Aminocarbonylation of 4-iodo-1H-imidazoles with an amino acid amide nucleophile: Synthesis of constrained H-Phe-Phe-NH2 analogues

Article abstract of DOI:10.1021/jo4020613

A simple and an expedient process to prepare 5-aryl-1-benzyl-1H-imidazole- 4-carboxamides by the aminocarbonylation of 5-aryl-4-iodo-1H-imidazoles using ex situ generation of CO from Mo(CO)₆ with an amino acid amide nucleophile is reported. Furthermore, a microwave-assisted protocol for the direct C-5 arylation of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to acquire starting material for our aminocarbonylation are presented. The method can be used to prepare imidazole based peptidomimetics, herein exemplified by the synthesis of constrained H-Phe-Phe-NH₂ analogues.

Full text of DOI:10.1021/jo4020613

Note
pubs.acs.org/joc
Aminocarbonylation of 4‑Iodo‑1H‑imidazoles with an Amino Acid
Amide Nucleophile: Synthesis of Constrained H‑Phe-Phe-NH2
Analogues
Anna Skogh, Rebecca Fransson, Christian Skold, Mats Larhed, and Anja Sandstrom*
̈
̈
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P.O. Box
574, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: A simple and an expedient process to prepare 5-aryl-1-
benzyl-1H-imidazole-4-carboxamides by the aminocarbonylation of 5-
aryl-4-iodo-1H-imidazoles using ex situ generation of CO from
Mo(CO)6 with an amino acid amide nucleophile is reported.
Furthermore, a microwave-assisted protocol for the direct C-5 arylation
of 1-benzyl-1H-imidazole and a regioselective C-4 iodination method to
acquire starting material for our aminocarbonylation are presented. The
method can be used to prepare imidazole based peptidomimetics,
herein exemplified by the synthesis of constrained H-Phe-Phe-NH2
analogues.
eterocyclic compounds have important applications in
medicinal chemistry. For example, incorporation of
H
heterocycles into peptide backbones is a common approach in
the construction of peptidomimetics in drug discovery.1−6
Functionalized imidazoles are an important class of heterocycles
which are frequently used as the core structure of biologically
active agents.7−10 Commonly, substituted imidazoles are
obtained via cyclization reactions resulting in 1,5-, 1,2-, or 4,5-
disubstitution patterns directly,11 or by lithiation of N1-
protected imidazoles to give 2- or 2,5-substituted products.12,13
Few examples are presented in literature in which imidazoles are
directly functionalized.14−16
Figure 1. Design of a constrained H-Phe-Phe-NH2 analogue
incorporating an N-terminal imidazole moiety along with a retro-
synthetic analysis.
In an ongoing medicinal chemistry program aimed at
developing constrained H-Phe-Phe-NH2 mimetics acting as the
neuropeptide substance P 1−7 (SP1−7),17,18 we have explored a
simple and fast route to functionalized imidazoles. More
precisely, it was planned to introduce an amino acid side chain
in the C-5 position and thereafter connect a peptide equivalent,
an amino acid amide, in the C-4 position through a carboxamide
coupling (forming a peptide bond), as outlined in Figure 1.
The palladium-catalyzed aminocarbonylation between
(hetero)aryl halides, carbon monoxide, and amines is a well
established synthetic method for the preparation of aryla-
mides.19,20 The processes of sequential palladium-catalyzed
oxidative aminocarbonylation−heterocyclization of alkyne pre-
cursors are also worth mentioning in this context.21−24 The need
for facile and high-throughput methods which are suitable for
small scale laboratory applications and parallel synthesis have led
to the development of solid substitutes for the highly toxic and
flammable CO gas, such as Mo(CO)6.25 The in situ CO-releasing
ability of Mo(CO)6 has been well explored in our laboratory and
demonstrated in a wide range of one-pot carbonylation reactions
using a range of different nucleophiles.26−28 Recently, Skydstrup
and co-workers developed a two-chamber system29−32 utilizing
ex situ generation of CO, and several aminocarbonylation
reactions have been published based on this method.33,34
Surprisingly, aminocarbonylation reactions with halogenated
imidazoles are relatively unexplored. To our knowledge, only a
couple of reactions using unsubstituted N1-protected imidazoles
as starting material have been reported.35,36
Herein, a versatile and high yielding strategy to prepare 5-aryl-
1-benzyl-1H-imidazole-4-carboxamides by aminocarbonylation
of 5-aryl-1-benzyl-4-iodo-1H-imidazole using ex situ generation
of CO from Mo(CO)6 with an amino acid derived nucleophile is
reported. Furthermore, a fast microwave-assisted protocol for
direct C-5 arylation of 1-benzyl-1H-imidazoles and a regiose-
lective C-4 iodination to generate the starting material for our
aminocarbonylation are presented.
Received: September 16, 2013
© XXXX American Chemical Society
A
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We first sought to explore the preparation of analogues to
compound I lacking an aryl substituent in the C-5 position
utilizing N1-protected 4-iodo-1H-imidazoles (1a−b) as model
substrates (Scheme 1). The conditions previously reported by
([α]D20 − 46 and +46). Taken together, no racemization of the
asymmetric center seems to occur under the reaction conditions
used. For the synthesis of 3a and 3b, DMAP turned out to be
crucial for the reaction, since its removal resulted in a drastic
decrease in isolated yield (44% and 42%, respectively).
