Practical synthesis of polysubstituted imidazoles via iodine- Catalyzed aerobic oxidative cyclization of aryl ketones and benzylamines

Article abstract of DOI:10.1002/adsc.201200582

A practical synthetic method for polysubstituted imidazoles via iodine-catalyzed aerobic oxidative cyclization of aryl ketones and benzylamines has been developed. It was found to tolerate a broad range of substrates to prepare polysubstituted imidazole derivatives in a one-pot manner, and thus importantly allowed product diversity for imidazole chemistry. Additionally, the resultant 1,2,4-trisubstituted imidazoles could be conveniently transformed to functionalized 1,2,4,5-tetrasubstituted imidazoles via electrophilic substitution or direct C-H functionalization, or 2,4-diaryl-1H-imidazoles by debenzylation reaction, which further indicates potential applications of this method in synthetic and pharmaceutical chemistry. Copyright

Full text of DOI:10.1002/adsc.201200582

FULL PAPERS
DOI: 10.1002/adsc.201200582
Practical Synthesis of Polysubstituted Imidazoles via Iodine-
Catalyzed Aerobic Oxidative Cyclization of Aryl Ketones and
Benzylamines
Huawen Huang,a Xiaochen Ji,a Wanqing Wu,a and Huanfeng Jianga,*
a
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Peopleꢀs
Republic of China
Fax : (+86)-20-8711-2906; e-mail: jianghf@scut.edu.cn
Received: July 4, 2012; Revised: August 12, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200582.
ꢀ
Abstract: A practical synthetic method for polysub- via electrophilic substitution or direct C H function-
stituted imidazoles via iodine-catalyzed aerobic oxi- alization, or 2,4-diaryl-1H-imidazoles by debenzyla-
dative cyclization of aryl ketones and benzylamines tion reaction, which further indicates potential appli-
has been developed. It was found to tolerate a broad cations of this method in synthetic and pharmaceuti-
range of substrates to prepare polysubstituted imida- cal chemistry.
zole derivatives in a one-pot manner, and thus im-
portantly allowed product diversity for imidazole
chemistry. Additionally, the resultant 1,2,4-trisubsti- Keywords: aerobic oxidative cyclization; aryl ke-
tuted imidazoles could be conveniently transformed tones; benzylamines; iodine-catalyzed reaction; poly-
to functionalized 1,2,4,5-tetrasubstituted imidazoles substituted imidazoles
Introduction
acyclic precursors has been rarely reported. Hence,
the development of a simple procedure for acquisition
Imidazole is one of ubiquitous structural units in nu- of imidazole derivatives from easily available starting
merous drug molecules and natural products.[1] More- materials remains as a continuing challenge.
over, imidazole derivatives play important roles in
Recently, increasing attention has been drawn to
synthetic chemistry: (a) as building blocks of naturally the preparation of nitrogen-containing heterocyclic
occurring products and complex meaningful mole- compounds via oxidative cyclization using benzyla-
cules,[2] (b) as efficient organic catalysts to promote mines as the starting materials.[17] Generally, the inter-
facile reaction processes,[3] (c) as ligands in metalloen- molecular cross-coupling or condensation reaction of
zymes,[4] (d) as precursors of carbene ligands[5] and en- benzylamine forms amine or imine species B [Eq. (1),
vironmentally friendly ionic solvents.[6] In the past A!B], and intermediate C can be accessed under ox-
3
[18]
ꢀ
years, while the classic Debus–Radziszewski reaction idative conditions by sp C H functionalization. In-
and Bredereck synthesis opened the way to the prepa- tramolecular attack of an O or N nucleophilic atom
ration of imidazoles,[7] various synthetic methods for to an electrophilically activated carbon atom initiates
imidazole derivatives have been developed.[8] In terms oxidative cyclization to afford the final nitrogen-con-
of the starting materials, these are mainly focused on taining heterocyclic compounds D. Although oxida-
amides,[9] imines,[10] nitriles,[11] amino acids,[12] isocya- tion in this system may not proceed as a distinct step,
nides,[13] and other precursors.[14] Despite primordial the overall reactivity patterns observed are reminis-
efficiency in synthetic chemistry, the synthesis of imi- cent and thus allow benzylamine compounds to be
dazole has yet to develop in terms of accessibility of perceived of as simpler and direct alternatives to a di-
starting materials and product diversity. As known in verse range of nitrogen-containing heterocyclic prod-
this case, 1,2,4-trisubstituted imidazoles,[15] which are ucts.
prevalent in bioactive natural products including
many inhibitors of kinase,[16] have been mainly ac-
cessed through condensation of a-halo ketones, alde-
hydes, and amines, however, the direct cyclization of
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Results and Discussion
tion revealed that the addition of 10 mL (0.24 equiv.)
of 12M HCl proved to be optimal for the selective
Very recently, our group has developed a new type of generation of 4aa giving exclusively the product in
one-pot, transition metal-free domino process to syn- 57% yield (entry 7), which revealed that the conden-
thesize polysubstituted oxazoles through a TBHP/I2- sation of acetophenone and benzylamine would be
mediated oxidative cyclization from easily available significantly promoted under acidic conditions.
arylalkenes and benzylic amines.[19] In order to further
When 0.2 equiv. of iodine were used, the yield de-
extend the applicability of this reaction system, we creased to 43% with some benzyl(1-phenylethyli-
were inspired to subject aryl ketones to this reaction dene)amine remaining, which indicated that more oxi-
AHCTUNGTRENNUNG
conditions to construct heterocyclic compounds.[20] We dant should be added for complete oxidative cycliza-
initially presumed that 2,5-disubstituted oxazoles and tion (Table 1, entry 8). Several oxidants were tested.
1,2,5-trisubstituted imidazoles could be selectively fur- While t-BuOOH (TBHP) and 2,2,6,6-tetramethylpi-
nished in an analogous manner. Interestingly, further peridine 1-oxyl (TEMPO) just gave poor selectivity,
investigation suggested that the 1,2,4-trisubstituted 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) gave
rather than the 1,2,5-trisubstituted imidazole deriva- lower yield of the desired product (entries 9–11).
tive was regioselectively formed under controlled re- Gratifyingly, the imidazole product was formed in
action conditions when we employed acetophenone good yield when the reaction was conducted under an
and benzylamine as the substrates (Scheme 1). As oxygen atmosphere (entry 12). Other Brønsted acids
part of our continuing interest in the synthesis of ni- such as HOTf were found to disfavour the reaction
trogen-containing heterocyclic compounds,[21] we selectivity (entry 13). While KI (1 equiv.) instead of
herein disclose a new and convenient protocol to con- iodine led to 4aa in a moderate yield (entry 14), nei-
struct highly substituted imidazoles via iodine-mediat- ther oxazole nor imidazole was detected without
ed aerobic oxidative cyclization of readily available iodine reagent (entry 15). Solvent testing showed that
aryl ketones and benzylamines.
