Copper-catalyzed N -arylation of 2-imidazolines with aryl iodides

Article abstract of DOI:10.1021/jo400120r

The first copper-catalyzed N-arylation of 2-imidazolines is described. The reaction affords compounds with desirable lead-like characteristics in high yield with practical simplicity under inexpensive, ligand-free conditions. The cross coupling was successful with electron-rich and electron-poor aromatic iodides. Substrates bearing halides, esters, nitriles, and free hydroxyls are well tolerated, providing reactive handles for further functionalization, as are pyridines. In addition, the regioselective N-arylation of a 4-substituted imidazoline is reported.

Full text of DOI:10.1021/jo400120r

Note
pubs.acs.org/joc
Copper-Catalyzed N‑Arylation of 2‑Imidazolines with Aryl Iodides
Owen A. Davis, Matthew Hughes, and James A. Bull*
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K.
S
* Supporting Information
ABSTRACT: The first copper-catalyzed N-arylation of 2-
imidazolines is described. The reaction affords compounds
with desirable lead-like characteristics in high yield with
practical simplicity under inexpensive, “ligand-free” conditions.
The cross coupling was successful with electron-rich and
electron-poor aromatic iodides. Substrates bearing halides,
esters, nitriles, and free hydroxyls are well tolerated, providing reactive handles for further functionalization, as are pyridines. In
addition, the regioselective N-arylation of a 4-substituted imidazoline is reported.
puckering of the ring and the out-of-plane orientation of the
midazolines are prominent motifs in biologically active
Inatural products and medicinal compounds (Figure 1). substituents.9,10
1
Despite the number of methods to prepare N-unfunction-
Perhaps most notably, Nutlin-3 has received considerable
attention as an inhibitor of the interaction between tumor
suppressor protein p53 and its regulator mdm2, which is
overexpressed in many cancer types.2 Consequently, there has
been significant recent interest in the preparation of novel
imidazoline analogues.3,4
alized imidazolines,11,12 approaches to further derivatize these
units by formation of C−N bonds are limited to reactions with
activated alkylating agents and carbonyl derivatives. To date
there are only two reports of C(sp2)−N cross coupling
involving imidazolines, both using Pd catalysis, and these are
limited to very electron-poor aryl halides.13,14 The ability to
efficiently link (hetero)aromatics to imidazolines in this manner
would allow rapid access to a wider range of derivatives, thus
opening up new areas of lead-like or fragment chemical space
(Scheme 1). Here we report the development of the first N-
arylation of substituted 2-imidazolines using inexpensive copper
catalysis, under ‘ligand-free’ reaction conditions, to afford
compounds with lead-like properties.
Scheme 1. Proposed N-Arylation of Imidazolines and
Possible Lead-like Characteristics10,15
Figure 1. Biologically active imidazoline-containing compounds.
Early-stage drug discovery can benefit from lead compounds
possessing inherently desirable physical properties, often
characterized through molecular weight and lipophilicity
parameters.5 It can also be desirable to incorporate more
three-dimensional shape and saturated carbon atoms into lead-
like and fragment-like compounds.5a,6 This disruption of
planarity can afford improvements in aqueous solubility7 and
can lead to improved selectivity and toxicity profiles relative to
highly aromatic compounds.6,8 Consequently, as an approach
to novel nonplanar lead-like compounds, we are interested in
synthetic methods for the functionalization of intact non-
aromatic heterocycles. The N-functionalization of imidazolines
would offer an attractive approach to lead-like compounds as
they provide low MW, high polarity, and a cyclic structure
appropriate for molecular scaffolds. Furthermore, 2-substituted-
N-arylimidazolines have been shown to be nonplanar due to sp3
Recent years have seen many important advances in the use
of transition metals for the formation of C−N bonds, notably
the Pd-catalyzed Buchwald−Hartwig coupling.16 Copper-
catalyzed N-arylation (Ullman condensation) has been
increasingly well developed utilizing a range of nitrogen-
containing functional groups.17 However, while protocols have
been developed for the copper-catalyzed N-arylation of
amidines,18 there are no examples involving imidazolines,
important cyclic variants. Surprisingly, no reaction was
observed between 2-phenyl imidazoline and PhBr when
applying conditions developed by Antilla for the copper-
catalyzed N-arylation of N,N′-unsubstituted amidines.19 Like-
Received: January 29, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400120r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
wise, protocols developed for other related substrates were also
unsuccessful.10
decomposition products. The reaction was moderately sensitive
to water with the addition of 1 equiv resulting in a drop in yield
(28% by H NMR). Performing the reaction under an inert
1
We noted that in the related N-arylation of amides
(Goldberg reaction), formation of the intermediate copper(I)
amidate occurs prior to activation of the aryl halide.20 Diamine
ligands have been shown to limit the coordination of a second
amide to form an inactive anionic bis(amido)-CuI complex,
which is the resting state in their absence.20 Relative to amide
substrates, imidazolines have strong coordinating properties,
and so have wide ranging uses as ligands for metal
complexes.21,11,14b We hypothesized that the desired N-
arylation reaction was prevented due to powerful coordination
to Cu, affording a stable bis(imidazolino)Cu complex that was
not catalytically active (eq 1). Indeed the product of N-
arylation would remain a strong ligand and may prevent
turnover.
atmosphere proved to be vital for the reaction to occur as 2-
phenylimidazole 4 formed when O2 was present.22 Finally, the
yield was maximized by employing 2 equiv of iodobenzene
(Table 1, entries 5−7), but increasing to 3 equiv of PhI did not
23
1
afford a significant further increase (86% by H NMR). The
reaction required 18 h to achieve maximum conversion. The
reaction was successful for reduced copper loadings (76% with
5 mol %; 39% with 1 mol %), though we proceeded with
10 mol % of CuBr for convenience. Under these optimized
conditions, a yield of 74% was obtained for 3a (Table 2, entry
1). The reaction gave a higher yield when performed on a
5 mmol scale (entry 2). Moreover, the reaction time could be
reduced using microwave heating, which afforded a comparable
yield of 3a after 60 min at 180 °C (entry 3).10
The reaction displayed wide substrate scope upon variation
of the aryl iodide (Table 2). p-Iodotoluene gave a high yield of
3b (entry 4); however, using o-iodotoluene gave a somewhat
reduced yield due to unfavorable steric interactions in forming
the more hindered C−N bond (entry 5). Increasing the
reaction time to 72 h raised the yield of 3c to 52% (entry 6).