Having demonstrated the successful aminocarbonylation of 1b
with 2 as the nucleophile, our next step was to access N1-
protected 5-aryl-1H-imidazoles according to the retrosynthetic
analysis in Figure 1. Previously, Bellina et al. published a direct
C−H activation method for the selective palladium-catalyzed C-
5 arylation of 1-benzyl-1H-imidazoles.15 In that study 5-aryl-1-
benzyl-1H-imidazoles were synthesized, in 43−73% yield with a
variety of aryl bromides using Pd(OAc)2 and P(2-furyl)3 as the
catalytic system and conventional heating for 27−88 h. Based on
these reaction conditions, we were interested in exploring a
microwave-assisted protocol for C-5 arylation in order to reduce
the reaction times.42 Initial experiments, using a sealed reaction
vessel with microwave heating and 4-bromotoluene as an
arylating agent identified the presence of the 2,5-diarylated
byproduct. In order to find optimized reaction conditions to
maximize product formation and minimize byproduct formation,
an experimental design was used to explore variation in
temperature, time, Pd-catalyst loading, and amount of aryl
bromide (see Supporting Information). To study the outcome of
the different experiments the ratios of product, 2,5-diarylated
byproduct, and remaining starting material were examined by 1H
NMR analysis of the crude reaction mixture. Subsequent
isolation, using column chromatography, led to the conclusion
that the highest isolated yield of 4b (63%, Table 1, entry 2) could
be achieved by running the reaction for 1 h at 160 °C with a low
catalyst loading (2 mol %) and 5 equiv of the arylbromide.
Furthermore, the addition of 30 mol % pivalic acid was observed
to enhance the yield.43 Using this protocol on electron-deficient
and -rich aryl bromides resulted in isolated yields of up to 65% for
compounds 4a−f (Table 1). The steric hindrance from ortho
methyl substituents had a negative impact on the reaction as
shown in entries 3 and 4. Compound 3c, containing one ortho
substituent, was isolated in 46% yield; however heating to 170 °C
improved the yield to 61%. As can be seen from entry 4, the
presence of two ortho substituents inhibited the arylation
reaction (4d, 0% yield). Since the isolated yields are in agreement
with the previously reported method,15 the optimized conditions
developed for this selective C-5 arylation of 1-benzyl-1H-
imidazoles indicate that the reaction time can be reduced from
27−88 to 1 h without negatively affecting the yields.
Scheme 1. Aminocarbonylation of N1-Protected 4-Iodo-1H-
imidazoles (1a−b) Using ex Situ Generation of CO
a
b
100 °C. DMAP (0.8 mmol, 2 equiv) was added to chamber B
before capping. Reaction conditions: Chamber A: Mo(CO)6 (0.2
mmol, 0.5 equiv), DBU (0.6 mmol, 1.5 equiv) in 1,4-dioxane (3 mL).
Chamber B: N1-protected 4-iodo-1H-imidazoles 1a−b (0.4 mmol, 1.0
equiv), H-Phe-NH2·HCl 2 (0.8 mmol, 2.0 equiv), Pd(PPh3)4 (5 mol
%, 0.05 equiv) and K2CO3 (0.8 mmol, 2.0 equiv) in 1,4-dioxane (3
mL).
Nordeman et al.33 were used as a starting point for our
investigation. Thus, the CO-releasing vessel (chamber A in the
two-chamber system) was charged with Mo(CO)6 (0.5 equiv)
and the CO-accepting chamber (chamber B, the reaction vessel)
with 1 equiv of N,N-dimethyl-4-iodo-1H-imidazole-1-sulfona-
mide (1a), 2 equiv of phenylalanine amide (2) as the nucleophile,
and tetrakis(triphenylphosphine)palladium(0) as the palladium
catalyst. Encouraged by the work presented by Odell et al.
DMAP was also added to chamber B as an acylation catalyst.37
Subsequently, the system was sealed and flushed with nitrogen
and 1,4-dioxane was added to both chambers followed by the
addition of DBU to chamber A and Et3N to chamber B. The two-
chamber system was placed into a heating block, and the reaction
was stirred at 85 °C for 15 h. Initial investigations identified urea
formation originating from two amino acid amide nucleophiles as
the major product.38,39 To minimize the byproduct formation,
the base in chamber B was exchanged from Et3N to K2CO3 and
compound 3a was isolated in a 57% yield. In an attempt to reach
full conversion, the reaction temperature was increased to 100 °C
and full consumption was observed; however, only a slightly
higher isolated yield was obtained (64%). Unfortunately, the
increased temperature led to the formation of the competing bis-
imidazole homocoupling byproduct.40,41 Since we suspected that
the sulfonamide protecting group could enhance dimerization of
the imidazole substrate, the N1-protecting group was changed to
a benzyl group (1b). Repeating the same conditions for 15 h at 85
°C resulted in full conversion of starting material, and an
excellent yield of 92% of compound 3b was isolated. Surprisingly,
the homocoupling byproduct formation was not observed in this
case and a similar isolated yield was obtained when the
temperature was increased to 100 °C (90%). The combination
of high temperature, basic reaction conditions, and a chiral
nucleophile made us concerned about possible racemization. To
investigate this, the products were analyzed using chiral HPLC,
showing chromatograms with single and symmetrical peaks.