DMSO was an incomparable medium (entries 16–18).
As shown in Table 1, we first performed the reac- Subjecting BnNH2·HCl to this reaction without addi-
tion with 1a (0.5 mmol), 2a (2.5 equiv.), I2 (1.0 equiv.), tional HCl slightly improved the yield (entry 19). But
CuO[20b,d] (1.0 equiv.) in DMSO (2 mL) at 908C for we gave up using amine hydrochloride for the pur-
5 h, and 2,5-diphenyloxazole 3aa was isolated in 78% pose of easy operation. Finally, this reaction was
yield (entry 1). A variety of additives was then exam- found to be optimal at 908C (entries 20 and 21).
ined. While 0.2 equiv. of CuO and CuCl2 afforded
To enhance understanding of the role of the
small amounts of imidazole product and FeCl3 afford- Brønsted acid, we decided to investigate the effect of
ed poor selectivity (entries 2–4), PdCl2 and TsOH HCl on the generation of imidazole and the stoichi-
gave significant rate enhancements (entries 5 and 6), ometry of the reaction (Figure 1). Generally, it was
suggesting the acid system could turn the selectivity beneficial for the formation of 4aa when using more
over favouring imidazole products. Further investiga- benzylamine, but obviously no or excessive HCl de-
Scheme 1. Proposed synthetic procedure from aryl ketones.
2
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Practical Synthesis of Polysubstituted Imidazoles via Iodine-Catalyzed Aerobic Oxidative Cyclization
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst
(equiv.)
Additive
(equiv.)
Solvent
Yield
[%][b]
3aa 4aa
1
2
3
4
5
6
7
8
9
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (0.2)
I2 (0.2)
CuO (1.0)
CuO (0.2)
CuCl2 (0.2)
FeCl3 (0.2)
PdCl2 (0.2)
TsOH (0.2)
HCl[c]
HCl
HCl, TBHP
(2.0)
HCl, DDQ
(2.0)
HCl, TEMPO
(2.0)
HCl
HOTf (0.2)
HCl
HCl
HCl
HCl
HCl
–
HCl
HCl
DMSO 78
DMSO 62
DMSO 70
DMSO 37
trace
10
12
42
61
Figure 1. The effect of HCl on the generation of imidazole
and the stoichiometry of the reaction.
DMSO
DMSO
8
7
48
DMSO trace 57
DMSO n.p. 43
DMSO 22
DMSO n.p. 12
DMSO 15 58
35
10
11
I2 (0.2)
I2 (0.2)
12[d] I2 (0.2)
13[d] I2 (0.2)
14[d] KI (1.0)
DMSO n.p. 85
DMSO 10 70
DMSO n.p. 40
DMSO n.p. n.p.
toluene n.p. trace
15[d]
–
16[d] I2 (0.2)
17[d] I2 (0.2)
18[d] I2 (0.2)
19[d,e] I2 (0.2)
20[d,f] I2 (0.2)
21[d,g] I2 (0.2)
DMF
H2O
n.p. 27
n.p. n.p.
DMSO n.p. 87
DMSO n.p. 80
DMSO n.p. 84
Figure 2. The effect of H2O on the generation of imidazole.
[a]
Unless otherwise indicated, the reaction was carried out
with 1a (0.5 mmol), 2a (2.5 equiv.) in solvent (2 mL) at
908C for 5 h; n.p. means no product was detected.
Isolated yield.
All HCl entries in this table refer to 10 mL (0.24 equiv.)
of 12M HCl.
Using an O2 balloon.
BnNH2·HCl instead of BnNH2 was used as the substrate.
At 808C.
[b]
[c]
of 4aa, it decreased linearly with the increase of
water.
Having identified the optimal reaction conditions,
we next explored the generality and scope of the sub-
strates of this reaction. Various aryl-substituted ke-
tones were successfully applied to this system. Gener-
ally, higher yields were obtained with electron-donat-
ing substituents on the aromatic ring, such as alkyl
[d]
[e]
[f]
[g]
At 958C.
creased the yield. Meaningfully, the addition of HCl and methoxy (Table 2, entries 2–7), and a certain in-
seemed to inhibit the oxidation of 2a to phenyl alde- fluence on the yield could be seen when substituents
hyde because a large excess of benzylamine was no are present on the para, meta, and ortho positions of
longer necessary in this oxidative system. More con- the aryl ketones, such as 1e, 1f, and 1g. Aryl ketones
centrated hydrochloric acid (20 mL) disfavoured the with halogen atoms on the aromatic ring were also
generation of imidazole product, because condensa- tolerated (Table 2, entries 8–10). Both 1-(4-nitrophen-
tion, one of the key steps, was sensitive to water, con- yl)-ethanone (1k) and 1-naphthalen-2-yl-ethanone
sistent with the control experiment, as could be seen (1l) successfully provided the functionalized imida-
in Figure 2. 1a and BnNH2·HCl were operated with zoles 4ka and 4la, although in moderate yields (58
20 mol% of iodine under an oxygen atmosphere, and and 49%, respectively) (Table 2, entries 11 and 12).
one to four equivalents of water as the additive was Besides, aryl ketones 1m and 1n showed considerably
added to the reaction to screen the transformation. It different reactivities for the target 1,2,4,5-tetrasubsti-
was found that while the addition of one equivalent tuted imidazoles (91% and 35%, respectively, Table 2,
of water had a slightly adverse influence on the yield entries 13 and 14).
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Table 2. Generality of the aryl ketones and benzylamines.
Entry 1 (R1/R2)
2 (R3)
4
Yield [%][b]
85
1
1a
2a
2a
2a
4aa
2
3
1b (4-Me/H)
1c (2-Me/H)
4ba 80
4ca 73
4da 89
4
1d (4-isobutyl/H) 2a
5
6
7
1e (4-OMe/H)
1f (3-OMe/H)
1g (2-OMe/H)
2a
2a
2a
4ea
4fa
4ga
88
80
65
Figure 3. X-ray structure of compound 4ab.
