Regioselective synthesis of 1,4-disubstituted imidazoles

Article abstract of DOI:10.1039/c1ob06690k

A short and efficient synthesis of 1,4-disubstituted imidazoles has been developed which provides the desired products with complete regioselectivity. This protocol allows preparation of compounds which are challenging to prepare by current literature met

Full text of DOI:10.1039/c1ob06690k

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PAPER
Regioselective synthesis of 1,4-disubstituted imidazoles†
Michael A. Schmidt* and Martin D. Eastgate
Received 6th October 2011, Accepted 3rd November 2011
DOI: 10.1039/c1ob06690k
A short and efficient synthesis of 1,4-disubstituted imidazoles has been developed which provides the
desired products with complete regioselectivity. This protocol allows preparation of compounds which
are challenging to prepare by current literature methods in a regioselective fashion, a sterically and
electronically diverse range of N-substituents being accessible. The sequence involves an unusual
double aminomethylenation of a glycine derivative, to yield a 2-azabuta-1,3-diene, onto which addition
of an amine nucleophile results in a transamination/cyclization to prepare the substituted imidazole.
The cyclization event is surprisingly insensitive to steric and electronic variations on the amine
component, enabling a diverse range of imidazoles to be prepared.
In the context of a recent project, we required a regiochemically
pure 1-substituted-4-carboxyimidazole 1 (Scheme 1). A thorough
literature search revealed a very limited number of methods
to efficiently prepare imidazoles of this type with complete
control over the regioselectivity of the process. The most common
route to imidazoles with this substitution pattern utilizes a
regioselective monodecarboxylation of an imidazoledicarboxylic
acid 2 (Scheme 1),1 which itself is prepared in three steps from
diaminomaleonitrile. Heating to 175 ◦C is required to affect
the regioselective monodecarboxylation along with additional
functional group interconversion (FGI) to prepare the desired
imidazole 1. While the lengthy sequence and high temperature
decarboxylation are significant disadvantages for this route, the
reliance on alkylation (to install R2) represents the most significant
challenge, limiting the breadth of derivatives available through
this procedure. A shorter alternative involves an alkylation2 or
arylation3 of an unsubstituted 4-carboxy-imidazole (Scheme 1);
while rapid and relatively mild, poor regioselectivities plague such
an approach, which is again completely reliant on alkylation or
arylation and is therefore limited by the availability of suitable
electrophiles.
The previous report involved reaction of an electron-deficient
amine derivative 3–5 (Scheme 2) and dimethylformamide dimethy-
lacetal (DMF·DMA) at 150 ◦C, forming the corresponding 2-
azabuta-1,3-diene (azadiene) 6;5 cyclization of 6 with anilines
in acetic acid at 100 ◦C afforded the imidazoles 7. While this
process seemed to offer several advantages in terms of efficiency
and regiochemical control, notable issues remained. Significantly,
the first reaction is conducted at high temperatures (150 ◦C,
approximately 40 ◦C above the boiling point of DMF·DMA) and
the products 6 are purified by distillation at very low pressures
(<0.05 torr). Additionally, only examples of anilines were reported
as suitable nucleophilic partners in the condensation, limiting the
method to the formation of N-aryl imidazoles 7.
In considering other methods to these imidazoles, ring forming
condensations (such as [4 + 1] cyclizations) stood out as a viable
strategy.4 For our desired analogs, the most relevant report was
present in the patent literature and described a two-step method
for the regioselective formation of N-aryl-1,4-disubstituted imida-
zoles, though this proved unreproducible in our hands.5 Herein we
describe the development of a practical, reliable and reproducible
method to convert a simple glycine derivative, in two steps, to a
diverse range of 1-substituted imidazoles.
Scheme 1 Previously established routes.1
Chemical Development, Bristol-Myers Squibb Company, 1 Squibb Drive,
New Brunswick, New Jersey 08903, USA. E-mail: Michael.Schmidt@
bms.com
† Electronic supplementary information (ESI) available: Characterization
data for all compounds are provided. See DOI: 10.1039/c1ob06690k
Scheme 2 Azadiene approach to imidazoles.5
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We started our investigation by examining the reactivity of
the aminoacetonitrile (5) toward DMF·DMA under the reported
conditions. Simply refluxing aminoacetonitrile in DMF·DMA
yielded clean, albeit trace, conversion to the desired azadiene.
We attributed the poor conversion to the low boiling point of
DMF·DMA (102–103 ◦C) as we were unable to reproduce the
reported results—even if the reaction was run at the reported bath
temperature (150 ◦C). We hypothesized that higher temperatures
may aid conversion; indeed carrying out the reaction in a sealed
tube at 150 ◦C gave full conversion in ~6 h, more consistent with the
original procedure but under significant pressure.5 We focused on
trying to eliminate the need for pressure equipment by exploring
other reagents to effect the azadiene synthesis.
ization and deprotonation. We therefore hoped that a mixture
of DMF·DMA and pyrrolidine would mimic the two beneficial
effects of Bredereck’s reagent as stated above.