Additionally, the corresponding D-analogue of compound 3b was
synthesized according to above-described method. Specific
optical rotation measurements of the two products (L- and D-
isomers) revealed equivalent values although of opposite sign
Introduction of iodine in the C-4 position of compounds 4a−c
and 4e−f was performed by using a reported method developed
for the iodination of electron-rich carbocycles consisting of a
combination of NIS with catalytic TFA in MeCN.44 Extending
the scope of the method provided a regioselective iodination, and
compounds 5a−c and 5e−f were isolated in good yields (73−
84%). Notably, the preparation of 5a−c and 5e−f was greatly
influenced by the electronic and steric effects of the C-5 aryl
substituent. In a typical reaction the 5-aryl-1-benzyl-1H-
imidazoles (4a−c, 4e−f), NIS, TFA, and MeCN were heated
at 80 °C for 1 h to reach full conversion. Substrates containing
ortho-substituent (4c) or electron-poor (4e) C-5 phenyl groups
required 2 or 4 h of heating at 80 °C, respectively. Compound 4f,
carrying an electron-donating 4-methoxy functionality, reached
full conversion of the starting material after stirring at 80 °C for
only 0.5 h (Scheme 2).
Having demonstrated the C-4 aminocarbonylation of 1b with
an amino acid amide in 92% yield (Scheme 1), we next tried this
B
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Table 1. Palladium Catalyzed C-5 Arylation of 1-Benzyl-1H-
imidazole with Aryl Bromides
Scheme 2. Iodination of 5-Aryl-1-benzyl-1H-imidazoles
(4a−c, 4e−f) with NIS and TFA
a
2 h. b 4 h. c 0.5 h. Reaction conditions: 5-aryl-1-benzyl-1H-imidazoles
4a−c, 4e−f (0.5−1.15 mmol), NIS (1.1 equiv), TFA (0.3 equiv) in
MeCN (4−8 mL).
Scheme 3. Aminocarbonylation of the 5-Aryl-1-benzyl-4-iodo-
a
1H-imidazoles (5a-c, 5e-f) Using ex Situ Generation of CO
a
Maximum expected CO pressure in the system is 2.3 bar (see
Supporting Information). b 15 h at 100 °C. c 15 h at 120 °C. d 48 h at
120 °C. Reaction conditions: Chamber A: Mo(CO)6 (0.5 equiv),
DBU (1.5 equiv) in 1,4-dioxane (3 mL). Chamber B: 5-aryl-1-benzyl-
4-iodo-1H-imidazoles 5a−c, 5e−f (0.38−0.46 mmol), H-Phe-NH2·
HCl 2 (2.0 equiv), Pd(PPh3)4 (0.05 equiv), K2CO3 (2.0 equiv), and
DMAP (2.0 equiv) in 1,4-dioxane (3 mL).
conditions did not seem to cause racemization of the product
according to chiral HPLC analysis and specific optical rotation of
the corresponding D-form, that was prepared for comparison
([α]D21 −42 and +42, for the L- and D-isomer of 6f, respectively).
This observation was in agreement with a previously reported,
similar aminocarbonylation of heterocycles at high temperature
using phenylalanine ethyl ester as a nucleophile.36
The final removal of the N1-protecting group was
demonstrated on compounds 3b and 6a (Scheme 4). N-
Debenzylation using Pd/C and H2 (1 atm) was unsuccessful.
However, full conversion was observed after 6 h at 60 °C with H2
(10 bar).
In conclusion, we have developed an efficient protocol for the
preparation of imidazole containing phenylalanine based
peptidomimetics in high and reproducible yields. First, a fast
microwave-assisted palladium-catalyzed protocol for the direct
C-5 arylation of 1-benzyl-1H-imidazole was developed. Micro-
wave heating was able to reduce the reaction time from 24−88 h
to 1 h without compromising the yields. Second, after successful
introduction of iodine in the C-4 position, aminocarbonylation
was performed to yield constrained H-Phe-Phe-NH2 analogues.
This was achieved utilizing Mo(CO)6 as the ex situ generating
solid CO-source and phenylalanine amide (2) as the nucleophile.
Aminocarbonylation of 1-benzyl-4-iodine-1H-imidazole 1b
lacking an aryl in the C-5 position resulted in an excellent
a
b
c
1
Determined by H NMR analysis of the crude. Isolated yield. 170
°C. Reaction conditions: The reaction was performed under
microwave irridation in a sealed vial: 1-Benzyl-1H-imidazole (1
mmol, 1.0 equiv), ArBr (5 mmol, 5 eqiuv), Pd(OAc)2 (0.02 mol, 0.02
equiv), P(2-furyl)3 (0.04 mol, 0.04 equiv), PivOH (0.3 mol, 0.3 equiv),
and K2CO3 (3 mmol, 3 equiv) in 4.0 mL of DMF.
strategy for the C-5 aryl containing compounds (5a−c, 5e−f).
We realized that steric congestion of the aryl substituent could
negatively affect the yield and, unfortunately, using the same
reaction conditions elaborated in Scheme 1 led to incomplete
conversion of the substrate and a low isolated yield of compound
6a (45%, Scheme 3). However, prolonging the reaction time and
increasing the temperature resulted in high isolated yields of the
desired products 6a−c and 6e−f (72−85%). Traces of
dehalogenated starting material due to the high reaction
temperature were observed, which lowered the yield compared
to compound 3b (Scheme 1). The aminocarbonylation of
compound 5c, having an ortho methyl substituent, required a
prolonged reaction time of 48 h for full consumption, and the
product was isolated as a 1:1 mixture of two atrop-diastereomers
according to 1H NMR. Notably, the changes in reaction
C
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system was heated in a heating block at 85/100 °C for 15 h under
vigorous stirring. The reaction tube was thereafter cooled to rt, excess
CO was evacuated carefully, and the crude mixture from chamber B was
filtered and evaporated to dryness. The crude reaction product was
further purified by flash column chromatography on silica gel with
DCM/MeOH/NH4OH (98:2:0.05) as the eluent. This procedure was
employed to prepare compounds 3a−b (Scheme 1).