8
1h (4-F/H)
2a
4ha 70
9
1i (4-Cl/H)
1j (4-Br/H)
1k (4-NO2/H)
1l (naphthyl/H)
1m (H/Ph)
1n (H/Me)
1a
1a
1a
1a
1a
1h
1h
1e
2a
2a
2a
2a
2a
2a
4ia
4ja
4ka 58
4la 49
4ma 91
4na 35
4ab 90
70
59
10
11
12
13
14
15
16
17
18
19
20
21
22
4ab was corroborated by the X-ray crystallographic
analysis (Figure 3).[22]
For further exploration of the synthetic utilities of
this method, benzyl-(1-phenylethylidene)-imine was
first prepared in 86% GC yield by TsOH-catalyzed
condensation of 1a and 2a in toluene under nitrogen
for 2 h (Scheme 2). We were delighted that the imine
was successfully reacted with alkylamines to afford
the expected 1,2,4-trisubstituted imidazoles via this
iodine-catalyzed oxidative cyclization reaction. Al-
though excess alkylamine was used in this process,
this one-pot synthesis of functionalized imidazoles in
competitive yields from readily available starting ma-
terials was attractive and more importantly allowed
product diversity.
2b (4-Me)
2c (4-F)
2d (3-Cl)
2e (4-OMe) 4ae
2f (3-OMe) 4af
2c
2e
2e
4ac
4ad 78
76
84
82
59
4hc
4he 81
4ee 90
[a]
The reaction was carried out with 1 (0.5 mmol), 2
(2.5 equiv.), I2 (20 mol%), and 10 mL (0.24 equiv.) of 12M
HCl in DMSO (2 mL) under O2 (1 atm) at 908C for 5 h.
Isolated yield.
[b]
The resultant 1,2,4-trisubstituted imidazoles contain
an unsubstituted 5-position on the imidazole ring as
handle for further manipulations.[23] For example, pal-
Furthermore, various benzylamine derivatives were ladium-catalyzed direct C-5 arylation of 4ia with iodo-
employed (Table 2, entries 15–19). In accordance with benzene smoothly gave 1,2,4,5-tetrasubstituted imida-
previous results, while the electron-donating group on zole 5ia in 72% yield (Scheme 3). Bromination[24] of
the aromatic ring was favourable, electron-deficient 4ia with N-bromosuccinimide (NBS) followed by pal-
substituents decreased the reaction yield. Finally, the ladium-catalyzed Suzuki–Miyaura cross-coupling reac-
electronic effect of the reaction was further confirmed tion with phenylboronic acid also proceeded well to
by using the substrates with 4-F and 4-OMe on the ar- give 5ia in 85% overall yield.
omatic ring (Table 2, entries 20–22). The structure of
Scheme 2. One-pot synthesis of 1,2,4-trisubstituted imidazole derivatives.
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Practical Synthesis of Polysubstituted Imidazoles via Iodine-Catalyzed Aerobic Oxidative Cyclization
Scheme 5. N-Debenzylation of N-protected imidazoles.
Scheme 3. C-5 arylation of 4ia. Method A: 1) NBS
(1.1 equiv.), CH2Cl2, room temperature, 20 min, 92%; 2)
PhB(OH)2 (2 equiv.), PdCl
(5 mol%), CsF (3 equiv.), PhMe/H2O, 1008C, 24 h, 94%.
Method B: PhI (2 equiv.), Pd(OAc)2 (5 mol%), PPh3
2ACHTNUGTREN(UNGN dppf) (5 mol%), Et3BnNCl
AHCTUNGTRENNUNG
(10 mol%), K2CO3 (3 equiv.), DMF, 1408C, 36 h, 72%.
In terms of the higher efficiency of the latter frac-
tional step method, we treated imidazoles 4 with NBS
in CH2Cl2 at room temperature and prepared a series
of 5-bromo-substituted imidazoles 5a–5f in excellent
yields (Scheme 4). Distinct reaction times were ob-
served by TLC monitoring when subjecting imida-
Scheme 6. Plausible reaction mechanism.
zoles with different substituents on the aromatic ring.
Interestingly, when 2.2 equivalents of NBS was em-
ployed, 4ab was converted to 5f in 96% yield after
6 h by electrophilic substitution on both the 5-position
of the imidazole ring and the para position of the
phenyl group.
Ultimately, the feasibility of the resultant N-benzyl-
protected imidazoles was established by a literature
procedure for the efficient debenzylation.[24] Imida-
zoles 4aa and 4ab were treated with an equal weight
of 10% Pd/C in methanol and a large molar excess of
anhydrous ammonium formate, and the mixture was
refluxed for 48 h to give 2,4-diaryl-substituted imida-
zoles 6aa and 6ab in 86% and 75% yield, respectively
(Scheme 5).
On the basis of the above results, a reasonable
mechanism for this oxidative cyclization reaction of
aryl ketones and benzylamines was proposed
(Scheme 6). Imine I, in situ-formed by condensation
of 1a and 2a, would undergo a-iodination to generate
II in the media of DMSO.[20d] Actually, an a-iodina-
tion/condensation sequence could also furnish inter-
mediate II. Coupling reaction of II with 2a led to in-
termediate III. Subsequently, III was oxidized to in-
Scheme 4. Bromination of 1,2,4-trisubstituted imidazoles.
All reactions were performed at 0.2M with 1.1 equiv. of
termediate V via sp3 C H functionalization under
ꢀ
NBS. 5f was obtained from 4ab by using 2.2 equiv. of NBS. iodine-mediated reaction conditions. Intramolecular
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nucleophilic cyclization of V and further oxidation The Effect of H2O on the Generation of Imidazole
gave the final imidazole 4aa. The resulting iodine
The mixture of acetophenone (1a, 0.5 mmol, 1 equiv.), ben-
anion could be oxidized to iodine under oxygen at-
zylamine hydrochloride (BnNH2·HCl, 2.5 equiv.), I2
mosphere, which was confirmed by the fact observed
previously that KI could also promote the reaction.
(20 mol%) and deionized water was stirred in DMSO
(2 mL) at 908C under oxygen atmosphere for 5 h. And then
the 10 mL water was added to quench the reaction. The
aqueous solution was extracted with diethyl ether (3ꢂ
10 mL) and the combined extract was dried over anhydrous
MgSO4. The solvent was removed and the crude product
was separated by flash column chromatography on silica gel
to give the product imidazole 4aa.
Conclusions
In summary, we have developed a new and efficient
method to construct polysubstituted imidazoles via
iodine-catalyzed aerobic oxidative cyclization of aryl
ketones and benzylamines in a one-pot manner. It is
General Procedure for the Synthesis of Poly-
substituted Imidazoles 4aa-4ee
ꢀ
noteworthy that three C N bonds were formed in this
transformation, and Brønsted acid has a dual function
of promoting the condensation and inhibiting the oxi-
The mixture of aryl ketone (1, 0.5 mmol), benzylamine (2,
2.5 mmol), I2 (20 mol%) and concentrated hydrochloric acid
dation of benzylamine. Moreover, the resultant 1,2,4- (10 mL, 20 mol%) was stirred in DMSO (2 mL) at 908C
under oxygen atmosphere for 5 h. And then the 10 mL
water was added to quench the reaction. The aqueous solu-
tion was extracted with diethyl ether (3ꢂ10 mL) and the
combined extract was dried with anhydrous MgSO4. The sol-
vent was removed and the crude product was separated by
flash column chromatography on silica gel to give the pure
product.
trisubstituted imidazoles could be efficiently convert-
ed to other functional imidazole products through
substitution, coupling reaction or other transforma-
tion. Ongoing research involves further broadening
the synthetic scope of the methodology and its poten-
tial applications in natural product synthesis is cur-
rently underway in our laboratory.