Gratifyingly, we observed clean conversion to the bispyrrolidino
azadiene 10 derivative in only 4 h at a modest 85 ◦C (Scheme 3).
In these early studies aminoacetonitrile (5), an unstable oil, had
been employed. However, under these new conditions, the shelf-
stable hydrochloride salt 9 could be utilized, simply by increasing
the amounts of DMF·DMA and pyrrolidine (3.25 equivalents
each). At complete conversion the product azadiene 10 (as a
mixture of geometric isomers) is accompanied by small amounts
(<10%) of the monopyrrolidino-monodimethyl 11–12 and bis-
dimethylamino azadienes 13 (Scheme 3); the dimethylamine being
derived from DMF·DMA. While additional pyrrolidine could be
added to drive the azadienes completely to the bispyrrolidino-
derivative 10, this was not necessary as all the azadienes (10–13)
undergo the subsequent cyclization (vide infra). After formation
of the azadiene, dilution with dichloromethane and a simple
aqueous extraction removed the pyrrolidinium salts and unreacted
alkoxyaminomethane compounds. The solvent was then removed
and the crude azadiene could then be used directly, without
recourse to high vacuum distillation for purification. With an easy,
mild and reliable method to prepare the azadiene in hand, the
cyclization to the imidazole could be optimized.
We thought that increasing the boiling point of the DMF–
acetal would improve the conversion. Thus, dimethylformamide
diethylacetal (bp = 130–133 ◦C), when heated to reflux, increased
the rate of reaction compared to DMF·DMA, with complete
conversion being observed in 4–6 days. Dimethylformamide di-
n-propylacetal (bp = 183–185 ◦C) at 150 ◦C provided com-
plete conversion, though still required 2 days (dimethylfor-
mamide di-n-propylacetal could be generated in situ by reacting
DMF·DMA and 1-propanol, which yielded identical results).6
While higher reaction temperatures provided increases in the
reaction rate, further increases and lower temperatures were
required to make this process practical. Screening additional
aminomethylene sources revealed that Bredereck’s reagent (tert-
butoxy bis(dimethylamino)methane 8, Fig. 1), was a much more
effective reagent in this context, forming the azadiene 6 (EWG =
◦
CN) in only ~4 h at 85 C;7 a remarkable increase in reactivity
compared to the DMF–acetals. We attempted to rationalize this
finding to help drive our research forward. First, we considered
that Bredereck’s reagent could ionize (and thus react) at a lower
temperature than a DMF–acetal based reagent (Fig. 1). Secondly,
the greater concentration of amine bases in the system (Me2NH
in this case) could increase the concentration of the nucleophilic
ionic-form of the substrate (via deprotonation), thus increasing the
rate of condensation. However, as Bredereck’s reagent is expensive,
we sought methods to reproduce these two effects in situ.
It is known that heating DMF·DMA in the presence of
secondary amines will result in an acetal exchange and generate
an alkoxydiaminomethane of the Bredereck’s type (8).8 We elected
to use pyrrolidine for this purpose due to its greater basicity
over other common secondary amines, thus favoring both ion-
Scheme 3 Formation of the azadienes 10–13.
To study the formation of the desired imidazoles we investigated
the cyclization using 4-bromoaniline (21) as our test nucleophile.
Initial conditions were: 4-bromoaniline (1.25 equivalents relative
to 9) in acetic acid (5 mL g-1) at 100 ◦C. Unfortunately, after a brief
optimization study the yield only averaged around 30–38%. We
hypothesized that the low yield was due to azadiene decomposition
during the reaction, by way of cyano group elimination (Scheme 4).
Fig. 1 Hypothesis on the greater reactivity of 8.
Scheme 4 Potential decomposition pathway for azadiene 10.
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In order to obviate this potential issue we decided to replace
the cyano group with a tertiary morpholino amide 16 (Table 1),
which should be a suitable substrate for the condensation and the
subsequent cyclization, but be much less likely to undergo this
potential decomposition pathway. The known amide 16 was easily
prepared from N-Boc glycine morpholino amide.9
Gratifyingly, the amide 16 was converted to the mixture of
azadienes (~90% 17, ~10% 18–20) under similar conditions as
the aminoacetonitrile hydrochloride (Table 1). The amide 16
underwent only partial conversion to the corresponding azadienes,
which necessitated an increase in the amount of DMF·DMA and
pyrrolidine (7.5 molar excess each); under these slightly modified
conditions, clean conversion to the azadienes 17–20 was obtained
in only 4 h. Heating the crude azadienes in the presence of 4-
bromoaniline (21, 1.5 equivalents) to 100 ◦C in acetic acid (5 mL
g-1) afforded the desired imidazole 22 in 73–75% yield over the
two steps (Table 1), a significant increase over the original cyano
substrate 10.