The reaction was successful with both electron-rich (entry 7)
and electron-poor substrates (entries 8−12). Compatibility
with functional groups is a desirable feature in lead-oriented
synthesis to allow further derivatization. Ethyl esters were
tolerated, though competitive hydrolysis afforded a reduced
yield due to the action of water or hydroxide generated in the
decomposition of CsHCO3 following deprotonation of the
imidazoline (entry 9).24,25 Performing the reaction in the
presence of 4 Å molecular sieves, to circumvent this, improved
the yield significantly (entry 10). Under these conditions, even
the corresponding methyl ester was successful, as was the nitrile
functional group (entries 11 and 12). Halides were well
tolerated (entries 13−15), providing reactive handles for
further functionalization. Pleasingly, iodide 2j bearing an
unprotected hydroxyl group was successfully cross-coupled in
high yield (entry 16), and heterocycles in the form of pyridine
rings could also be readily introduced (entries 17 and 18).
Next the 2-substituent of the imidazoline was varied (Table
3). A variety of 2-arylimidazolines were successfully applied,
with various electronic demands tolerated (entries 1−3) as was
2-(4-pyridyl)imidazoline (entry 4). The use of 2-methylimida-
zoline was successful (entry 5), which is notable due to the
introduction of relatively acidic protons and the reduction in
the aromatic ring count.
The introduction of a substituent at the 4-position of the
imidazoline provides an additional nonplanar element but
introduces a question of regiochemistry in the arylation. The
arylation of 4-methyl-2-phenylimidazoline 1g displayed a >6:1
regioselectivity in favor of the less hindered position, affording
10a as the major product (entry 6). We propose this is due to
the reacting nitrogen in the minor diastereoisomer 10b being
more sterically crowded.
In summary, we have described the first N-arylation of
imidazolines using inexpensive Cu catalysis under convenient
“ligand-free” conditions. The reaction is tolerant of a range of
electron-rich and electron-poor aromatics and heteroaromatics
as well as various functional groups, including halides, esters,
and free hydroxyls. The methodology allows rapid diversifica-
tion to novel imidazoline containing structures that are
compliant with lead-like and fragment guideline criteria.10
To disrupt coordination of this substrate, we chose to elevate
the temperature (150 °C) and examined a range of solvents
and ligands.10 Employing NMP as solvent without an
exogenous ligand gave 5% conversion to the desired product.
Presumably the NMP has a dual role as a ligand for the Cu
species, and as such we proceeded without the inclusion of an
external ligand (Table 1). The use of NMP was critical through
a
Table 1. Selected Optimization of Reaction Conditions
b
entry
PhX (equiv)
Cu cat.
Cs2CO3 (equiv)
yield (%)
1
2
3
4
5
6
7
PhBr (1.0)
PhI (1.0)
PhI (1.0)
PhI (1.0)
PhI (1.0)
PhI (1.5)
PhI (2.0)
CuI
2.0
2.0
2.0
2.0
1.5
1.5
1.5
<5
29
CuI
CuTC
CuBr
CuBr
CuBr
CuBr
37
43
59
70
84 (74)
a
Conditions: 1a (0.3 mmol), PhX, Cu cat. (10 mol %), Cs2CO3, NMP
b
(0.5 M), 18 h. Yield determined by 1H NMR with an internal
standard (1,3,5-trimethoxybenzene) except where shown in paren-
theses. CuTC = copper(I) thiophene-2-carboxylate.
the optimization, DMA and DMF showed significantly poorer
conversion and no conversion was observed with other solvents
tested. Using PhI in place of PhBr gave a significant increase in
yield (to 29%, entry 2). The copper salt was examined next
(entries 3−4); CuTC provided an improved yield relative to
CuI, but the inexpensive CuBr was preferable. Several inorganic
and amine bases were screened, but Cs2CO3 remained the most
effective, at a loading of 1.5 equiv (entry 5). Notably, the use of
Ag2CO3 did not afford the product of N-arylation; rather
oxidation to 2-phenyl-imidazole (4, not shown) occurred
cleanly in 69% yield.
A reaction concentration of 0.5 M was found to give
reproducible results. Attempts to reduce the temperature led to
a decrease in yield, whereas raising the temperature further gave
B
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The Journal of Organic Chemistry
Note
a
Table 2. Reaction Scope Varying the Aryl Halide in the Cu-Catalyzed Arylation of 1a
a
b
Conditions: 1a (1 equiv, 0.5 mmol), Ar-I 2a−n (2.0 equiv), CuBr (10 mol %), Cs2CO3 (1.5 equiv), NMP (0.5 M), 150 °C, 18 h. Reaction on 5
c
d
e
f
mmol scale. Microwave heating, 180 °C, 60 min. Reaction time of 72 h. Powdered 4 Å molecular sieves (250 mg) added. Isolated with an
inseparable minor impurity derived from ArI.