1-Benzyl-2,4-diphenyl-1H-imidazole[25]
(4aa): White solid,
1
mp 122–1248C. H NMR (400 MHz, CDCl3): d=7.82 (d, J=
8.4 Hz, 2H), 7.59–7.57 (m, 2H), 7.39–7.18 (m, 10H), 7.07 (d,
J=6.7 Hz, 2H), 5.13 (s, 2H); 13C NMR (100 MHz, CDCl3):
d=148.4, 141.3, 136.7, 133.9, 130.3, 128.9, 128.84, 128.83,
128.5, 128.4, 127.8, 126.7, 126.5, 124.8, 116.8, 50.3; HR-MS
(ESI): m/z=311.1522, calcd. for C22H18N2 [M+H]+:
311.1548.
Experimental Section
General Methods
Melting points were measured with a melting point instru-
1
ment and were uncorrected. H and 13C NMR spectra were
1-Benzyl-2-phenyl-4-p-tolyl-1H-imidazole (4ba): White
solid, mp 109–1118C. IR (KBr): n=1670, 1451, 1178, 824,
recorded using a 400 MHz NMR spectrometer. The chemi-
cal shifts were referenced to signals at 7.26 and 77.0 ppm, re-
spectively, and CDCl3 was used as the solvent with TMS as
the internal standard. IR spectra were obtained as potassi-
um bromide pellets or as liquid films between two potassi-
um bromide pellets. High-resolution mass spectra were ob-
tained with a LCMS-IT-TOF mass spectrometer. TLC was
performed by using commercially prepared 100–400 mesh
silica gel plates (GF254) and visualization was effected at
254 nm.
1
764, 730, 698 cmꢀ1; H NMR (400 MHz, CDCl3): d=7.74 (d,
J=8.1 Hz, 2H), 7.63–7.61 (m, 2H), 7.44–7.31 (m, 6H), 7.22–
7.13 (m, 5H), 5.22 (s, 2H), 2.36 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=148.4, 141.5, 136.8, 136.5, 131.0,
129.2, 129.0, 128.98, 128.97 128.6, 128.3, 127.9, 126.7, 124.9,
116.3, 50.5, 21.2: HR-MS (ESI): m/z=325.1703, calcd. for
C23H20N2 [M+H]+: 325.1705.
1-Benzyl-2-phenyl-4-o-tolyl-1H-imidazole (4ca): White
solid, mp 104–1068C. IR (KBr): n=1671, 1457, 1402, 1363,
1
1244, 1032, 761, 730, 698 cmꢀ1; H NMR (400 MHz, CDCl3):
The Effect of Brønsted Acid on the Generation of
Imidazole and the Stoichiometry of the Reaction
d=7.95 (d, J=7.7 Hz, 1H), 7.64–7.61 (m, 2H), 7.41–7.11 (m,
12H), 5.27 (s, 2H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=147.6, 140.7, 136.9, 134.9, 130.7, 130.3, 130.0,
129.99, 129.9, 129.0, 128.9, 128.6, 127.9, 126.8, 126.5, 125.9,
119.6, 50.4, 21.8; HR-MS (ESI): m/z=325.1697, calcd. for
C23H20N2 [M+H]+: 325.1705.
The mixture of acetophenone (1a, 0.5 mmol, 1 equiv.), ben-
zylamine (2a), I2 (20 mol%) and concentrated hydrochloric
acid (12M) was stirred in DMSO (2 mL) at 908C under
oxygen atmosphere for 5 h. And then the reaction was
quenched by the addition of 10 mL water. The aqueous so-
lution was extracted with diethyl ether (3ꢂ10 mL) and the
combined extract was dried with anhydrous MgSO4. The sol-
vent was removed and the crude product was separated by
flash column chromatography on silica gel to give the pure
product 4aa.
1-Benzyl-4-(4-isobutylphenyl)-2-phenyl-1H-imidazole
(4da): White solid, mp 112–1148C. IR (KBr): n=1606, 1457,
1361, 1176, 1022, 848, 763, 728, 699 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=7.76 (d, J=7.8 Hz, 2H), 7.63–7.61
(m, 2H), 7.43–7.30 (m, 6H), 7.22 (s, 1H), 7.17–7.13 (m, 4H),
5.22 (s, 2H), 2.49 (d, J=7.1 Hz, 2H), 1.93–1.83 (m, 1H),
0.92 (d, J=6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
148.4, 141.6, 140.4, 136.9, 131.4, 130.4, 129.3, 129.0, 128.94,
128.92, 128.6, 127.9, 126.6, 124.7, 116.4, 50.4, 45.2, 30.2, 22.3;
HR-MS (ESI): m/z=367.2172, calcd. for C26H26N2 [M+H]+:
367.2174.
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Practical Synthesis of Polysubstituted Imidazoles via Iodine-Catalyzed Aerobic Oxidative Cyclization
1-Benzyl-4-(4-methoxyphenyl)-2-phenyl-1H-imidazole
5.25 (s, 2H); 13C NMR (100 MHz, CDCl3): d=149.6, 146.3,
(4ea): White solid, mp 110–1128C. IR (KBr): n=1612, 1496,
140.4, 139.3, 136.2, 129.8, 129.5, 129.1, 129.0, 128.8, 128.3,
126.8, 125.1, 124.1, 119.2, 50.8; HR-MS (ESI): m/z=
356.1395, calcd. for C22H17N3O2 [M+H]+: 356.1399.
1454, 1245, 1174, 1028, 947, 836, 768, 728, 699 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.78 (d, J=8.7 Hz, 2H),
7.63–7.61 (m, 2H), 7.44–7.31 (m, 6H), 7.16–7.13 (m, 3H),
6.92 (d, J=8.7 Hz, 2H), 5.20 (s, 2H), 3.82 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=158.7, 148.4, 141.4, 137.0, 130.6,
129.04, 129.01, 128.9, 128.6, 128.0, 127.0, 126.7, 126.2, 115.8,
114.0, 55.3, 50.5: HR-MS (ESI): m/z=341.1649, calcd. for
C23H20N2O [M+H]+: 341.1654.