With a high yielding method to selectively prepare the 4-
bromophenyl imidazole 22 in hand, we examined electronic and
steric effects on the aniline nucleophile. The efficiency of the
cyclization was only weakly affected by the electronics of the
aromatic system; both electron-rich and electron-deficient anilines
(Table 1, entries 1–4) afforded the imidazoles in good yield. The
more electron-deficient p-nitroaniline (27) required a longer reac-
tion time (4 h), but still afforded the imidazole 28 in an acceptable
61% yield. Surprisingly the cyclization was remarkably tolerant to
steric variation; examination of bulky anilines revealed that even
the extremely sterically demanding 2,6-diisopropylaniline (29)
gave a 56% yield of the corresponding imidazole 30 (Table 1, entry
5), a truly surprising result. Heterocyclic anilines also afforded
the desired imidazoles (Table 1, entries 6,7). 3-Aminopyridine
31 formed the corresponding imidazole 32 in an acceptable 62%
yield; however, 5-aminoindole (33) provided only 37% yield of 34,
presumably due to the acid sensitivity of the indole itself.
We were interested to try alkyl amines as they were not among
the substrates noted in the original report.5 We immediately
determined that the more basic primary alkyl amines were far
slower to cyclize to the corresponding imidazole (17–24 h). We
were concerned about the stability of the azadiene in AcOH over
these extended reaction times; indeed the azadienes were found
to be moderately unstable at elevated temperatures in acetic acid.
Thus it was clear that increasing the rate of the reaction with
simple amines would be needed to achieve acceptable yield of the
imidazole products.
butylamine 41 produced the imidazole 42 in an exceptional 75%
yield.
The cyclization was by far the most effective when carried
out in acetic acid, other solvents giving significant reductions
in yield (DMF, toluene, ethanol, acetonitrile and water were
screened at a concentration of 5 mL g-1). After completion of
the reaction, the solvent is quenched with aqueous potassium
carbonate and the imidazole extracted into dichloromethane to
afford the crude product after concentration. The major side
products, the N-acetylamino compounds, unreacted amine and
small amounts of N-formyl pyrrolidine are conveniently removed
by either crystallization or column chromatography.
In summary, we have examined the regioselective formation of
1,4-disubstituted imidazoles from a simple glycine derivative via
azadiene formation and subsequent condensation. By incorpo-
rating pyrrolidine in the condensation step with DMF·DMA, we
have lowered the reaction temperature from 150 ◦C to 85 ◦C,
and eliminated the purification of the intermediate azadienes.
The combined use of DMF·DMA and pyrrolidine was utilized
as an inexpensive replacement for Bredereck’s reagent. We have
broadened the scope of the cyclization to include a wide range
of primary amines with varying steric requirements, where the
cyclization can be catalyzed by small amounts of N-methylaniline.
Experimental section
(1-(4-Bromophenyl)-1H-imidazol-4-yl)(morpholino)methanone
(22)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride9 (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h
before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.37 g). The orange oil was diluted with acetic acid
(5.00 mL) and 4-bromoaniline (21, 1.45 g, 8.30 mmol, 1.5 equiv.)
was added. The dark mixture was heated to 100 ◦C for 2 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a dark brown
solid. The solid was slurried in 25% v/v THF in hexanes (20 mL)
for 2 min then filtered through a Buchner filter. The cake was rinsed
with hexanes (2 ¥ 5 mL) yielding the imidazole 22 as a light brown
powder (1.35 g, 73%). A duplicate reaction aff◦orded 1.44 g (77%)
We were excited to find that the addition of a catalytic amount
(10 mol %) of a secondary aniline, N-methylaniline, greatly
increased the rate of the addition/cyclization (full conversion
with 1-butylamine 35 was obtained in only 2 h).10 These modified
conditions were successful for a range of primary amines (Table
1, entries 8–11). 1-Butylamine (35) afforded the imidazole 36
in excellent yield (82%). Alpha-branched systems such as (S)-
(-)-a-methylbenzylamine ((-)-37, 99% e.e.) and (1R,2S)-(+)-cis-1-
amino-2-indanol ((+)-39, 99% e.e.) formed the desired imidazoles
without loss of stereochemical information (98.3% e.e. for (+)-
38 and 99.5% e.e. for (+)-40). The benzylamine 37 afforded the
imidazole in 74% yield; however, the aminoindanol 39 formed
the imidazole 40 with reduced efficiency (42%). Sterics again had
little impact on the reactivity of the primary alkyl amines—tert-
1
of product. H NMR (500 MHz, CDCl3, 23 C): d 7.89 (d, J =
1.6 Hz, 1H, HImid), 7.75 (d, J = 1.3 Hz, 1H, HImid), 7.64 (app d, J =
8.5 Hz, 2H, ArH), 7.30, (app d, J = 8.8 Hz, 2H, ArH), 4.35 (br s,
2H, Hmorph), 3.78 (br s, 6H, Hmorph). 13C NMR (125.8 MHz, CDCl3,
23 ◦C): d 162.2, 139.1, 135.6, 134.0, 133.2, 124.0, 123.1, 121.8,
67.0 (br s), 47.3 (br s), 43.0 (br s). FTIR (thin film) (cm-1): 3121
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Table 1 Regioselective synthesis of 1,4-disubstituted imidazoles
Entry
Amine
Imidazole
Yielda
75%
1
2
3
68%
65%
4
61%
5
6
56%
62%
7
37%
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Table 1 (Contd.)