1
spectrometer. Chemical shifts for H NMR spectra are recorded in
parts per million from tetramethylsilane with the solvent resonance as
the internal standard (CHCl3: 7.27 ppm). Data were reported as
follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet,
m = multiplet and br = broad), coupling constant, integration and
assignment]. 13C NMR spectra were recorded with complete proton
decoupling. Chemical shifts are reported in parts per million from
tetramethylsilane with the solvent resonance as the internal standard
(13CDCl3: 77.0 ppm). J values are reported in Hz. Assignments of 1H
NMR spectra were made by analysis of the δ/J values and COSY
experiments as appropriate. Selective NOE experiments were
employed to establish the identity of compounds 10a/10b.10 In
some examples, the resonance from the fully substituted imidazoline
NCN carbon in the 13C NMR was very broad due to quadrupole
coupling to 14N nuclei, and thus very difficult to observe. In these
cases, the carbon resonance is not reported. Melting points are
uncorrected. Reactions with microwave heating were performed using
a Biotage Initiator 2.0 Microwave Synthesizer with an external IR
temperature sensor. Reagents: Commercial reagents were used as
supplied or purified by standard techniques where necessary. Purity of
the CuBr ≥98.0% (RT, CuBr2 ≤3%). Purity of the Cs2CO3, 99%.
Imidazolines 1. Imidazolines 1a and 1f were purchased from
commercial suppliers and used as supplied. Imidazolines 1b,12b 1c,12a
1d,12a and 1e,12b were prepared according to the referenced literature
procedures.
Table 3. Scope of the Imidazoline in Reaction with
Iodobenzene 2a
a
a
Conditions: 1b−g (1 equiv, 0.5 mmol), 2a (2.0 equiv), CuBr (10 mol
( )-4-Methyl-2-phenyl-4,5-dihydro-1H-imidazole (1g). Pro-
cedure adapted from that reported by Togo.26 1,2-Diaminopropane
(0.47 mL, 5.5 mmol) was added to a solution of benzaldehyde (0.51
mL, 5.0 mmol) in tert-butyl alcohol (45 mL). After the mixture was
stirred for 30 min at rt, potassium carbonate (2.17 g, 16 mmol) and
iodine (2.47 g, 10 mmol) were added. The mixture was stirred at 70
°C for 3 h and then quenched with saturated aqueous Na2SO3 until
the iodine color had dispersed and then extracted with chloroform (4
× 50 mL). The combined organic phases were washed with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), and
concentrated in vacuo to afford 4-methyl-2-phenylimidazoline 1g as a
dark brown oil (382 mg, 48%): IR (film) cm−1 3196 (br NH), 3060,
b
%), Cs2CO3 (1.5 equiv), NMP (0.5 M), 150 °C, 18 h. 4-
Chloroiodobenzene 2j employed in place of 2a. Combined yield of
c
isomers. Isomers separable by flash chromatography. Structures
determined by NOE studies.10
EXPERIMENTAL SECTION
■
General Consideration. All nonaqueous reactions were run under
an inert atmosphere (argon) atmosphere with oven-dried glassware
using standard techniques. Anhydrous solvents were obtained by
filtration through drying columns (toluene) or used as supplied (DMF,
1,4-dioxane, NMP). Flash column chromatography was performed
using 230−400 mesh silica with the indicated solvent system.
Analytical thin-layer chromatography was performed on precoated,
glass-backed silica gel plates. Visualization of the developed chromato-
gram was performed by UV absorbance (254 nm) and potassium
permanganate stain. Infrared spectra (FTIR) were recorded in
reciprocal centimeters (cm−1) using a FT-IR ATR spectrometer.
Nuclear magnetic resonance spectra were recorded on a 400 MHz
1
2968, 2928, 1616, 1564, 1510, 1460, 1376, 1272, 784, 695; H NMR
(400 MHz, CDCl3) δ = 8.03−7.94 (m, 2 H, 2 × Ph-H), 7.56−7.48 (m,
1 H, Ph-H), 7.45−7.37 (m, 2 H, 2 × Ph-H), 4.33−4.21 (m, 1 H,
NCH(Me)), 3.99 (dd, J = 11.6, 10.4 Hz, 1 H, CHH), 3.45 (dd, J =
11.7, 7.7 Hz, 1 H, CHH), 1.37 (d, J = 6.4 Hz, 3 H, Me); 13C NMR
(100 MHz, CDCl3) δ 163.9, 132.5, 128.8, 128.1, 126.7, 55.4, 55.1,
+
21.6; HRMS (ESI/TOF) m/z calcd for C10H13N2 [M + H]+
161.1073, found 161.1071. Compound previously reported.27
C
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The Journal of Organic Chemistry
Note
General Experimental Procedure for the N-Arylation of
Imidazolines. Conventional Heating. A microwave vial (2−5 mL
volume) was charged with imidazoline (0.50 mmol), cesium carbonate
(244 mg, 0.75 mmol), and copper(I) bromide (7.2 mg, 0.05 mmol).
The reaction vial was sealed with a cap and flushed with argon for
approx 15 min. Anhydrous N-methyl-2-pyrrolidone (1.0 mL) was
added to the sealed vial followed by the aryl iodide (1.00 mmol). The
stirred mixture was heated in an oil bath at 150 °C for 18 h and then
cooled to rt, diluted with water (15 mL), and extracted with EtOAc (1
× 4 mL, 5 × 2 mL). The combined organics were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography. Where necessary, residual NMP was removed
by warming under vacuum (60 °C, up to 2 h, 0.5−1 mbar).
Microwave Heating. As for general procedure above, but the
reaction was heated under microwave irradiation at 180 °C for 60 min.