Scheme 4. Palladium Catalyzed N-Debenzylation of
Compounds 3b and 6a
a
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-(N,N-dime-
thylsulfamoyl)-1H-imidazole-4-carboxamide (3a). Obtained from
1a (0.4 mmol) as a white solid (94 mg, 64% yield); 1H NMR (400 MHz,
CD3OD) δ 8.08 (d, J = 1.4 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.29−7.16
(m, 5H), 4.82−4.80 (m, 1H), 3.26−3.20 (m, 1H), 3.10−3.03 (m, 1H),
2.88 (s, 6H).13C NMR (101 MHz, CDCl3) δ 173.2, 161.4, 137.6, 136.7,
a
Reaction conditions: The reaction was performed in an autoclave:
Substrate 3b/6a (0.5 mmol) and 10% Pd/C in MeOH (4 mL).
21
136.3, 129.4, 128.8, 127.1, 120.2, 54.0, 38.3, 38.1. [α]D −30 (c 0.5,
CHCl3). HRMS (ES) m/z calcd for [M+H+]: C15H19N5O4S 366.1236;
found 366.1235.
isolated yield of 92%. Also, aminocarbonylations on the sterically
congested C-5 aryl imidazoles (5a−c, 5e−f) were successful and
resulted in high isolated yields (72−85%) despite the competing
dehalogenation due to the elevated temperature. These are the
first reported examples of aminocarbonylation of an iodinated
imidazole scaffold using Mo(CO)6 as the ex situ generating CO-
source with an amino acid amide as the nucleophile, thus
providing a method to incorporate imidazole based phenyl-
alanine mimetics into the N-terminal of a peptide chain.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-1H-
imidazole-4-carboxamide (3b). Obtained from 1b (0.4 mmol) as an
off-white solid (128 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 7.61
(d, J = 8.3 Hz, 1H), 7.50 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H),
7.38−7.13 (m, 10H), 6.37 (s, 1H), 5.75 (s, 1H), 5.07 (s, 2H), 4.86−4.80
(m, 1H), 3.23−3.09 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 173.5,
162.7, 137.1, 137.0, 136.8, 135.1, 129.5, 129.3, 128.8, 128.7, 127.7, 126.9,
20
122.7, 53.9, 51.5, 37.8. [α]D −46 (c 1.0, CHCl3). HRMS (ES) m/z
calcd for [M+H+]: C20H20N4O2 349.1665; found 349.1663.
Preparation of the Corresponding D-Isomer. (R)-N-(1-amino-1-
oxo-3-phenylpropan-2-yl)-1-benzyl-1H-imidazole-4-carboxamide. Ob-
tained from 1b and H-D-Phe-NH2. H NMR (400 MHz, CDCl3) δ
EXPERIMENTAL SECTION
■
1
General Information. For technical specifications of the glassware
(the two-chamber system) used for the aminocarbonylation, see earlier
publications.33,34 All the C-5 arylation reactions were performed in
sealed microwave-transparent process vials designed for 2−5 mL
reaction volumes. The microwave heating was performed in an Initiator
single mode reactor (or a Smith single mode reactor for the
experimental design), producing controlled irradiation at 2450 MHz.
The reaction temperature was determined using the built-in online IR-
sensor. Pd(OAc)2 was purchased from STREM, and Pd(PPh3)4, from
Sigma-Aldrich. N,N-Dimethyl-4-iodo-1H-imidazole-1-sulfonamide
(1a), H-Phe-NH2·HCl (2), and H-D-Phe-NH2 are commercially
available and were used without further purification. Analytical thin-
layer chromatography was performed on silica gel 60 F-254 plates and
visualized with UV light. Flash column chromatography was performed
on a silica gel 60 (40−63 μm). 1H and 13C NMR spectra were recorded
at 400 and 101 MHz, respectively, using CD3OD, DMSO-d6, or CDCl3
7.69 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 1.4 Hz,
1H), 7.34−7.10 (m, 10H), 6.58 (s, 1H), 6.08 (s, 1H), 5.03 (s, 2H),
4.90−4.79 (m, 1H), 3.23−3.05 (m, 2H).[α]D20 +46 (c 1.0, CHCl3).
General Procedure for Palladium Catalyzed C-5 Arylation of
1-Benzyl-1H-imidazole with Aryl Bromides. A 5 mL process vial
was charged with 1-benzyl-1H-imidazole (158.0 mg, 1.0 mmol, 1.0
equiv), Pd(OAc)2 (4.48 mg, 0.02 mmol, 0.02 equiv), P(2-furyl)3 (9.28
mg, 0.04 mmol, 0.04 equiv), PivOH (30.6 mg, 0.3 mmol, 0.3 equiv), and
K2CO3 (414.0 mg, 3 mmol, 3 equiv). The vial was capped with a gastight
cap, evacuated, and backfilled with nitrogen gas. Thereafter, DMF (4.0
mL) and aryl bromide (5 mmol, 5 equiv) were added by a syringe under
a flow of nitrogen. The resulting mixture was exposed to microwave
heating at 160 °C for 1 h (compound 4c heated at 170 °C for 1 h). The
reaction tube was thereafter cooled to rt, and the crude mixture was
filtered and evaporated to dryness. The crude reaction product was
further purified by flash column chromatography on silica gel with iso-
hexane/acetone (50:50) as the eluent. This procedure was employed to
prepare compounds 4a−f (Table 1).
1
as a solvent. Chemical shifts for H and 13C are referenced via the
residual solvent signal. The HRMS experiment was performed on a 7-T
hybrid ion trap (LTQ) FT mass spectrometer modified with a
nanospray ion source. Reprosil Chiral NR and NR-R columns (Dr.