Entry
8
Amine
Imidazole
Yielda
82%b
9
74%b
42%b
10
11
75%b
a Yield is over two steps and is an average of two runs. b 10 mol % N-methylaniline was used.
(w), 2957 (w), 1602 (m), 1505 (m), 1113 (m). HRMS (ESI) (m/z):
Calc’d for C14H15BrN3O2 [M + H]+: 336.03422, Found: 336.03409.
Melting point: 219–221 ◦C.
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a dark brown
solid. The solid was slurried in 25% v/v THF in hexanes (20 mL)
for 2 min then filtered through a Buchner filter. The cake was
rinsed with hexanes (2 ¥ 5 mL) yielding the imidazole 24 as a light
brown powder (1.09 g, 69%). A second reaction a◦fforded 1.07 g
(67%) of product. 1H NMR (500 MHz, CDCl3, 23 C): d 7.84 (d,
J = 1.6 Hz, 1H, HImid), 7.67 (d, J = 1.3 Hz, 1H, HImid), 7.31 (app d,
J = 8.8 Hz, 2H, ArH), 6.99, (app d, J = 8.8 Hz, 2H, ArH), 4.37 (br
s, 2H, Hmorph), 3.85 (s, 3H◦, CH3), 3.77 (br s, 6H, Hmorph). 13C NMR
(125.8 MHz, CDCl3, 23 C): d 162.5, 159.3, 138.3, 134.4, 129.8,
124.6, 124.0, 123.2, 115.0, 67.1 (br s), 55.5, 47.2 (br s), 42.9 (br s).
FTIR (thin film) (cm-1): 3122 (w), 2959 (w), 1608 (m), 1456 (m),
1112 (m). HRMS (ESI) (m/z): Calc’d for C15H18N3O3 [M + H]+:
288.13427, Found: 288.13389. Melting point: 174–175 ◦C.
(1-(4-Methoxyphenyl)-1H-imidazol-4-yl)(morpholino)methanone
(24)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was
added slowly via syringe slowly over 1 min, followed by dimethyl-
formamide dimethylacetal (mild exotherm noted, 5.54 mL,
41.52 mmol, 7.50 equiv.). The clear solution was heated to 85 ◦C for
4 h before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.72 g). The orange oil was diluted with acetic acid
(5.00 mL) and p-anisidine (23, 1.02 g, 8.30 mmol, 1.5 equiv.) was
added. The dark mixture was heated to 100 ◦C for 2 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
Ethyl 4-(4-(morpholine-4-carbonyl)-1H-imidazol-1yl)benzoate
(26)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.)
was added slowly via syringe slowly over 1 min, followed by
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dimethylformamide dimethylacetal (mild exotherm noted,
5.54 mL, 41.52 mmol, 7.50 equiv.). The clear solution was heated to
85 ◦C for 4 h before being cooled to room temperature. The yellow
solution was diluted with dichloromethane (75 mL), washed with
water (2 ¥ 50 mL), and brine (50 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated in vacuo to afford
an orange oil (2.63 g). The orange oil was diluted with acetic acid
(5.00 mL) and benzocaine (25, 2.33 g, 13.84 mmol, 2.50 equiv.)
was added. The dark mixture was heated to 100 ◦C for 2 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a brown solid.
The solid was slurried in 25% v/v THF in hexanes (20 mL) for
5 min then filtered through a Buchner filter. The cake was rinsed
with hexanes (2 ¥ 20 mL). This process was repeated a second
time to yield the imidazole 26 as a light yellow solid (1.18 g, 65%).
67.3 (br s), 67.1 (br s), 47.3 (br s), 43.1 (br s). FTIR (thin film)
(cm-1): 3125 (w), 1616 (w), 1596 (m), 1342 (m), 1111 (m). HRMS
(ESI) (m/z): Calc’d for C14H15N4O4 [M + H]+: 303.10878, Found:
303.10864. Melting Point: 278 ◦C (decomposition).
(1-(2,6-Diisopropylphenyl)-1H-imidazol-4-
yl)(morpholino)methanone (30)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h before
being cooled to room temperature. The yellow solution was diluted
with dichloromethane (75 mL), washed with water (2 ¥ 50 mL),
andbrine(50mL). Theorganiclayerwasdriedoversodiumsulfate,
filtered and concentrated in vacuo to afford an orange oil (2.51 g).