1-Benzyl-4-naphthalen-2-yl-2-phenyl-1H-imidazole (4la):
White solid, mp 127–1298C. IR (KBr): n=1629, 1456, 1456,
1
1243, 1045, 854, 765, 697 cmꢀ1; H NMR (400 MHz, CDCl3):
d=8.41 (s, 1H), 7.91–7.80 (m, 4H), 7.66 (d, J=8.0 Hz, 2H),
7.46–7.33 (m, 9H), 7.17 (d, J=7.4 Hz, 2H), 5.24 (s, 2H);
13C NMR (100 MHz, CDCl3): d=148.8, 141.4, 136.7, 133.8,
132.6, 131.2, 130.2, 129.12, 129.08, 129.0, 128.7, 128.10,
128.06, 128.0, 127.6, 126.7, 126.0, 125.3, 123.7, 123.1, 117.3,
50.5; HR-MS (ESI): m/z=361.1698, calcd. for C26H20N2
[M+H]+: 361.1705.
1-Benzyl-4-(3-methoxyphenyl)-2-phenyl-1H-imidazole
(4fa): White solid, mp 98–1008C. IR (KBr): n=1603, 1458,
1238, 1168, 1042, 844, 769, 729, 696 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=7.62–7.59 (m, 2H), 7.45–7.24 (m,
10H), 7.12 (d, J=7.3 Hz, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.20
(s, 2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
159.9, 148.5, 141.3, 136.7, 135.4, 130.3, 129.4, 129.0, 128.97,
128.95, 128.6, 127.9, 126.6, 117.4, 117.1, 113.0, 109.8, 55.3,
50.4; HR-MS (ESI): m/z=341.1648, calcd. for C23H20N2O
[M+H]+: 341.1654.
1-Benzyl-2,4,5-triphenyl-1H-imidazole[27]
ACHTUNGTRENUN(NG 4ma): White
1
solid, mp 159–1618C. H NMR (400 MHz, CDCl3): d=7.64–
7.57 (m, 4H), 7.32–7.07 (m, 14H), 6.75 (d, J=5.7 Hz, 2H),
5.04 (s, 2H); 13C NMR (100 MHz, CDCl3): d=147.8, 137.9,
137.3, 134.3, 130.8, 130.7, 129.9, 128.8, 128.6, 128.5, 128.4,
128.3, 128.3, 127.9, 127.8, 127.1, 126.6, 126.1, 125.7, 48.0;
HR-MS (ESI): m/z=387.1858, calcd. for C28H23N2 [M+H]+:
387.1861.
1-Benzyl-4-(2-methoxyphenyl)-2-phenyl-1H-imidazole
(4ga): White solid, mp 105–1078C. IR (KBr): n=1611, 1452,
1258, 1167, 1073, 852, 771, 730, 696 cmꢀ1
;
1H NMR
1-Benzyl-5-methyl-2,4-diphenyl-1H-imidazole[28]
ACHTUNGTRENNUNG(4na):
(400 MHz, CDCl3): d=8.36 (d, J=7.7 Hz, 1H), 7.61–7.58
(m, 3H), 7.39–7.19 (m, 7H), 7.12 (d, J=7.4 Hz, 2H), 7.05 (t,
J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 5.23 (s, 2H), 3.88
(s, 3H); 13C NMR (100 MHz, CDCl3): d=155.9, 147.3, 137.2,
136.8, 130.5, 128.94, 128.87, 128.8, 128.5, 127.7, 127.5, 127.3,
126.4, 122.6, 121.4, 120.8, 110.5, 55.2, 50.3; HR-MS (ESI):
m/z=341.1640, calcd. for C23H20N2O [M+H]+: 341.1654.
1-Benzyl-4-(4-fluorophenyl)-2-phenyl-1H-imidazole (4ha):
White solid, mp 92–948C. IR (KBr): n=1668, 1495, 1456,
White solid, mp 139–1418C. 1H NMR (400 MHz, CDCl3):
d=7.76 (d, J=7.7 Hz, 2H), 7.56–7.54 (m, 2H), 7.40–7.21 (m,
9H), 7.00 (d, J=7.3 Hz, 2H), 5.14 (s, 2H), 2.25 (s, 3H);
13C NMR (100 MHz, CDCl3): d=147.3, 137.6, 136.8, 135.1,
130.7, 128.8, 128.6, 128.5, 128.3, 128.1, 127.4, 127.1, 126.1,
125.4, 124.7, 47.8, 10.3; HR-MS (ESI): m/z=325.1718, calcd.
for C23H20N2 [M+H]+: 325.1705.
1-(4-Methylbenzyl)-4-phenyl-2-p-tolyl-1H-imidazole
(4ab): White solid, mp 111–1138C. IR (KBr): n=1608, 1450,
1224, 841, 768, 731, 698 cmꢀ1; H NMR (400 MHz, CDCl3):
1243, 1181, 1025, 823, 738, 695 cmꢀ1 1H NMR (400 MHz,
;
1
d=7.80 (dd, J=8.8, 5.5 Hz, 2H), 7.63–7.60 (m, 2H), 7.45–
7.32 (m, 6H), 7.19 (s, 1H), 7.14 (d, J=6.8 Hz, 2H), 7.06 (t,
J=8.8 Hz, 2H), 5.22 (s, 2H); 13C NMR (100 MHz, CDCl3):
d=162.0, 148.6, 140.6, 136.7, 130.2, 129.1, 129.0, 128.99,
128.8, 128.6, 128.0, 126.7, 126.5, 116.4, 115.4, 50.5; HR-MS
(ESI): m/z=329.1461, calcd. for C22H17FN2 [M+H]+:
329.1454.
CDCl3): d=7.81 (d, J=7.7 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H),
7.33 (t, J=7.7 Hz, 2H), 7.21–7.18 (m, 4H), 7.12 (d, J=
7.9 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 5.11 (s, 2H), 2.36 (s,
3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): d=148.7,
141.3, 138.9, 137.7, 134.3, 134.0, 129.7, 129.3, 129.0, 128.6,
127.7, 126.8, 126.7, 125.0, 116.7, 50.3, 21.4, 21.1; HR-MS
(ESI): m/z=339.1859, calcd. for C24H22N2 [M+H]+:
339.1861.
1-Benzyl-4-(4-chlorophenyl)-2-phenyl-1H-imidazole (4ia):
White solid, mp 128–1308C. IR (KBr): n=1601, 1450, 1261,
1-(4-Fluorobenzyl)-2-(4-fluorophenyl)-4-phenyl-1H-imida-
zole (4ac): White solid, mp 108–1108C. IR (KBr): n=1613,
1072, 996, 834, 763, 728, 699 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.77 (d, J=8.4 Hz, 2H), 7.62–7.60 (m, 2H),
7.44–7.32 (m, 8H), 7.22 (s, 1H), 7.14 (d, J=7.1 Hz, 2H),
5.21 (s, 2H); 13C NMR (100 MHz, CDCl3): d=148.7, 140.4,
136.6, 132.6, 132.3, 130.2, 129.1, 129.0, 128.97, 128.62, 128.61,
128.0, 126.7, 126.2, 116.9, 50.5; HR-MS (ESI): m/z=
345.1149, calcd. for C22H17ClN2 [M+H]+: 345.1158.