In the Presence of Molecular Sieves. As for the general procedure
above except that the reaction vial was charged with flame-activated 4
Å powdered molecular sieves followed by other solid reagents prior to
sealing the vial.
1,2-Diphenyl-4,5-dihydro-1H-imidazole (3a). Purification by
flash chromatography (10% MeOH in EtOAc): dark brown crystalline
solid (82.0 mg, 74%); Rf = 0.04 (10% MeOH in EtOAc); mp = 72−76
°C (lit.28 mp 74 °C); IR (film) cm−1 3061, 2934, 2866, 1586, 1572,
1496, 1379, 1271, 758, 697; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J
= 7.5 Hz, 2 H, Ph-H), 7.36 (t, J = 7.3 Hz, 1 H, Ph-H), 7.28 (t, J = 7.2
Hz, 2 H, Ph-H), 7.17 (t, J = 7.7 Hz, 2 H, Ph-H), 6.99 (t, J = 7.4 Hz, 1
H, Ph-H) 6.80 (d, J = 7.9 Hz, 2 H, Ph-H), 4.07 (br s, 4 H, 2 × CH2);
13C NMR (100 MHz, CDCl3) δ 142.9, 131.1, 129.8, 128.6, 128.5,
2-Phenyl-1-(3-trifluoromethylphenyl)-4,5-dihydro-1H-imi-
dazole (3e). Purification by flash chromatography (5−10% MeOH in
EtOAc). Dark yellow oil (97 mg, 67%): Rf = 0.15 (10% MeOH in
EtOAc); IR (film) cm−1 3065, 2948, 2873, 1597, 1495, 1453, 1324,
1268, 1164, 1118, 1071, 1026, 770, 695; 1H NMR (400 MHz, CDCl3)
δ 7.48 (m, 2 H, Ph-H), 7.38 (m, 1 H, Ph-H), 7.32 (m, 2 H, Ar-H),
7.24−7.18 (m, 2 H, Ph-H), 7.00 (br s, 1 H, Ar-H), 6.84 (m, 1 H, Ar-
H), 4.09 (br s, 4 H, 2 × CH2); 13C NMR (100 MHz, CDCl3) δ 162.1,
143.3, 131.0 (q, JCF = 33 Hz), 130.8, 130.1, 129.0, 127.7, 124.6, 123.6
(q, JCF = 273 Hz), 119.1 (q, JCF = 4 Hz), 118.0 (q, JCF = 4 Hz), 53.3;
19F NMR (375 MHz, CDCl3) δ −63.0; HRMS (ESI/TOF) m/z calcd
+
for C16H14F3N2 [M + H]+ 291.1104, found 291.1101.
1-(4-Benzoic acid ethyl ester)-2-phenyl-4,5-dihydro-1H-
imidazole (3f). Molecular sieves (4 Å) added. Purification by flash
chromatography (1−10% MeOH in EtOAc). Pale brown oil (101.5
mg, 69%): Rf = 0.39 (10% MeOH in EtOAc); IR (film) cm−1 3059,
2980, 2930, 2918, 2873, 1651, 1704, 1604, 1530, 1516, 1367, 1268,
1174, 1102; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 2 H,
Ar-H), 7.47 (d, J = 7.4 Hz, 2 H, Ph-H), 7.41 (t, J = 7.4 Hz, 1 H, Ph-H),
7.32 (t, J = 7.3 Hz, 2 H, Ph-H), 6.72 (d, J = 8.7 Hz, 2 H, Ar-H), 4.31
(q, J = 7.1 Hz, 2 H, Et), 4.17−4.08 (m, 4 H, 2 × CH2), 1.34 (t, J = 7.1
Hz, 3 H, Et); 13C NMR (100 MHz, CDCl3) δ 166.1, 146.1, 130.8,
130.5, 130.3, 128.5, 124.1, 120.2, 60.8, 53.0, 52.8, 14.4; HRMS (ESI/
+
TOF) m/z Calcd for C18H19N2O2 [M + H]+ 295.1441, found
295.1438.
1-(4-Benzoic acid methyl ester)-2-phenyl-4,5-dihydro-1H-
imidazole (3g). Molecular sieves (4 Å) added. Purification by flash
chromatography (10% MeOH in EtOAc). Brown oil (58.8 mg, 42%):
Rf = 0.12 (10% MeOH in EtOAc); IR (film) cm−1 2949, 2872, 1701,
128.0, 123.2, 122.4, 53.9, 53.0; HRMS (ESI/TOF) m/z calcd for
1
+
C15H15N2 [M + H]+ 223.1230, found 223.1233. Observed data (1H,
1596, 1514, 1496, 1435, 1376, 1269, 1180, 1113, 770, 701; H NMR
13C, mp) consistent with those previously reported.28,29
(400 MHz, CDCl3) δ 7.82 (d, J = 8.6 Hz, 2 H, Ar-H), 7.47 (d, J = 7.6
Hz, 2 H, Ph-H), 7.42 (t, J = 7.6 Hz, 1 H, Ph-H), 7.33 (t, J = 7.6, 2 H,
Ph-H), 6.73 (d, J = 8.6 Hz, 2 H, Ar-H), 4.21−4.04 (m, 4 H, 2 × CH2),
3.85 (s, 3 H, OCH3); 13C NMR (100 MHz, CDCl3) δ 166.6, 161.5,
146.0, 130.6, 130.4, 130.3, 128.51, 128.45, 123.7, 120.2, 53.0, 52.6,
51.9; HRMS (ESI/TOF) m/z calcd for C17H17N2O2 [M + H]+
281.1285, found 281.1283.