The orange oil was diluted with acetic acid (5.00 mL) and 2,6-
diisopropylphenylaniline (29, 1.74 mL, 8.30 mmol, 1.50 equiv.)
was added. The dark mixture was heated to 100 ◦C for 2 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a black oil. The
crude mixture was purified by flash column chromatography over
silica gel (120 g, 75 to 100% gradient of ethyl acetate in hexanes)
to afford a yellow light solid. The solid was slurried in 10% v/v
THF in hexanes (20 mL) for 2 min then filtered through a Buchner
filter. The cake was rinsed with hexanes (2 ¥ 5 mL) yielding the
imidazole 30 as a white solid (1.06 g, 56%). A second reaction
1
A second reaction afforded 1.18 g (65%) of product. H NMR
(500 MHz, CDCl3, 23 ◦C): d 8.19 (d, J = 8.5 Hz, 2H, ArH), 7.98
(d, J = 1.6 Hz, 1H, HImid), 7.86 (d, J = 1.6 Hz, 1H, HImid), 7.50 (d,
J = 8.8 Hz, 2H, ArH), 4.41 (q, J = 7.0 Hz, 2 H, CH2), 4.35 (br s, 2H,
Hmorph), 3.78 (br s, 6H, Hmorph), 1.42 (t, J = 7.3 Hz, 3H, CH3). 13
C
◦
NMR (125.8 MHz, CDCl3, 23 C): d 165.3, 162.1, 139.8, 139.3,
133.9, 131.6, 130.1, 123.6, 120.8, 67.2 (br s), 67.1 (br s), 61.4, 47.3
(br s), 43.0 (br s), 14.3. FTIR (thin film) (cm-1): 3137 (w), 1719
(m), 1610 (m), 1537 (m), 1116 (m). HRMS (ESI) (m/z): Calc’d
for C17H20N3O4 [M + H]+: 330.14483, Found: 330.14456. Melting
Point: 192–194 ◦C.
(1-(4-Nitrophenyl)-1H-imidazol-4-yl)(morpholino)methanone (28)
1
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was
added slowly via syringe slowly over 1 min, followed by dimethyl-
formamide dimethylacetal (mild exotherm noted, 5.54 mL,
41.52 mmol, 7.50 equiv.). The clear solution was heated to 85 ◦C for
4 h before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.85 g). The orange oil was diluted with acetic acid
(10.00 mL) and p-nitroaniline (27, 1.15 g, 8.30 mmol, 1.5 equiv.)
was added. The dark mixture was heated to 100 ◦C for 3 h, before
being cooled to room temperature. The mixture added slowly to
a beaker containing a 10% wt/wt aqueous solution of potassium
carbonate (125 mL, Gas evolution noted). The precipitated solid
was filtered and washed with water (2 ¥ 20 mL) and dried. The
solid was slurried in acetone (20 mL) for 5 min, then filtered. The
cake was washed with acetone (2 ¥ 20 mL) and dried to yield the
imidazole 28 as a light yellow powder (1.03 g, 62%). A second
afforded 1.04 g (55%) of product. H NMR (500 MHz, CDCl3,
23 ◦C): d 7.64 (d, J = 1.6 Hz, 1H, HImid), 7.45 (t, J = 7.8 Hz, 1H,
ArH), 7.39 (d, J = 1.3 Hz, 1H, HImid), 7.26 (d, J = 7.0 Hz, 2H,
ArH), 4.55 (br s, 2H, Hmorph), 3.81 (br s, 6H, Hmorph), 2.39 (septet,
J = 6.8 Hz, 2H, CH), 1.14 (d, J = 6.0 Hz, 6H, CH3), 1.12 (d, J =
5.7 Hz, 6H, CH3). 13C NMR (125.8 MHz, CDCl3, 23 ◦C): d 162.2,
146.2, 138.0. 137.2, 132.0, 130.2, 128.0, 123.9, 67.2 (br s), 47.2 (br
s), 43.0 (br s), 28.2, 24.4, 24.2. FTIR (thin film) (cm-1): 3105 (w),
2964 (s), 1616 (s), 1534 (s), 1116 (m). HRMS (ESI) (m/z): Calc’d
for C20H28N3O2 [M + H]+: 342.21760, Found: 342.21737. Melting
Point: 165–166 ◦C.
(1-(Pyridin-3-yl)-1H-imidazol-4-yl)(morpholino)methanone (32)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h
before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried
over sodium sulfate, filtered and concentrated in vacuo to afford
an orange oil (3.23 g). The orange oil was diluted with acetic acid
1
reaction afforded 1.01 g (60%) of product. H NMR (500 MHz,
CDCl3, 23 ◦C): d 8.42 (d, J = 7.3 Hz, 2H, ArH), 8.02 (s, 1H, HImid),
7.90 (s, 1H, HImid), 7.62 (d, J = 7.3 Hz, 2H, ArH), 4.35 (br s, 2H,
Hmorph), 3.80 (br s, 6H, Hmorph). 13C NMR (125.8 MHz, CDCl3,
23 ◦C): d 161.8, 146.9, 141.2, 140.0, 133.9, 125.9, 123.5, 121.5,
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(5.00 mL) and 3-aminopyridine (31, 782 mg, 8.30 mmol, 1.5 equiv.)
was added. The dark mixture was heated to 100 ◦C for 3 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL),
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a light brown
solid. The solid was slurried in MTBE (20 mL) for 5 min then
filtered. The cake was washed with MTBE (2 ¥ 20 mL) and dried
to yield the imidazole 32 as a light brown solid (920 mg, 64%).