1455, 1285, 1053, 946, 737, 700 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.81 (d, J=8.4 Hz, 2H), 7.54–7.50 (m, 2H), 7.35
(t, J=7.7 Hz, 2H), 7.24–7.19 (m, 2H), 7.08–6.97 (m, 6H),
5.09 (s, 2H); 13C NMR (100 MHz, CDCl3): d=163.1, 162.3,
147.4, 141.5, 133.7, 132.3, 130.8, 128.5, 128.3, 126.9, 126.4,
124.8, 116.6, 115.9, 115.6, 49.7; HR-MS (ESI): m/z=
347.1356, calcd. for C22H16F2N2 [M+H]+: 347.1360.
1-Benzyl-4-(4-bromophenyl)-2-phenyl-1H-imidazole[26]
A
1-(3-Chlorobenzyl)-2-(3-chlorophenyl)-4-phenyl-1H-imi-
dazole (4ad): White solid, mp 125–1278C. IR (KBr): n=
CDCl3): d=7.66 (d, J=8.5 Hz, 2H), 7.58–7.55 (m, 2H), 7.42
(d, J=8.5 Hz, 2H), 7.38–7.25 (m, 6H), 7.15 (s, 1H), 7.06 (d,
J=8.0 Hz, 2H), 5.11 (s, 2H); 13C NMR (100 MHz, CDCl3):
d=148.6, 140.2, 136.5, 132.9, 131.4, 130.1, 128.9, 128.8, 128.7,
128.5, 127.9, 126.5, 126.3, 120.2, 116.9, 50.3; HR-MS (ESI):
m/z=389.0637, calcd. for C22H17BrN2 [M+H]+: 389.0653.
1-Benzyl-4-(4-nitrophenyl)-2-phenyl-1H-imidazole (4ka):
White solid, mp 121–1238C. IR (KBr): n=1598, 1509, 1332,
1599, 1473, 1203, 1083, 887, 784, 750, 691 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=7.83 (d, J=8.4 Hz, 2H), 7.63 (s, 1H),
7.40–7.24 (m, 9H), 7.12 (s, 1H), 7.99–6.97 (m, 1H), 5.18 (s,
2H); 13C NMR (100 MHz, CDCl3): d=147.0, 142.0, 138.4,
135.1, 134.7, 133.6, 131.9, 130.4, 129.9, 129.21, 129.18, 128.6,
128.4, 127.1, 126.78, 126.77, 124.9, 124.7, 117.1, 50.0; HR-MS
(ESI): m/z=379.0763, calcd. for C22H16Cl2N2 [M+H]+:
379.0769.
1
1182, 1106, 945, 732, 699 cmꢀ1; H NMR (400 MHz, CDCl3):
d=8.21 (d, J=9.0 Hz, 2H), 7.96 (d, J=8.9 Hz, 2H), 7.63–
7.61 (m, 2H), 7.46–7.32 (m, 7H), 7.15 (d, J=6.6 Hz, 2H),
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-4-phenyl-1H-
imidazole (4ae): White solid, mp 117–1198C. IR (KBr): n=
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
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Huawen Huang et al.
FULL PAPERS
1611, 1514, 1452, 1249, 1177, 1030, 834, 743, 697 cmꢀ1
;
completion of the reaction, 10 mL water were added to
quench the reaction. The aqueous solution was extracted
with diethyl ether (3ꢂ10 mL) and the combined extract was
dried with anhydrous MgSO4. The solvent was removed and
the crude product was separated by flash column chroma-
tography on silica gel to give the pure product.
1H NMR (400 MHz, CDCl3): d=7.84 (d, J=8.4 Hz, 2H),
7.57–7.53 (m, 2H), 7.36 (t, J=7.7 Hz, 2H), 7.26–7.20 (m,
2H), 7.06 (d, J=8.7 Hz, 2H), 6.97–6.94 (m, 2H), 6.89–6.86
(m, 2H), 5.11 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=160.1, 159.2, 148.3, 141.0, 134.1,
130.3, 128.8, 128.4, 128.0, 126.6, 124.8, 122.9, 116.3, 114.2,
113.9, 55.22, 55.19, 49.9; HR-MS (ESI): m/z=371.1755,
calcd. for C24H22N2O2 [M+H]+: 371.1760.
1-Ethyl-2,4-diphenyl-1H-imidazole (4aaa): White solid,
1
mp 90–928C. H NMR (400 MHz, CDCl3): d=7.85 (d, J=
8.0 Hz, 2H), 7.64 (d, J=7.7 Hz, 2H), 7.49–7.43 (m, 3H),
7.38 (t, J=7.6 Hz, 2H), 7.33 (s, 1H), 7.24 (t, J=7.6 Hz, 1H),
4.06 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=147.8, 141.3, 134.2, 130.8, 129.0,
128.8, 128.6, 128.5, 126.7, 124.9, 115.5, 41.7, 16.5; HR-MS
(ESI): m/z=249.1405, calcd. for C17H16N2 [M+H]+:
249.1392.
1-(3-Methoxybenzyl)-2-(3-methoxyphenyl)-4-phenyl-1H-
imidazole (4af): White solid, mp 113–1158C. IR (KBr): n=
1601, 1460, 1262, 1155, 1040, 863, 784, 734, 695 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.83 (d, J=7.4 Hz, 2H),
7.37–7.17 (m, 8H), 6.94 (d, J=7.1 Hz, 1H), 6.83 (d, J=
8.3 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.65 (s, 1H), 5.17 (s,
2H), 3.74 (s, 3H), 3.73 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=160.1, 159.6, 148.3, 141.4, 138.4, 133.9, 131.5,
130.0, 129.6, 128.5, 126.7, 124.9, 121.1, 118.8, 116.9, 115.3,
114.0, 113.1, 112.4, 55.18, 55.16, 50.4; HR-MS (ESI): m/z=
371.1753, calcd. for C24H22N2O2 [M+H]+: 371.1760.
2,4-Diphenyl-1-propyl-1H-imidazole[26]
ACHTUNGTREN(NUNG 4aab): White
1
solid, mp 87–898C. H NMR (400 MHz, CDCl3): d=7.85 (d,
J=7.2 Hz, 2H), 7.63 (d, J=7.7 Hz, 2H), 7.49–7.36 (m, 5H),
7.31 (s, 1H), 7.24 (t, J=7.4 Hz, 1H), 3.97 (t, J=7.6 Hz, 2H),
1.86–1.76 (m, 2H), 0.91 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=148.1, 141.1, 134.2, 131.0, 129.1,
128.8, 128.6, 128.5, 126.6, 124.9, 116.0, 48.5, 24.4, 11.1; HR-
MS (ESI): m/z=263.1542, calcd. for C18H18N2 [M+H]+:
263.1548.