2-Phenyl-1-(4-methylphenyl)-4,5-dihydro-1H-imidazole
(3b). Purification by flash chromatography (10% MeOH in EtOAc):
dark brown oil (76 mg, 65%); Rf = 0.09 (20% MeOH in EtOAc); IR
(film) cm−1 3061, 2925, 2864, 1596, 1512, 1499, 1377, 1271, 816, 773,
696; 1H NMR (400 MHz, CDCl3) δ 7.49 (br m, 2 H, Ph-H), 7.33 (br
m, 1 H, Ph-H), 7.26 (br m, 2 H, Ph-H), 6.96 (d, J = 7.8 Hz, 2 H, Ar−
H), 6.70 (d, J = 7.8 Hz, 2 H Ar-H), 4.01 (br s, 4 H, 2 × CH2), 2.24 (s,
3 H, CH3); 13C NMR (100 MHz, CDCl3) δ 140.7, 133.1, 131.2, 129.7,
129.2, 128.4, 128.0, 122.8 53.1, 20.6; HRMS (ESI/TOF) m/z calcd for
3-(2-Phenyl-4,5-dihydro-1H-imidazol-1-yl)benzonitrile (3h).
Molecular sieves (4 Å) added. Purification by flash chromatography
(10% MeOH in EtOAc). Pale brown oil (67.1 mg, 55%): Rf = 0.11
(10% MeOH in EtOAc); IR (film) cm−1 3063, 2949, 2870, 2229,
+
C16H17N2 [M + H]+ 237.1386, found 237.1388. Observed data (1H,
13C) consistent with that previously reported.29
1
1593, 1573, 1483, 1373, 1270, 1131, 1003, 772, 697; H NMR (400
MHz, CDCl3) δ 7.47−7.37 (m, 3 H, Ph-H), 7.33 (t, J = 7.5 Hz, 2 H,
Ph-H), 7.24−7.15 (m, 2 H, Ar-H), 7.02 (s, 1 H, Ar-H), 6.92−6.87 (m,
1 H, Ar-H), 4.08 (s, 4 H, 2 × CH2). 13C NMR (100 MHz, CDCl3) δ
161.4, 143.2, 130.6, 130.1, 129.4, 128.5, 128.4, 126.1, 125.8, 124.3,
2-Phenyl-1-(2-methylphenyl)-4,5-dihydro-1H-imidazole (3c).
Reaction time of 72 h. Purification by flash chromatography (1−10%
MeOH in EtOAc): pale brown crystalline solid (61.6 mg, 52%); Rf =
0.05 (10% MeOH in EtOAc); mp = 86 °C (lit.30 mp 85 °C); IR (film)
cm−1 3060, 2937, 2864, 1598, 1571, 1491, 1369, 1272, 764, 724, 695;
1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2 H, Ph-H), 7.26 (m, 1 H,
Ar-H), 7.19 (m, 3 H, Ph-H), 7.07 (td, J = 7.5, 1.4 Hz, 1 H, Ar-H), 6.99
(td, J = 7.6, 1.5 Hz, 1 H, Ar-H), 6.81 (dd, J = 7.8, 1.1 Hz, 1 H, Ar-H),
4.10 (br s, 3 H, CH2 + CH) 3.59 (br s, 1 H, CH), 2.34 (s, 3 H, CH3);
13C NMR (100 MHz, CDCl3) δ 165.0, 142.7, 134.9, 131.0, 130.5,
+
118.3, 112.7, 53.2, 52.8; HRMS (ESI/TOF) m/z calcd for C16H14N3
[M + H]+ 248.1182, found 248.1180.
2-Phenyl-1-(3-fluorophenyl)-4,5-dihydro-1H-imidazole (3i).
Purification by flash chromatography (5−10% MeOH in EtOAc).
Brown oil (81 mg, 67%): Rf = 0.12 (10% MeOH in EtOAc); IR (film)
cm−1 3060, 2946, 2875, 1608, 1592, 1493, 1378, 1266, 1155, 853, 770,
694; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2 H, Ph-H),
7.41 (t, J = 7.3 Hz, 1 H, Ph-H), 7.33 (t, J = 7.4 Hz, 2 H, Ph-H), 7.15−
7.04 (m, 1 H, Ar-H), 6.68 (td, J = 8.2, 2.3 Hz, 1 H, Ar-H), 6.59−6.44
(m, 2 H, 2 × Ar-H), 4.07 (br s, 4 H, 2 × CH2). 13C NMR (100 MHz,
129.8, 128.4, 127.9, 127.2, 126.7, 126.4, 54.3, 53.4, 18.1; HRMS (ESI/
TOF) m/z calcd for C16H17N2+ [M + H]+ 237.1386, found 237.1377.
Compound previously reported.30
1-(4-Methoxyphenyl)-2-phenyl-4,5-dihydro-1H-imidazole
(3d). Purification by flash chromatography (5−10% MeOH in
EtOAc). Dark yellow amorphous solid (84.1 mg, 67%): mp = 70 °C
(9:1 EtOAc/MeOH) (lit.30 mp 78 °C (hexane)); Rf = 0.02 (10%
MeOH in EtOAc); IR (film) cm−1 3060, 2935, 2868, 1611, 1596,
CDCl3) δ 162.6 (d, JCF = 246 Hz), 144.3, 130.8, 130.2, 129.6 (d, JCF
=
10 Hz), 128.5, 128.3, 117.5, 109.7 (d, JCF = 21 Hz), 109.0 (d, JCF = 24
Hz), 53.5, 53.0. 19F NMR (375 MHz, CDCl3) δ −111.8; HRMS (ESI/
TOF) m/z calcd for C15H14FN2+ [M + H]+ 241.1136, found 241.1138.