(cm-1): 3124 (w), 2918 (w), 1594 (s), 1549 (m), 1111 (s). HRMS
(ESI) (m/z): Calc’d for C16H17N4O2 [M + H]+: 297.13460, Found:
297.13425. Melting Point: 215–216 ◦C.
(1-Butyl-1H-imidazol-4-yl)(morpholino)methanone (36)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h before
being cooled to room temperature. The yellow solution was diluted
with dichloromethane (75 mL), washed with water (2 ¥ 50 mL),
andbrine(50mL). Theorganiclayerwasdriedoversodiumsulfate,
filtered and concentrated in vacuo to afford an orange oil (2.71
g). The orange oil was diluted with acetic acid (5.00 mL) and
N-methylaniline (60 mL, 0.55 mmol, 0.10 equiv.) was added. n-
Butylamine (35, 1.37 mL, 13.84 mmol, 2.50 equiv.) was added
slowly over 5 min (caution: exotherm). The dark mixture was
heated to 100 ◦C for 3 h, before being cooled to room temperature.
The mixture was diluted with dichloromethane (50 mL) and
added slowly to a beaker containing a 10% wt/wt aqueous
solution of potassium carbonate (75 mL, gas evolution noted).
The layers were separated and the aqueous layer was extracted
with dichloromethane (50 mL). The combined organic layers were
washed with brine (50 mL), dried over sodium sulfate, filtered and
concentrated in vacuo to afford a dark brown residue. The crude
mixture was purified by flash column chromatography over silica
gel (120 g, 0 to 10% gradient of methanol in dichloromethane)
to yield the imidazole 36 as a tan solid (1.08 g, 82%). A second
1
A second reaction afforded 875 mg (61%) of product. H NMR
(500 MHz, CDCl3, 23 ◦C): d 8.78 (app d, J = 2.2 Hz, 1H, HPyr), 8.68
(app d, J = 3.8 Hz, 1H, HPyr), 7.94 (d, J = 1.3 Hz, 1H, HImid), 7.80
(d, J = 1.3 Hz, 1H, HImid), 7.76 (ddd, J = 8.2, 2.5, 1.3 Hz, 1H, HPyr),
7.48 (app dd, J = 7.6, 4.7 Hz, 1H, HPyr), 4.34 (br s, 2H, Hmorph), 3.78
(br s, 6H, Hmorph). 13C NMR (125.8 MHz, CDCl3, 23 ◦C): d 162.0,
149.4, 142.9, 139.4, 134.0, 133.1, 129.0, 124.3, 123.8, 67.1 (br s),
66.9 (br s), 47.2 (br s), 42.9 (br s). FTIR (thin film) (cm-1): 3113
(w), 2968 (w), 1608 (s), 1435 (m), 1107 (m). HRMS (ESI) (m/z):
Calc’d for C13H15N4O2 [M + H]+: 259.11895, Found: 259.11864.
Melting Point: 173–174 ◦C.
(1-(1H-Indol-5-yl)-1H-imidazol-4-yl)(morpholino)methanone (34)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h
before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.49 g). The orange oil was diluted with acetic acid
(5.00 mL) and 5-aminoindole (33, 1.14 g, 8.30 mmol, 1.50 equiv.)
was added. The dark mixture was heated to 100 ◦C for 2 h, before
being cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a yellow solid.
The solid was slurried in MTBE (20 mL) for 20 min then filtered
through a Buchner filter. The cake was rinsed with MTBE (2 ¥
20 mL). This process was repeated a second time to yield the
imidazole 34 as a light yellow solid (623 mg, 38%). A second
reaction aff◦orded 591 mg (36%) of product. 1H NMR (500 MHz,
CDCl3, 23 C): d 8.71 (br s, 1H, NH), 7.92 (d, J = 1.3 Hz, 1H,
HImid), 7.76 (d, J = 1.3 Hz, 1H, HImid), 7.63 (d, J = 1.9 Hz, 1H,
HIndole), 7.48 (d, J = 8.5 Hz, 1H, HIndole), 7.35 (app t, J = 2.7 Hz,
1H, HIndole), 7.18 (dd, J = 8.5, 2.2 Hz, 1H, HIndole), 6.62 (app t,
J = 2.2 Hz, 1H, HIndole), 4.42 (br s, 2H, Hmorph), 3.80 (br s, 6H,
Hmorph). 13C NMR (125.8 MHz, CDCl3, 23 ◦C): d 162.9, 138.0,
135.2, 135.1, 129.7, 128.3, 126.5, 126.4, 125.4, 116.7, 114.4, 112.14,
112.09, 103.1, 103.0, 67.2 (br s, 47.4 (br s), 43.0 (br s). FTIR (KBr)
1
reaction afforded 1.06 g (81%) of product. H NMR (500 MHz,
CDCl3, 23 ◦C): d 7.57 (s, 1H, HImid), 7.38 (s, 1H, HImid), 4.36 (br s,
2H, Hmorph), 3.94 (t, J = 7.1 Hz, 2H, CH2), 3.74 (br s, 6H, Hmorph),
1.78 (pentet, J = 7.3 Hz, 2H, CH2), 1.33 (sextet, J = 7.4 Hz, 2H,
CH2), 0.94 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (125.8 MHz, CDCl3,
23 ◦C): d 162.7, 137.8, 135.7, 125.2, 67.2 (br s), 47.2 (br s), 47.1,
42.9 (br s), 32.8, 19.6, 13.4. FTIR (thin film) (cm-1): 3107 (w),
2959 (s), 1616 (s), 1541 (s), 1115 (m). HRMS (ESI) (m/z): Calc’d
for C12H20N3O2 [M + H]+: 238.15500, Found: 238.15488. Melting
point: 64–65 ◦C.
