT
S
Supporting Information. Data obtained from the DOE
b
study. ARC data for compounds 2, 4 ,and 14 as well as 1H NMR
and IR spectra, GC and MS analyses for key intermediates 18, 14,
15, 6a, 6b. This material is available free of charge via the Internet
at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
*ana.barrios_sosa@roche.com Telephone: 843-629-4000. Fax:
(843)-629-4128.
’ ACKNOWLEDGMENT
We thank Paul Spurr and Dr. Pingsheng Zhang for their
helpful comments. We also thank Dieu Nguyen for her assistance
in the translation of relevant articles and Stephen Chan, Crystal
Fields, and Jim Suchy for their assistance with MS and IR data.
’ REFERENCES
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1-(4-Fluorophenyl)-4-iodo-2,5-dimethyl-1H-imidazole
(15). Sodium periodate (3.67 g, 17.1 mmol), 1-(4-fluoro-
phenyl)-2,5-dimethyl-1H-imidazole (14) (9.99 g, 52.6 mmol),
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in methanol (100 mL) was added over 1 h. The mixture was
stirred for 4 h at this temperature. The mixture was cooled to
20 °C, and a solution of sodium bisulfite (0.175 g, 1.68 mmol) in
water (50 mL) was added. The pH of the mixture was adjusted to
pH = 14 with 42% sodium hydroxide. The solids were filtered
and washed with water (20 mL). The solids were dried under
vacuum at 60 °C overnight to give 1-(4-fluorophenyl)-4-iodo-
2,5-dimethyl-1H-imidazole (15) (11.1 g, 67%) as a brown solid.
1
MS m/z 316 [M]þ. H NMR (400 MHz, DMSOd6) δ 7.54-
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zole (6a). 1-(4-Fluorophenyl)-4-iodo-2,5-dimethyl-1H-imidazole
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(11) Shibahara, F.; Yamaguchi, E.; Kitagawa, A.; Imai, A.; Murai, T.
Tetrahedron 2009, 65, 5062.
(12) Thermal stability of the reaction mixture was assessed with
accelerating rate calorimetry (ARC, Thermal Hazard Technology:
EuroARC) using a standard heat-wait-search (HWS) approach. A
sample of the reaction mixture after completion of the reaction was
tested in an ARC—the sample showed a minor self-heating exotherm
with an onset at 82 °C. The exotherm did not show acceleration of self-
heat rates or generation of pressure with the system falling back into
HWS mode at 125 °C. A second decomposition exotherm is seen with
an onset at 218 °C, accelerating self-heat-rates and gas generation and
a maximum calculated final adiabatic temperature of 406.8 °C. A stan-
dard safety margin of 50 °C from the exothermic onset at 218 °C gives
a maximum safe temperature of 168 °C.
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dx.doi.org/10.1021/op100335q |Org. Process Res. Dev. 2011, 15, 449–454