Maisch GmbH HPLC; 8 μm; 250 mm × 4.6 mm; eluted at 1.5 mL/min;
UV 254 nm) were used for ee determination of compounds 3a−b, 6a−c,
and 6e−f with iso-hexane/2-propanol.
1-Benzyl-5-phenyl-1H-imidazole (4a).15. White solid (144 mg,
61%); 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.40−7.25 (m, 8H),
7.15 (s, 1H), 7.04−6.99 (m, 2H), 5.15 (s, 2H).13C NMR (101 MHz,
CDCl3) δ 138.8, 136.9, 133.6, 129.9, 129.0 (2 overlapping signals),
128.8, 128.4, 128.2, 128.0, 126.8, 48.8. HRMS (ES) m/z calcd for [M
+H+]: C16H14N2 235.1235; found 235.1230.
Caution! Pressurized reactions should not be conducted in a sealed
two-chamber system without an appropriate pressure release device.
The aminocarbonylation reactions described in this paper should not be
repeated in a larger scale, as this could result in an explosion.
1-Benzyl-4-iodo-1H-imidazole (1b). Prepared as described by He
1-Benzyl-5-(p-tolyl)-1H-imidazole (4b).15. Yellow solid (155 mg,
63%); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33−7.14 (m, 7H),
7.11 (s, 1H), 7.04−6.99 (m, 2H), 5.13 (s, 2H), 2.36 (s, 3H).13C NMR
(101 MHz, CDCl3) δ 138.5, 138.0, 137.0, 133.6, 129.4, 128.9, 128.9,
128.1, 127.9, 126.8, 126.7, 48.7, 21.3. HRMS (ES) m/z calcd for [M
+H+]: C17H16N2 249.1392; found 249.1395.
et al.45 White solid (218−356 mg, 62−85%); H NMR (400 MHz,
1
CD3OD) δ 7.67−7.63 (m, 1H), 7.37−7.20 (m, 5H), 7.19−7.15 (m,
1H), 5.15 (s, 2H). 13C NMR (101 MHz, CD3OD) δ 140.7, 137.5, 130.0,
129.4, 128.7, 126.7, 81.2, 51.9. HRMS (ES) m/z calcd for [M+H+]:
C10H9IN2 284.9889; found 284.9890.
1-Benzyl-5-(o-tolyl)-1H-imidazole (4c). Colorless oil (151 mg,
61%); 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.34−7.12 (m, 7H),
7.03 (s, 1H), 6.94−6.89 (m, 2H), 4.91 (s, 2H), 2.07 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 138.6, 137.6, 136.4, 131.7, 131.3, 130.2, 129.2,
129,0, 128.7, 128.5, 127.9, 127.3, 125.7, 48.8, 19.9. HRMS (ES) m/z
calcd for [M+H+]: C17H16N2 249.1392; found 249.1391.
General Procedure for the Aminocarbonylation of the N1-
Protected 4-Iodo-1H-imidazoles (1a−b). Chamber A was loaded
with Mo(CO)6 (0.2 mmol, 0.5 equiv). Chamber B was loaded with N1-
protected 4-iodo-1H-imidazole (1a−b) (0.4 mmol, 1.0 equiv), H-Phe-
NH2·HCL (2) (0.8 mmol, 2.0 equiv), Pd(PPh3)4 (5 mol %, 0.05 equiv),
K2CO3 (0.8 mmol, 2.0 equiv), and DMAP (0.8 mmol, 2.0 equiv). The
two chambers were capped with a gastight cap, evacuated, and backfilled
with nitrogen gas. Thereafter, 1,4-dioxane (3 + 3 mL) was added to both
chambers by a syringe under a flow of nitrogen. Next, DBU (0.6 mmol,
1.5 equiv) was added to chamber A by syringe and the two-chamber
1-Benzyl-5-(4-(trifluoromethyl)phenyl-1H-imidazole (4e).15
1
White solid (195 mg, 65%); H NMR (400 MHz, CDCl3) δ 7.62−
7.60 (m, 2H), 7.59 (s, 1H), 7.41−7.37 (m, 2H), 7.34−7.27 (m, 3H),
7.21 (s, 1H), 7.03−6.98 (m, 2H), 5.17 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ 139.6, 136.3, 133.4, 132.1, 129.9 (q, JCF = 32.6 Hz), 129.4,
3
129.0, 128.8, 128.1, 126.5, 125.6 (q, JCF = 3.8 Hz), 124.0 (q, JCF = 272.1
3
3
D
dx.doi.org/10.1021/jo4020613 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz), 48.9. HRMS (ES) m/z calcd for [M+H+]: C17H13F3N2 303.1109;
found 303.1111.
mixture from chamber B was filtered and evaporated to dryness. The
crude reaction product was further purified by flash column
chromatography on silica gel with DCM/MeOH/NH4OH
(98:2:0.05) as the eluent. This procedure was employed to prepare
compounds 6a−c and 6e−f (Scheme 3).