(S)-( )-(1-(1-Phenylethyl)-1H-imidazol-4-
yl)(morpholino)methanone (38)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h
before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.66 g). The orange oil was diluted with acetic acid
(5.00 mL) and N-methylaniline (60 mL, 0.55 mmol, 0.10 equiv.)
was added. (S)-a-Methylbenzylamine (37, 1.78 mL, 13.84 mmol,
2.5 equiv.) was added slowly over 5 min (caution: exotherm).
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The dark mixture was heated to 100 ◦C for 3 h, before being
cooled to room temperature. The mixture was diluted with
dichloromethane (50 mL) and added slowly to a beaker containing
a 10% wt/wt aqueous solution of potassium carbonate (75 mL,
gas evolution noted). The layers were separated and the aqueous
layer was extracted with dichloromethane (50 mL). The combined
organic layers were washed with brine (50 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to afford a
dark brown residue. The crude mixture was purified by flash
column chromatography over silica gel (120 g, 0 to 9% gradient of
methanol in dichloromethane) to yield the imidazole 38 as a thick
oil that slowly solidifies (1.19 g, 75%). The product was found to be
98.3% ee by chiral HPLC (Chiralpak AD-H, 60% heptanes, 40%
methanol–ethanol (1 : 1 v/v), 1.0 mL min-1, 220 nm, tR (minor) =
8.22 min, tR (major) = 11.53 min). A second reaction using (R)-a-
methylbenzylamine afforded 1.15 g (73%, 99.2% ee, [a]2D3 -22.2 (c
0.01, CH2Cl2)) of product. 1H NMR (500 MHz, CDCl3, 23 ◦C): d
7.65 (d, J = 1.6 Hz, 1H, HImid), 7.47 (d, J = 1.3 Hz, 1H, HImid), 7.31–
7.38 (m, 3 H, ArH), 7.18 (app d, J = 6.6 Hz, 2H, ArH), 5.34 (q, J =
7.0 Hz, 1H, CH), 4.38 (br s, 2H, Hmorph), 3.74 (br s, 6H, Hmorph), 1.87
(d, J = 6.9 Hz, 3H, CH3). 13C NMR (125.8 MHz, CDCl3, 23 ◦C):
d 162.6, 140.4, 137.7, 134.8, 129.0, 128.4, 126.1, 124.3, 67.2 (br s),
57.1, 47.2 (br s), 42.9 (br s), 21.9. FTIR (thin film) (cm-1): 3113
(w), 2855 (s), 1610 (s), 1538 (m), 1114 (m). HRMS (ESI) (m/z):
Calc’d for C16H20N3O2 [M + H]+: 286.15500, Found: 286.15488.
[a]2D3 = +22.0 (c = 0.01, CH2Cl2). Melting point: 96–97 ◦C.
(43%, 99.7% ee, [a]2D3 -59.3 (c 0.01, CH2Cl2)) of product. 1H NMR
(500 MHz, CDCl3, 23 ◦C): d 7.42 (s, 1H, HImid), 7.32–7.36 (m, 2H,
HImid, ArH), 7.27–7.28 (m, 1H, ArH), 7.23 (app td, J = 6.5, 1.9 Hz,
1H, ArH), 7.15 (d, J = 7.6 Hz, 1H, ArH), 5.48 (d, J = 5.0 Hz, 1H,
CH), 4.70 (m, 1H, CH), 4.40 (br s, 1H, OH), 4.30 (br s, 2H, Hmorph),
3.70 (br s, 6H, Hmorph), 3.23 (dd, J = 16.2, 5.8 Hz, 1H, CH2), 3.02
(dd, J = 16.2, 4.6 Hz, 1H, CH2). 13C NMR (125.8 MHz, CDCl3,
23 ◦C): d 162.7, 141.1, 137.4, 136.4, 136.1, 129.5, 127.6, 126.1,
125.6, 125.3, 73.4, 67.0 (br s), 65.2, 47.3 (br s), 42.9 (br s), 38.8.
FTIR (thin film) (cm-1): 3312 (br s), 2920 (w), 1597 (s), 1456 (m),
1113 (m). HRMS (ESI) (m/z): Calc’d for C17H20N3O3 [M + H]+:
314.14992, Found: 314.14969. [a]2D3 = +58.5 (c = 0.01, CH2Cl2).
Melting point: 165–166 ◦C.