2-Phenyl-1-(4-chlorophenyl)-4,5-dihydro-1H-imidazole (3j).
Purification by flash chromatography (10% MeOH in EtOAc). Yellow
oil (91 mg, 70%): Rf = 0.06 (10% MeOH in EtOAc); IR (film) cm−1
3062, 2936, 2870, 1612, 1592, 1571, 1491, 1376, 1271, 1093, 996, 824,
1
1570, 1508, 1496, 1241, 1039, 830, 774, 697; H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 7.2 Hz, 2 H, Ph-H), 7.31−7.34 (m, 1 H, Ph-H),
7.23−7.28 (m, 2 H, Ph-H), 6.86−6.78 (m, 2 H, Ar-H), 6.76−6.69 (m,
2 H, Ar-H), 4.10−4.00 (m, 2 H, CH2), 4.00−3.92 (m, 2 H, CH2), 3.73
(s, 3 H, OCH3); 13C NMR (100 MHz, CDCl3) δ 163.5, 156.3, 136.5,
130.7, 129.8, 128.6, 128.0, 125.1, 114.0, 55.3, 55.0, 52.7; HRMS (ESI/
TOF) m/z calcd for C16H17N2O+ [M + H]+ 253.1335, found
253.1331. Observed data (1H, 13C, mp) consistent with those
previously reported.29,30
1
771, 726, 695, 566; H NMR (400 MHz, CDCl3) δ 7.49−7.41 (m, 2
H, Ph-H), 7.38−7.31 (m, 1 H, Ph-H), 7.27 (m, 2 H, Ph-H), 7.11−7.04
(m, 2 H, Ar-H), 6.72−6.62 (m, 2 H, Ar-H), 4.09−3.92 (m, 4 H, 2 ×
CH2); 13C NMR (100 MHz, CDCl3) δ 161.9, 141.4, 130.7, 129.9,
128.5, 128.4, 128.1, 123.3, 53.6, 52.9; HRMS (ESI/TOF) m/z calcd
D
dx.doi.org/10.1021/jo400120r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
for C15H14ClN2+ [M + H]+ 257.0840, found 257.0839. Observed data
(1H, 13C) consistent with that previously reported.29
Dark brown oil (59 mg, 47%): Rf = 0.11 (10% MeOH in EtOAc); IR
(film) cm−1 3062, 2936, 2868, 1590, 1492, 1377, 1269, 1089, 1014,
833, 824, 771, 724, 694, 558; H NMR (400 MHz, CDCl3) δ 7.48−
1
2-Phenyl-1-(4-bromophenyl)-4,5-dihydro-1H-imidazole (3k).
Purification by flash chromatography (10% MeOH in EtOAc). Brown
oil (107.4 mg, 71%): Rf = 0.12 (10% MeOH in EtOAc); IR (film)
cm−1 3059, 2937, 2868, 1612, 1588, 1488, 1376, 1272, 1001, 821, 772,
698; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.5 Hz, 2 H, Ph-H),
7.39 (t, J = 7.4 Hz, 1 H, Ph-H), 7.31 (t, J = 7.4 Hz, 2 H, Ph-H), 7.29−
7.23 (m, 2 H, Ar-H), 6.65 (d, J = 8.7 Hz, 2 H, Ar-H), 4.04 (s, 4 H, 2 ×
CH2); 13C NMR (100 MHz, CDCl3) δ 162.1, 141.9, 132.0, 131.7,
130.2, 128.6, 128.3, 126.9, 123.8, 53.7, 52.8; HRMS (ESI/TOF) m/z
7.40 (m, 2 H, Ar-H), 7.29−7.21 (m, 2 H, Ar-H), 7.19 (dd, J = 8.5, 7.3
Hz, 2 H, Ph-H), 7.02 (t, J = 7.4 Hz, 1 H, Ph-H), 6.84−6.75 (m, 2 H,
Ph-H), 4.04 (br s, 4 H, 2 × CH2). 13C NMR (100 MHz, CDCl3) δ
161.6, 142.8, 135.8, 129.9, 129.5, 128.8, 128.3, 123.6, 122.7, 54.1, 53.0;
+
HRMS (ESI/TOF) m/z calcd for C15H14ClN2 [M + H]+ 257.0840,
found 257.0839.
4-(1-Phenyl-4,5-dihydro-1H-imidazol-2-yl)pyridine (8). Puri-
fication by flash chromatography (1−10% MeOH in EtOAc). Pale
yellow oil (40.8 mg, 37%): Rf = 0.05 (10% MeOH in EtOAc); IR
(film) cm−1 3042, 2935, 2872, 1591, 1495, 1410, 1386, 1275, 1137,
+
calcd for C15H14BrN2 [M + H]+ 301.0335, found 301.0335.
[4-(2-Phenyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methanol
(3l). Purification by flash chromatography (5−10% MeOH in EtOAc).
Pale yellow oil (88.4 mg, 70%): Rf = 0.04 (10% MeOH in EtOAc); IR
(film) cm−1 3190 br, 2937, 2867, 1594, 1568, 1512, 1386, 1271, 1002,
907, 772, 725, 694; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz,
2 H, 2 × Ph-H), 7.38 (t, J = 7.6 Hz, 1 H, Ph-H), 7.29 (t, J = 7.6 Hz, 2
H, 2 × Ph-H), 7.18 (d, J = 8.0 Hz, 2 H, 2 × Ar-H), 6.78 (d, J = 8.0 Hz,
2 H, 2 × Ar-H), 4.58 (s, 2 H, CH2OH), 4.06 (s, 4 H, 2 × CH2N), 3.10
(br s, 1 H, OH); 13C NMR (100 MHz, CDCl3) δ 162.7, 142.2, 136.2,
130.8, 130.0, 128.6, 128.2, 127.5, 122.6, 64.5, 54.0, 52.6; HRMS (ESI/
TOF) m/z calcd for C16H17N2O+ [M + H]+ 253.1335, found
253.1330.