1-(4-Fluorobenzyl)-2,4-bis(4-fluorophenyl)-1H-imidazole
(4hc): White solid, mp 124–1268C. IR (KBr): n=1604, 1503,
1227, 1157, 1093, 840, 765 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d=7.78 (dd, J=8.6, 5.5 Hz, 2H), 7.55 (dd, J=8.5,
5.4 Hz, 2H), 7.17–7.02 (m, 9H), 5.15 (s, 2H); 13C NMR
(100 MHz, CDCl3): d=162.7, 162.4, 162.0, 147.6, 140.8,
132.3, 130.9, 130.1, 128.4, 126.5, 116.28, 116.26, 116.0, 115.8,
115.4, 49.9; HR-MS (ESI): m/z=365.1269, calcd. for
C22H15F3N2 [M+H]+: 365.1266.
1-Butyl-2,4-diphenyl-1H-imidazole (4aac): White solid,
1
mp 81–838C. H NMR (400 MHz, CDCl3): d=8.20 (d, J=
7.3 Hz, 2H), 7.97 (d, J=6.7 Hz, 2H), 7.80 (d, J=7.4 Hz,
2H), 7.74–7.68 (m, 3H), 7.65 (s, 1H), 7.58 (t, J=7.5 Hz,
1H), 4.34 (t, J=7.4 Hz, 2H), 2.14–2.06 (m, 2H), 1.70–1.60
(m, 2H), 1.23 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=148.1, 141.1, 134.2, 130.9, 129.1, 128.7, 128.50,
128.46, 126.6, 124.8, 116.0, 46.6, 33.1, 19.7, 13.5. HR-MS
(ESI): m/z= 277.1712, calcd. for C19H20N2 [M+H]+:
277.1705.
4-(4-Fluorophenyl)-1-(4-methoxybenzyl)-2-(4-methoxy-
phenyl)-1H-imidazole (4he): White solid, mp 121–1238C. IR
(KBr): n=1607, 1505, 1249, 1178, 1030, 949, 836, 765 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.78 (dd, J=8.6, 5.5 Hz,
2H), 7.54 (d, J=8.6 Hz, 2H), 7.14 (s, 1H), 7.08–7.02 (m,
4H), 6.96 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.11
(s, 2H), 3.84 (s, 3H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=161.9, 160.2, 159.3, 148.4, 140.3, 130.4, 128.8,
128.1, 126.4, 122.9, 115.9, 115.3, 114.4, 114.0, 111.5, 55.30,
55.27, 50.0; HR-MS (ESI): m/z=389.1660, calcd. for
C24H21FN2O2 [M+H]+: 389.1665.
1-Isopropyl-2,4-diphenyl-1H-imidazole[29]
G
1
solid, mp 117–1198C. H NMR (400 MHz, CDCl3): d=7.85
(d, J=7.2 Hz, 2H), 7.58 (dd, J=8.0, 1.5 Hz, 2H), 7.48–7.34
(m, 6H), 7.21 (t, J=7.4 Hz, 1H), 4.57–4.47 (m, 1H), 1.44 (s,
3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): d=147.4,
141.3, 134.2, 131.0, 129.2, 128.7, 128.5, 128.4, 126.5, 124.7,
111.7, 47.9, 23.9; HR-MS (ESI): m/z=263.1534, calcd. for
C18H18N2 [M+H]+: 263.1548.
1-(4-Methoxybenzyl)-2,4-bis(4-methoxyphenyl)-1H-imida-
zole (4ee): White solid, mp 118–1208C. IR (KBr): n=1609,
1455, 1278, 1150, 1042, 828, 739, 697 cmꢀ1
;
1H NMR
1-sec-Butyl-2,4-diphenyl-1H-imidazole
(4aae):
White
(400 MHz, CDCl3): d=7.74 (d, J=8.8 Hz, 2H), 7.54 (d, J=
8.8 Hz, 2H), 7.10 (s, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.96–6.86
(m, 6H), 5.10 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (s,
3H); 13C NMR (100 MHz, CDCl3): d=160.1, 159.2, 158.6,
148.1, 141.0, 130.4, 128.9, 128.1, 127.0, 126.1, 123.0, 115.3,
114.3, 114.0, 113.9, 55.28, 55.26, 55.2, 49.9; HR-MS (ESI):
m/z=401.1855, calcd. for C25H24N2O3 [M+H]+: 401.1865.
1
solid, mp 94–968C. H NMR (400 MHz, CDCl3): d=7.87 (d,
J=8.0 Hz, 2H), 7.58 (d, J=7.8 Hz, 2H), 7.48–7.35 (m, 6H),
7.24 (t, J=7.4 Hz, 1H), 4.28–4.20 (m, 1H), 1.84–1.70 (m,
2H), 1.48 (d, J=6.7 Hz, 3H), 0.76 (t, J=7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=148.3, 141.5, 134.3, 131.2,
129.4, 128.8, 128.5, 128.4, 126.5, 124.8, 111.6, 53.8, 31.0, 22.1,
10.6; HR-MS (ESI): m/z=277.1709, calcd. for C19H20N2
[M+H]+: 277.1705.
1-tert-Butyl-2,4-diphenyl-1H-imidazole
(4aaf):
White
General Procedure for the Synthesis of Poly-
substituted Imidazoles 4aaa–4aag in a One-Pot
Manner
1
solid, mp 134–1368C. H NMR (400 MHz, CDCl3): d=7.82
(d, J=7.1 Hz, 2H), 7.51–7.48 (m, 2H), 7.44–7.33 (m, 6H),
7.21 (t, J=7.4 Hz, 1H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3): d=147.7, 138.9, 134.9, 134.2, 130.8, 128.9, 128.4,
127.9, 126.5, 124.8, 113.7, 57.1, 31.6; HR-MS (ESI): m/z=
277.1691, calcd. for C19H20N2 [M+H]+: 277.1705.