1-Benzyl-5-(4-methoxyphenyl)-1H-imidazole (4f).15 White
1
solid (169 mg, 64%); H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H),
7.38−7.23 (m, 3H), 7.22−7.13 (m, 2H), 7.08 (s, 1H), 7.04−6.98 (m,
1H), 6.92−6.86 (m, 2H), 5.11 (s, 2H), 3.81 (s, 3H).13C NMR (101
MHz, CDCl3) δ 159.7, 138.4, 137.1, 133.4, 130.5, 129.0, 128.0, 128.0,
126.8, 122.2, 114.2, 55.4, 48.7. HRMS (ES) m/z calcd for [M+H+]:
C17H16N2O 265.1341; found 265.1338.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-5-
phenyl-1H-imidazole-4-carboxamide (6a). Obtained from 5a
1
(0.455 mmol) as a yellow solid (140 mg, 72%); H NMR (400 MHz,
CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.41−7.14 (m, 13H),
6.97−6.89 (m, 2H), 6.35 (s, 1H), 5.17 (s, 1H), 4.93 (s, 2H), 4.91−4.80
(m, 1H), 3.18−3.02 (m, 2H).13C NMR (101 MHz, CDCl3) δ 173.5,
162.6, 137.1, 136.6, 135.9, 135.8, 132.0, 130.6, 129.5, 129.1, 129.0, 128.7,
General Procedure for Iodination of 5-Aryl-1-benzyl-1H-
imidazoles (4a−c, 4e−f) with NIS and TFA. 5-Aryl-1-benzyl-1H-
imidazole (4a−c, 4e−f) (0.5−1.15 mmol) was dissolved in MeCN (4−8
mL). Thereafter, NIS (1.1 equiv) and TFA (0.3 equiv) were added and
the reaction mixture was stirred at 80 °C for 0.5−4 h. After the specified
time, the solvent was evaporated to dryness. The crude product was
dissolved in DCM, washed with saturated thiosulphate and brine, and
dried over Na2SO4. The crude product was further purified by flash
column chromatography on silica gel with iso-hexane/acetone (50:50)
as the eluent. This procedure was employed to prepare compounds 5a−
c and 5e−f (Scheme 2).
20
128.5, 128.3, 128.3, 127.1, 126.7, 53.5, 48.9, 38.4. [α]D −48 (c 0.65,
CHCl3). HRMS (ES) m/z calcd for [M+H+]: C26H24N4O2 425.1978;
found 425.1974.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-5-(p-
tolyl)-1H-imidazole-4-carboxamide (6b). Obtained from 5b (0.377
1
mmol) as a yellow solid (132 mg, 80% yield); H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.38−7.11 (m, 12H),
7.02−6.95 (m, 2H), 6.46 (s, 1H), 5.49 (s, 1H), 4.97 (s, 2H), 4.94−4.85
(m, 1H), 3.20−3.08 (m, 2H), 2.40 (s, 3H).13C NMR (101 MHz,
CDCl3) δ 173.6, 162.6, 139.0, 137.1, 136.4, 136.0, 135.9, 131.7, 130.4,
129.5, 129.0, 128.9, 128.5, 128.2, 127.0 (2C), 126.7, 125.5, 53.4, 48.7,
38.2, 21.4. [α]D21 −112 (c 0.3, CHCl3). HRMS (ES) m/z calcd for [M
+H+]: C27H26N4O2 439.2134; found 439.2130.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-5-(o-
tolyl)-1H-imidazole-4-carboxamide (6c). Obtained from 5c (0.450
mmol) as a yellow solid (168 mg, 85%) and isolated as a 1:1 mixture of
two atrop-diastereomers; 1H NMR (400 MHz, DMSO-d6) δ 7.91−7.88
(m, 2H), 7.65 (t, J = 7.9 Hz, 2H), 7.33−7.01 (m, 28H), 6.87−6.82 (m,
4H), 4.95−4.86 (m, 4H), 4.62−4.53 (m, 2H), 3.12−3.03 (m, 3H),
3.00−2.93 (m, 2H), 1.78 (s, 3H), 1.73 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 172.71, 172.68, 161.3, 161.1, 138.38, 138.37, 137.51,
137.48, 137.3, 137.2, 136.4, 136.3, 135.0, 133.1, 133.0, 132.3, 130.2,
130.1, 129.8, 129.6, 129.2, 128.92, 128.90, 128.73, 128.69, 128.4, 128.2,
128.05, 127.96, 127.6, 127.2, 126.3, 126.2, 125.24, 125.19, 52.9, 52.6,
48.01, 47.96, 38.1, 33.0, 19.2, 19.1. HRMS (ES) m/z calcd for [M+H+]:
C27H26N4O2 439.2134; found 439.2137.
1-Benzyl-4-iodo-5-phenyl-1H-imidazole (5a). Obtained from
1
4a (0.61 mmol) as a yellow oil (174 mg, 79%); H NMR (400 MHz,
CDCl3) δ 7.53 (s, 1H), 7.40−7.36 (m, 3H), 7.28−7.21 (m, 5H), 6.96−
6.91 (m, 2H), 5.01 (s, 2H).13C NMR (101 MHz, CDCl3) δ 139.4, 136.0,
135.4, 130.6, 129.1, 129.0, 128.8, 128.3, 127.1, 84.6, 50.0. HRMS (ES)
m/z calcd for [M+H+]: C16H14IN2 361.0202; found 361.0195.
1-Benzyl-4-iodo-5-(p-tolyl)-1H-imidazole (5b). Obtained from
1
4b (0.5 mmol) as a yellow oil (147 mg, 79%); H NMR (400 MHz,
CDCl3) δ 7.53 (s, 1H), 7.30−7.27 (m, 2H), 7.23−7.19 (m, 2H), 7.17−
7.12 (m, 2H), 6.99−6.95 (m, 2H), 5.02 (s, 2H), 2.38 (s, 3H).13C NMR
(101 MHz, CDCl3) δ 139.2, 139.0, 136.1, 135.4, 130.5, 129.5, 129.0,
128.2, 127.0, 125.9, 84.5, 49.9, 21.5. HRMS (ES) m/z calcd for [M+H+]:
C17H15IN2 375.0358; found 375.0363.