3-(2-Phenyl-4,5-dihydro-1H-imidazol-2-yl)pyridine (3m). Pu-
rification by flash chromatography (5−10% MeOH in EtOAc). Pale
brown oil (58.3 mg, 52%): Rf = 0.05 (10% MeOH in EtOAc); IR
(film) cm−1 3035, 2947, 2868, 1568, 1481, 1426, 1374, 1270, 771, 696;
1H NMR (400 MHz, CDCl3) δ 8.25−8.12 (m, 2 H, 2 × pyr-H), 7.45
1
994, 830, 760, 700; H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 4.6,
1.4 Hz, 2 H, pyr-H), 7.37 (dd, J = 4.6, 1.5 Hz, 2 H, pyr-H), 7.21 (t, J =
7.9 Hz, 2 H, Ph-H), 7.06 (t, J = 7.4 Hz, 1 H, Ph-H), 6.81 (d, J = 7.7
Hz, 2 H, Ph-H), 4.15−4.02 (m, 4 H, 2 × CH2); 13C NMR (100 MHz,
CDCl3) δ 160.9, 149.9, 142.4, 138.8, 129.1, 124.3, 123.0, 122.8, 54.3,
+
53.4; HRMS (ESI/TOF) m/z Calcd for C14H14N3 [M + H]+
224.1182, found 224.1191.
1-(4-Chlorophenyl)-2-methyl-4,5-dihydro-1H-imidazole (9).
Purification by flash chromatography (1−10% MeOH in CH2Cl2).
Dark brown oil (42 mg, 41%): Rf = 0.32 (10% MeOH in CH2Cl2); IR
(film) cm−1 3091, 2936, 1647, 1599, 1492, 1292, 1091, 818; 1H NMR
(400 MHz, CDCl3) δ 7.13 (d, J = 8.8 Hz, 2 H, Ar-H), 6.54 (d, J = 8.8
Hz, 2 H, Ar-H), 3.54−3.48 (m, 2 H, CH2), 3.29−3.26 (m, 2 H, CH2),
2.01 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ 171.0, 146.5,
129.0, 122.0, 113.7, 44.2, 39.1, 23.2; HRMS (CI) m/z Calcd for
+
C10H15ClN3 [M + NH4]+ 212.0949, found 212.0961. Compound
(d, J = 7.6 Hz, 2 H, 2 × Ph-H), 7.37 (t, J = 7.3 Hz, 1 H, Ph-H), 7.29
(d, J = 7.3 Hz, 2 H, Ph-H), 7.04 (dd, J = 8.3, 4.5 Hz, 1 H, pyr-H), 6.98
(d, J = 8.1 Hz, 1 H, pyr-H), 4.06 (s, 4 H, 2 × CH2); 13C NMR (100
MHz, CDCl3) δ 161.5, 143.8, 143.3, 139.4, 130.4, 130.2, 128.5, 128.33,
previously reported.31
( )-4-Methyl-1,2-diphenyl-4,5-dihydro-1H-imidazole (10a)
and ( )-5-Methyl-1,2-diphenyl-4,5-dihydro-1H-imidazole
(10b). Isomeric ratio in the crude product mixture = 6.4:1 10a:10b
by 1H NMR. Purification by flash chromatography (1−10% MeOH in
EtOAc) afforded major product N-Ar imidazoline 10a as a brown oil
(60.6 mg, 51%) followed by minor product N-Ar imidazoline 10b as a
pale yellow oil (10.4 mg, 8%).
Major product 10a: Rf = 0.21 (10% MeOH in CH2Cl2); IR (film)
cm−1 3061, 2963, 2924, 2866, 1591, 1569, 1493, 1382, 1267, 729, 693;
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2 H, Ph-H), 7.37
+
128.26, 123.0, 53.2; HRMS (ESI/TOF) m/z calcd for C14H14N3 [M
+ H]+ 224.1182, found 224.1183.
2-Chloro-5-(2-phenyl-4,5-dihydro-1H-imidazol-2-yl)pyridine
(3n). Purification by flash chromatography (5−10% MeOH in
EtOAc). Brown oil (51.4 mg, 40%): Rf = 0.16 (10% MeOH in
EtOAc); IR (film) cm−1 3057, 2948, 2871, 1615, 1463, 1397, 1271,
1107, 907, 771, 735, 696; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J =
2.9 Hz, 1 H, pyr-H), 7.50−7.40 (m, 3 H, Ph-H), 7.35 (t, J = 7.4 Hz, 2
H, Ph-H), 7.08 (d, J = 8.6 Hz, 1 H, pyr-H), 6.96 (dd, J = 8.6, 3.0 Hz, 1
H, pyr-H), 4.18−4.02 (m, 4H, 2 × CH2). 13C NMR (100 MHz,
CDCl3) δ 161.3, 144.6, 142.3, 138.2, 131.2, 130.5, 129.9, 128.6, 128.3,
(t, J = 7.4 Hz, 1 H, Ph-H), 7.28 (t, J = 7.5 Hz, 2 H, Ph-H), 7.18 (t, J =
7.9 Hz, 2 H, Ph-H), 7.02 (t, J = 7.4 Hz, 1 H, Ph-H), 6.83 (d, J = 7.5
Hz, 2 H, Ph-H), 4.48−4.31 (m, 1 H, CHCH3), 4.25 (t, J = 9.7 Hz, 1 H,
CHH′), 3.69 (dd, J = 9.3, 8.0 Hz, 1 H, CHH′), 1.42 (d, J = 6.4 Hz, 3
H, CH3). 13C NMR (100 MHz, CDCl3) δ 161.4, 141.8, 130.5, 129.5,
128.84, 128.77, 128.2, 124.0, 122.7, 60.7, 58.2, 21.9; HRMS (ESI/
TOF) m/z calcd for C16H17N2+ [M + H]+ 237.1386, found 237.1387.