(1-(tert-Butyl)-1H-imidazol-4-yl)(morpholino)methanone (42)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was
added slowly via syringe slowly over 1 min, followed by dimethyl-
formamide dimethylacetal (mild exotherm noted, 5.54 mL,
41.52 mmol, 7.50 equiv.). The clear solution was heated to 85 ◦C for
4 h before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.48 g). The orange oil was diluted with acetic acid
(5.00 mL) and N-methylaniline (60 mL, 0.55 mmol, 0.10 equiv.)
was added. The mixture was cooled in an ice water bath and
t-butylamine (41, 1.49 mL, 13.84 mmol, 2.5 equiv.) was added
slowly over 5 min (caution: large exotherm). The dark mixture was
heated to 100 ◦C for 3 h, before being cooled to room temperature.
The mixture was diluted with dichloromethane (50 mL) and
added slowly to a beaker containing a 10% wt/wt aqueous
solution of potassium carbonate (75 mL, gas evolution noted).
The layers were separated and the aqueous layer was extracted with
dichloromethane (2 ¥ 50 mL). The combined organic layers were
washed with brine (50 mL), dried over sodium sulfate, filtered and
concentrated in vacuo to afford a brown solid. The crude mixture
was purified by flash column chromatography over silica gel (120
g, 0 to 8% gradient of methanol in dichloromethane) to yield
the imidazole 42 as an off white solid (985 mg, 75%). A second
reaction afforded 979 mg (75%) of product. 1H NMR (500 MHz,
CDCl3, 23 ◦C): d 7.74 (d, J = 1.6 Hz, 1H, HImid), 7.54 (d, J =
1.6 Hz, 1H, HImid), 4.39 (br s, 2H, Hmorph), 3.76 (br s, 6H, Hmorph),
1.58 (s, 9H, CH3). 13C NMR (125.8 MHz, CDCl3, 23 ◦C): d 162.8,
137.3, 133.0, 123.1, 67.1 (br s), 55.5, 47.2 (br s), 42.9 (br s), 30.5.
FTIR (thin film) (cm-1): 3131 (w), 2965 (w), 1610 (m), 1534 (m),
1116 (m). HRMS (ESI) (m/z): Calc’d for C12H20N3O2 [M + H]+:
238.15500, Found: 238.15497. Melting point: 164–166 ◦C.
( )-(1-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-1H-
imidazol-4-yl)(morpholino)methanone (40)
To a 25 mL round bottomed flask was added 2-amino-1-
morpholinoethanone hydrochloride (16, 1.00 g, 5.54 mmol,
1 equiv.). Pyrrolidine (3.45 mL, 41.52 mmol, 7.50 equiv.) was added
slowly via syringe over 1 min, followed by dimethylformamide
dimethylacetal (mild exotherm noted, 5.54 mL, 41.52 mmol,
7.50 equiv.). The clear solution was heated to 85 ◦C for 4 h
before being cooled to room temperature. The yellow solution
was diluted with dichloromethane (75 mL), washed with water
(2 ¥ 50 mL), and brine (50 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated in vacuo to afford an
orange oil (2.70 g). The orange oil was diluted with acetic acid
(5.00 mL) and N-methylaniline (60 mL, 0.55 mmol, 0.10 equiv.)
and (1R,2S)-(+)-cis-1-amino-2-indanol (39, 1.24 g, 8.30 mmol,
1.50 equiv.) were added. The dark mixture was heated to 100 ◦C
for 2 h, before being cooled to room temperature. The mixture
was diluted with dichloromethane (50 mL) and added slowly to
a beaker containing a 10% wt/wt aqueous solution of potassium
carbonate (75 mL, gas evolution noted). The layers were separated
and the aqueous layer was extracted with dichloromethane (2 ¥
50 mL). The combined organic layers were washed with brine
(50 mL), dried over sodium sulfate, filtered and concentrated in
vacuo to afford a black oil. The crude mixture was purified by
flash column chromatography over silica gel (120 g, 0 to 10%
gradient of methanol in dichloromethane) to yield the imidazole
40 as a light brown gel that quickly solidified (713 mg, 41%). The
product was found to be 99.5% ee by chiral HPLC (Chiralpak IA,
60% heptanes, 40% methanol-ethanol (1 : 1 v/v), 1.0 mL min-1,
220 nm, tR (minor) = 6.14 min, tR (major) = 9.92 min). A second
reaction using (1S,2R)-(-)-cis-1-amino-2-indanol afforded 738 mg
Acknowledgements
We are grateful to Mr Michael Peddicord for obtaining mass
spectrometric data and Mr Juan Garcia for obtaining optical
rotation data. We thank Professor Phil Baran for discussions on
the use of N-methylaniline. We thank Dr Joerg Deerberg and
Dr Susanne Kiau for assistance in translating ref. 5. Dr David
Kronenthal, Dr Rajendra Deshpande are thanked for supporting
1086 | Org. Biomol. Chem., 2012, 10, 1079–1087
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this work and Dr Monica Fitzgerald, Dr Omid Soltani, Dr
Srinivas Tummala and Dr Jacob Albrecht are thanked for useful
discussions.
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