1-Benzyl-4-iodo-5-(o-tolyl)-1H-imidazole (5c). Obtained from
4c (0.874 mmol) as a colorless oil (239 mg, 73%); 1H NMR (400 MHz,
CDCl3) δ 7.59 (s, 1H), 7.36−7.17 (m, 6H), 7.07−7.03 (m, 1H), 6.88−
6.83 (m, 2H), 4.86 (d, J = 15.1 Hz, 1H), 4.81 (d, J = 15.3 Hz, 1H), 1.92
(s, 3H).13C NMR (101 MHz, CDCl3) δ 139.1, 138.7, 135.4, 135.1,
131.4, 130.3, 129.7, 128.7, 128.3, 128.2, 127.6, 125.9, 85.2, 50.1, 19.6.
HRMS (ES) m/z calcd for [M+H+]: C17H15IN2 375.0358; found
375.0355.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-5-(4-
(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide (6e).
Obtained from 5e (0.396 mmol) as a yellow solid (146 mg, 75%); 1H
NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 1H), 7.64−7.58 (m,
2H), 7.52 (s, 1H), 7.41−7.34 (m, 2H), 7.32−7.16 (m, 8H), 6.95−6.88
(m, 2H), 6.00 (s, 1H), 5.46 (s, 1H), 4.96 (s, 2H), 4.80−4.70 (m, 1H),
3.14 (d, J = 7.1 Hz, 2H).13C NMR (101 MHz, CDCl3) δ 173.4, 162.5,
1-Benzyl-4-iodo-5-(4-trifluoromethyl)phenyl-1H-imidazole
(5e). Obtained from 4e (1.15 mmol) as a yellow oil (398 mg, 81%); 1H
NMR (400 MHz, CDCl3) δ 7.65−7.61 (m, 2H), 7.58 (s, 1H), 7.38−
7.33 (m, 2H), 7.29−7.24 (m, 3H), 6.94−6.89 (m, 2H), 5.03 (s, 2H).13C
NMR (101 MHz, CDCl3) δ 140.1, 135.6, 134.0, 132.8, 131.0 (q, J CF
=
3
137.2, 136.9, 135.5, 134.3, 132.6, 132.4, 131.1 (q, JCF = 32.2 Hz), 131.1,
3
32.6 Hz), 131.0, 129.2, 128.5, 127.0, 125.7 (q, J CF = 3.7 Hz), 124.0 (q, J
3
129.5, 129.2, 128.7, 128.5, 127.0, 126.9, 125.3 (q, JCF = 3.7 Hz, 2C),
= 272.4 Hz), 85.4, 50.2. HRMS (ES) m/z calcd for [M+H+]:
3
CF3
123.17 (q, JCF = 272.4 Hz), 53.7, 49.1, 38.1. [α]D21 −32 (c 0.5, CHCl3).
3
C17H12F3IN2 429.0076; found 429.0084.
HRMS (ES) m/z calcd for [M+H+]: C27H23F3N4O2 493.1851; found
493.1856.
1-Benzyl-4-iodo-5-(4-methoxyphenyl)-1H-imidazole (5f). Ob-
1
tained from 4f (0.51 mmol) as a yellow oil (168 mg, 84%); H NMR
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1-benzyl-5-(4-
(400 MHz, CDCl3) δ 7.54 (s, 1H), 7.30−7.27 (m, 3H), 7.19−7.14 (m,
2H), 6.99−6.95 (m, 2H), 6.94−6.90 (m, 2H), 5.02 (s, 2H), 3.84 (s,
3H).13C NMR (101 MHz, CDCl3) δ 160.1, 139.2, 136.1, 135.3, 132.0,
129.0, 128.2, 127.1, 121.0, 114.2, 84.7, 55.4, 49.9. HRMS (ES) m/z calcd
for [M+H+]: C17H15IN2O 391.0307; found 391.0310.
methoxyphenyl)-1H-imidazole-4-carboxamide (6f). Obtained
1
from 5f (0.431 mmol) as a yellow solid (162 mg, 83%); H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.32−7.23
(m, 8H), 7.20−7.16 (m, 2H), 6.97−6.93 (m, 2H), 6.92−6.87 (m, 2H),
6.17 (s, 1H), 5.28 (s, 1H), 4.95 (s, 2H), 4.84−4.75 (m, 1H), 3.81 (s,
3H), 3.21−3.09 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 173.5, 162.9,
160.3, 137.1, 136.4, 136.0, 135.9, 131.9, 131.7, 129.6, 129.1, 128.7, 128.3,
General Procedure for Aminocarbonylation of the 5-Aryl-1-
benzyl-4-iodo-1H-imidazoles (5a−c, 5e−f). Chamber A was loaded
with Mo(CO)6 (0.5 equiv). Chamber B was loaded with H-Phe-NH2·
HCl (2) (2 equiv), Pd(PPh3)4 (0.05 equiv), K2CO3 (2.0 equiv), and
DMAP (2.0 equiv). The two chambers were capped with a gastight cap,
evacuated, and backfilled with nitrogen gas. Thereafter, the 5-aryl-1-
benzyl-4-iodo-1H-imidazole (5a−c, 5e−f) (0.38−0.46 mmol, 1.0
equiv), dissolved in 1,4-dioxane (3 mL), was added by a syringe to
chamber B under a stream of nitrogen. Next, 1,4-dioxane (3 mL) and
DBU (1.5 equiv) were added to chamber A. The two-chamber system
was heated in a heating block at 120 °C for 24 h (compound 5c heated at
120 °C for 48 h) under vigorous stirring. The reaction tube was
thereafter cooled to rt, excess CO was evacuated carefully, and the crude
21
127.1, 126.9, 120.5, 113.9, 55.4, 53.6, 48.8, 37.9. [α]D −42 (c 0.3,
CHCl3). HRMS (ES) m/z calcd for [M+H+]: C27H26N4O3 455.2083;
found 455.2080.