Minor product 10b: Rf = 0.12 (10% MeOH in CH2Cl2); IR (film)
cm−1 3061, 2967, 2925, 2864, 1592, 1571, 1493, 1376, 1267, 768, 697;
1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 2 H, Ph-H), 7.32
(t, J = 7.3 Hz, 1 H, Ph-H), 7.23 (dt, J = 13.3, 7.7 Hz, 4 H, Ph-H), 7.08
(t, J = 7.4 Hz, 1 H, Ph-H), 6.90 (d, J = 7.1 Hz, 2 H, Ph-H), 4.31−4.13
(m, 2 H, CH and CHH′), 3.66 (dd, J = 13.2, 6.7 Hz, 1 H, CHH′), 1.38
(d, J = 5.8 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3) δ 163.3,
142.4, 130.9, 129.9, 129.0, 128.7, 128.0, 125.1, 124.8, 61.6, 61.0, 20.8;
+
123.6, 53.1, 53.0; HRMS (ESI/TOF) m/z calcd for C14H13ClN3 [M
+ H]+ 258.0793, found 258.0789.
2-(4-Methylphenyl)-1-phenyl-4,5-dihydro-1H-imidazole (5).
Purification by flash chromatography (5−10% MeOH in EtOAc).
Yellow oil (62 mg, 52%): Rf = 0.02 (10% MeOH in EtOAc); IR (film)
cm−1 3034, 2925, 2865, 1594, 1497, 1375, 1270, 1130, 1001, 823, 756,
724, 695; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.1 Hz, 2 H, Ar-
H), 7.20−7.13 (m, 2 H, Ph-H), 7.08 (d, J = 8.0 Hz, 2 H, Ar-H), 6.96−
7.00 (m, 1 H, Ph-H), 6.79−6.82 (m, 2 H, Ph-H), 4.04 (s, 4 H, 2 ×
CH2), 2.33 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3) δ 162.5,
143.2, 140.0, 128.7, 128.6, 128.5, 128.0, 123.2, 122.5, 54.0, 52.7, 21.3;
+
HRMS (ESI/TOF) m/z calcd for C16H17N2 [M + H]+ 237.1386,
+
HRMS (ESI/TOF) m/z calcd for C16H17N2 [M + H]+ 237.1386,
found 237.1384.
found 237.1388. Observed data (1H NMR) consistent with those
previously reported.32
2-(3-Methoxyphenyl)-1-phenyl-4,5-dihydro-1H-imidazole
(6). Purification by flash chromatography (5−10% MeOH in EtOAc).
Dark brown oil (99 mg, 78%): Rf = 0.08 (10% MeOH in EtOAc); IR
(film) cm−1 2938, 2869, 1594, 1574, 1494, 1377, 1274, 1235, 1037,
909, 727, 709, 694; 1H NMR (400 MHz, CDCl3) δ 7.19 − 7.09 (m, 3
H, Ar-H), 7.07 (br s, 1 H, Ar-H), 7.01−6.93 (m, 2 H, Ar-H), 6.88 (dd,
J = 8.3, 2.5 Hz, 1 H, Ar-H), 6.79 (d, J = 7.3 Hz, 2 H, Ar-H), 4.03 (s, 4
H, 2 × CH2), 3.69 (s, 3 H, OCH3). 13C NMR (100 MHz, CDCl3) δ
162.4, 159.1, 142.8, 132.2, 129.0, 128.6, 123.3, 122.5, 121.0, 116.4,
113.2, 55.1, 53.9, 52.8; HRMS (ESI/TOF) m/z calcd for C16H17N2O+
[M + H]+ 253.1335, found 253.1336.
ASSOCIATED CONTENT
■
S
* Supporting Information
Optimization of reaction conditions; microwave heating;
analysis of calculated lead-like and fragment characteristics of
imidazolines 3 and 5−10; DFT geometry optimization for 3a;
1
NOE studies on compounds 10a/b; copies of H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
2-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-imidazole (7).
Purification by flash chromatography (5−10% MeOH in EtOAc).
E
dx.doi.org/10.1021/jo400120r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(16) Selected recent references: (a) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27. (b) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 11049.
(17) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
(c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(d) Beletskaya, I. P.; Cheprakov, A. V Coord. Chem. Rev. 2004, 248,
2337. (e) Ley, S. V; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400.
(18) For a review on the N-arylation on acyclic amidines, see:
(a) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc. Rev. 2012, 41, 2463.
Also see: (b) Gao, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2008, 73, 6864.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.bull@imperial.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for a Career Acceleration Fellowship (to
J.A.B.) and Imperial College London. We are grateful to Prof.
Alan Armstrong for generous support. We thank EPSRC
National Mass Spectrometry Service, Swansea.
(19) Cortes-Salva, M.; Garvin, C.; Antilla, J. C. J. Org. Chem. 2011,
76, 1456.
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2009, 131, 78. (b) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4120. (c) Bacon, R. G. R.; Karim, A. J.
Chem. Soc., Perkin Trans. 1 1973, 272.
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F
dx.doi.org/10.1021/jo400120r | J. Org. Chem. XXXX, XXX, XXX−XXX