The mixture of acetophenone (1a, 0.5 mmol), benzylamine
(2a, 0.5 mmol) and TsOH (10 mol%) was stirred in toluene
(2 mL) at reflux conditions under nitrogen atmosphere for
2 h. And then the solution was evaporated to dryness under
reduced pressure. Arylamine (2.5 equiv.), I2 (20 mol%) and
DMSO (2 mL) were added and the reaction was heated to
908C under oxygen atmosphere with stirring for 5 h. After
1-Cyclohexyl-2,4-diphenyl-1H-imidazole (4aag): White
1
solid, mp 125–1278C. H NMR (400 MHz, CDCl3): d=7.85
(d, J=7.3 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H), 7.50–7.35 (m,
6H), 7.23 (t, J=7.4 Hz, 1H), 4.13–4.05 (m, 1H), 2.06 (d, J=
8
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Practical Synthesis of Polysubstituted Imidazoles via Iodine-Catalyzed Aerobic Oxidative Cyclization
13.7 Hz, 2H), 1.88 (d, J=12.9 Hz, 2H), 1.75–1.66 (m, 3H),
1.37–1.23 (m, 3H); 13C NMR (100 MHz, CDCl3): d=147.5,
141.1, 134.3, 131.1, 129.2, 128.7, 128.6, 128.4, 126.5, 124.8,
112.7, 55.8, 34.7, 25.6, 25.2; HR-MS (ESI): m/z=303.1859,
calcd. for C21H22N2 [M+H]+: 303.1861.
2H), 7.15 (d, J=7.8 Hz, 2H), 6.94 (d, J=7.8 Hz, 2H), 5.26
(s, 2H), 2.38 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=149.4, 139.4, 137.3, 137.3, 133.2, 132.2, 131.3,
129.5, 129.3, 128.6, 128.3, 127.3, 125.7, 121.0, 101.5, 49.2,
21.3, 21.0; HR-MS (ESI): m/z=495.0063, calcd. for
C24H20Br2N2 [M+H]+: 495.0071.
1-Benzyl-4-(4-chlorophenyl)-2,5-diphenyl-1H-imidazole
(5ia): White solid, mp 176–1788C. 1H NMR (400 MHz,
CDCl3): d=7.67–7.65 (m, 2H), 7.54–7.52 (m, 2H), 7.41–7.30
(m, 6H), 7.21–7.16 (m, 7H), 6.82–6.79 (m, 2H), 5.11 (s,
2H); 13C NMR (101 MHz, CDCl3): d=148.1, 137.3, 137.0,
133.0, 131.9, 130.9, 130.7, 130.6, 130.2, 129.0, 128.9, 128.8,
128.7, 128.6, 128.5, 128.1, 127.9, 127.3, 125.9, 48.25; HR-MS
(ESI): m/z=421.1454, calcd. for C28H21ClN2 [M+H]+:
421.1472.
General Procedure for Bromination of the Resultant
1,2,4-Trisubstituted Imidazoles
A round-bottom flask equipped with a magnetic stirrer bar
was charged with 0.2 mmol of imidazole dissolved in 1.0 mL
CH2Cl2, and the solution of NBS (1.1 equiv. in 1.0 mL
CH2Cl2) was dropwise added at room temperature. After
completion of the reaction (as monitored by TLC), the mix-
ture was directly subjected to flash column chromatography
on silica gel to give the pure product.
1-Benzyl-5-bromo-2,4-diphenyl-1H-imidazole (5a): White
1
solid, mp 106–1088C. H NMR (400 MHz, CDCl3): d=8.09
Acknowledgements
(d, J=7.2 Hz, 2H), 7.56–7.53 (m, 2H), 7.44–7.27 (m, 9H),
7.04 (d, J=7.0 Hz, 2H), 5.29 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=149.1, 138.5, 136.3, 133.1, 130.3, 129.3, 128.9,
128.7, 128.6, 128.2, 127.6, 127.3, 126.8, 125.8, 101.6, 49.3;
HR-MS (ESI): m/z=389.0646, calcd. for C22H17BrN2 [M+
H]+: 389.0653.
We thank the National Natural Science Foundation of China
(20932002 and 21172076), the National Basic Research Pro-
gram of China (973 Program) (No. 2011CB808600), the
Guangdong
Natural
Science
Foundation
(No.
10351064101000000), the China Postdoctoral Science Foun-
dation (2011M501318) and the Fundamental Research Funds
for the Central Universities (2010ZP0003, 2012ZP0011) for
financial support.
1-Benzyl-5-bromo-4-(4-bromophenyl)-2-phenyl-1H-imida-
1
zole (5b): White solid, mp 149–1518C. H NMR (400 MHz,
CDCl3): d=7.99 (d, J=8.5 Hz, 2H), 7.56–7.54 (m, 4H),
7.42–7.30 (m, 6H), 7.06 (d, J=7.4 Hz, 2H), 5.31 (s, 2H);
13C NMR (100 MHz, CDCl3): d=149.3, 137.5, 136.1, 132.1,
131.3, 130.1, 129.5, 128.9, 128.71, 128.67, 128.3, 127.7, 125.8,
121.2, 101.8, 49.4; HR-MS (ESI): m/z=466.9752, calcd. for References
C22H16Br2N2 [M+H]+: 466.9758.
5-Bromo-1-(4-fluorobenzyl)-2,4-bis(4-fluorophenyl)-1H-
imidazole (5c): White solid, mp 150–1528C. 1H NMR
(400 MHz, CDCl3): d=8.03 (dd, J=8.3, 5.7 Hz, 2H), 7.49
(dd, J=8.2, 5.5 Hz, 2H), 7.14–6.99 (m, 8H), 5.25 (s, 2H);
13C NMR (100 MHz, CDCl3): d=163.5, 162.3, 162.3, 148.2,
138.0, 131.8, 130.8 129.1, 128.6, 127.7, 126.4, 116.1, 115.9,
115.3, 101.2, 48.8; HR-MS (ESI): m/z=443.0364, calcd. for
C22H14BrF3N2 [M+H]+: 443.0371.
5-Bromo-4-(4-fluorophenyl)-1-(4-methoxybenzyl)-2-(4-
methoxyphenyl)-1H-imidazole (5d): White solid, mp 147–
1498C. 1H NMR (400 MHz, CDCl3): d=8.05 (dd, J=8.6,
5.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.10 (t, J=8.7 Hz,
2H), 6.97 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.86
(d, J=8.6 Hz, 2H), 5.21 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H);
13C NMR (100 MHz, CDCl3): d=162.2, 160.5, 159.1, 149.1,
137.5, 130.2, 129.5, 128.6, 128.4, 127.3, 122.8, 115.2, 114.3,
114.1, 100.8, 55.3, 55.3, 48.9; HR-MS (ESI): m/z=467.0756,
calcd. for C24H20BrFN2O2 [M+H]+: 467.0770.
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8.3 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9 Hz,
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FULL PAPERS
12 Practical Synthesis of Polysubstituted Imidazoles via Iodine-
Catalyzed Aerobic Oxidative Cyclization of Aryl Ketones
and Benzylamines
Adv. Synth. Catal. 2012, 354, 1 – 12
Huawen Huang, Xiaochen Ji, Wanqing Wu,
Huanfeng Jiang*
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