Preparation of the Corresponding D-Isomer. (R)-N-(1-Amino-1-
oxo-3-phenylpropan-2-yl)-1-benzyl-5-(4-methoxyphenyl)-1H-imida-
1
zole-4-carboxamide. Obtained from 5f and H-D-Phe-NH2. H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.32−7.09
(m, 12H), 6.97 −6.92 (m, 2H), 6.41 (s, 1H), 5.45 (s, 1H), 4.92 (s, 2H),
4.90- 4.81 (m, 1H), 3.17−3.00 (m, 2H), 2.35 (s, 3H). [α]D21 +42 (c 0.3,
CHCl3).
E
dx.doi.org/10.1021/jo4020613 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
General Procedure for the Pd-Catalyzed N-Debenzylation of
Compounds 3b and 6a. 10% Pd/C was added to a solution of the
substrate (3b/6a) (0.5 mmol, 1.0 equiv) in MeOH (4 mL). The
resulting mixture was stirred at 60 °C for 6 h in an autoclave under a H2
atmosphere (10 bar), filtered, and concentrated under reduced pressure.
The product was isolated with analytical purity. This procedure was
employed to prepare compounds 7a and I (Scheme 4).
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-1H-imidazole-
4-carboxamide (7a). Obtained from 3b (0.5 mmol) as a white solid
(120 mg, 93%); 1H NMR (400 MHz, CD3OD) δ 7.67 (d, J = 1.2 Hz,
1H), 7.62 (d, J = 1.2 Hz, 1H), 7.29−7.21 (m, 4H), 7.20−7.14 (m, 1H),
4.82−4.77 (m, 1H), 3.25−3.18 (m, 1H), 3.08−3.01 (m, 1H). 13C NMR
(101 MHz, DMSO-d6) δ 174.5, 157.8, 138.8, 136.5, 130.2, 129.3, 128.0,
127.6, 121.7, 56.1, 38.0. HRMS (ES) m/z calcd for [M+H+]:
C13H14N4O2 259.1195; found 259.1197.
(16) Chatani, N.; Fukuyama, T.; Tatamidani, H.; Kakiuchi, F.; Murai,
S. J. Org. Chem. 2000, 65, 4039.
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̈
̈
(21) Gabriele, B.; Plastina, P.; Salerno, G.; Mancuso, R. Synthesis 2006,
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(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)-5-phenyl-1H-
(24) Gabriele, B.; Mancuso, R.; Ziccarelli, I.; Salerno, G. Tetrahedron
Lett. 2012, 53, 6694.
imidazole-4-carboxamide (I). Obtained from 6a (0.5 mmol) as a
1
white solid (150 mg, 90%); H NMR (400 MHz, CD3OD) δ 7.67 (s,
(25) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(26) Odell, L. R.; Russo, F.; Larhed, M. Synlett 2012, 685.
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Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
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Skrydstrup, T. Org. Lett. 2011, 13, 2444.
(31) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Am.
Chem. Soc. 2011, 133, 18114.
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15, 948.
(33) Nordeman, P.; Odell, L. R.; Larhed, M. J. Org. Chem. 2012, 77,
11393.
1H), 7.60−7.55 (m, 2H), 7.40−7.31 (m, 3H), 7.28−7.13 (m, 5H), 4.78
(dd, J = 8.2, 5.7 Hz, 1H), 3.24−3.17 (m, 1H), 3.07−2.98 (m, 1H). 13C
NMR (101 MHz, DMSO-d6) δ 172.9, 162.0, 137.6, 135.0, 132.9, 130.1,
129.6, 129.2, 128.8, 128.1, 128.0, 127.9, 126.3, 53.1, 38.1. HRMS (ES)
m/z calcd for [M+H+]: C19H18N4O2 335.1508; found 335.1513.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, LC-MS, and chiral HPLC chromato-
grams. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
(34) Borhade, S. R.; Sandstrom, A.; Arvidsson, P. I. Org. Lett. 2013, 15,
̈
■
1056.
Corresponding Author
*E-mail: anja.sandstrom@orgfarm.uu.se.
(35) Letavic, M. A.; Ly, K. S. Tetrahedron Lett. 2007, 48, 2339.
(36) Qu, B.; Haddad, N.; Han, Z. S.; Rodriguez, S.; Lorenz, J. C.;
Grinberg, N.; Lee, H.; Busacca, C. A.; Krishnamurthy, D.; Senanayake,
C. H. Tetrahedron Lett. 2009, 50, 6126.
Notes
The authors declare no competing financial interest.
(37) Odell, L. R.; Savmarker, J.; Larhed, M. Tetrahedron Lett. 2008, 49,
̈
6115.
ACKNOWLEDGMENTS
■
(38) Enquist, P. A.; Nilsson, P.; Edin, J.; Larhed, M. Tetrahedron Lett.
2005, 46, 3335.
(39) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem.
2004, 69, 4741.
We thank the Carl Trygger Foundation for Scientific Research
for financial support. We also thank Dr. Luke Odell for linguistic
revision of the manuscript.
(40) Luo, F. T.; Jeevanandam, A.; Basu, M. K. Tetrahedron Lett. 1998,
39, 7939.
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dx.doi.org/10.1021/jo4020613 | J. Org. Chem. XXXX, XXX, XXX−XXX