Highly substituted imidazole derivatives from a new four-component synthesis employing methoxyallene

Article abstract of DOI:10.1055/s-2007-990933

A novel four-component reaction of alkoxyallenes with imines, iodine, and nitriles provided highly substituted imidazole derivatives in high overall yields. The simple three step protocol, exemplified by the reaction of methoxyallene (1) with imine 2, ace

Full text of DOI:10.1055/s-2007-990933

990
PRACTICAL SYNTHETIC PROCEDURES
Highly Substituted Imidazole Derivatives from a New Four-Component
Synthesis Employing Methoxyallene
H
ighly Substituted Imi
a
dazole
D
er
c
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
PSP
Received 14 August 2007
No117
Abstract: A novel four-component reaction of alkoxyallenes with imines, iodine, and nitriles provided highly substituted imidazole deriv-
atives in high overall yields. The simple three step protocol, exemplified by the reaction of methoxyallene (1) with imine 2, acetonitrile,
and iodine leading to iodoethenyl imidazole 6 is presented with full experimental detail. Imidazole 6 could be further functionalized by
palladium-catalyzed couplings yet offering an entry into diversity-oriented synthesis.
Key words: allenes, imines, nitriles, imidazoles, alkynes, palladium catalysis
1) n-BuLi
2)
H
Ph
I
I2 (2.5 equiv)
Me
TfOH
(1.2 equiv)
N
OMe
H
OMe
Ph
N
N
N
N
(2)
C
N
(4), r.t.
Ph
I
OMe
Ph
Me
Me
THF
–40 °C to –20 °C
CH2Cl2
r.t.
Ph
H
N
Ph
Ph
Ph
1
3
5
6
80% overall
Scheme 1 Four-component synthesis (1 + 2 + I2 + 4) leading to dihydroimidazole derivative 5 and elimination to tetrasubstituted imidazole 6
Alkoxyallenes are very versatile C3-building blocks for the 1-iodoethenyl-substituted imidazole derivative 6 in
the synthesis of heterocycles.1 They allow a flexible entry 80% overall yield after chromatography (Scheme 1).
into functionalized furan,2 pyrane,3 pyrrole, pyrrolidine,4
This new four-component synthesis9 proceeded via (a) at-
pyridine,5 and 1,2-oxazine derivatives6 as well as car-
tack of iodine to the central allene carbon of 3, (b) Ritter-
bocyclic compounds.7 The addition of lithiated alkoxyal-
type addition10 of nitrile 4 onto the intermediate allyl cat-
lenes to imines provides a-allenyl amines and we have
ion, and (c) nucleophilic ring closure of the amino group
with the nitrilium ion to provide 5. The final elimination
step leading to imidazole 6 was preferentially carried out
using strong trifluoromethanesulfonic acid.
previously reported high-yielding cyclizations of these in-
termediates to dihydropyrrole derivatives.4a,f,h–k During
our cyclization studies, we examined a number of differ-
ent electrophilic reagents, for example, iodine in acetoni-
By variation of nitrile and imine components, this ap-
trile. Surprisingly, this promoter system did not lead to
proach could be generalized. The highest yields of imida-
dihydropyrroles but to dihydroimidazole derivatives by
zoles were obtained using acetonitrile (4) but propionitrile
and benzonitrile were also suitable. Further, the imine
substituents could be varied by introducing, for example,
alkyl groups at C-5 or tosyl groups at the nitrogen.8
means of a new four-component reaction.8 The dihy-
droimidazole derivatives could subsequently be converted
into a variety of highly substituted imidazoles. In this PSP
we provide full experimental detail for some of these use-
ful novel transformations.
Deprotonation of methoxyallene (1) with n-butyllithium
in THF at –40 °C and subsequent addition of aldimine 2
furnished the a-allenyl amine 3 in high yield. Crude 3 was
dissolved in acetonitrile 4 and treated with 2.5 equivalents
of iodine at room temperature to give the intermediate di-
hydroimidazole derivative 5. Final treatment of 5 with
1.2 equivalents of trifluoromethanesulfonic acid afforded
KOt-Bu
(2.0 equiv)
N
N
N
N
I
Me
Me
THF, 0 °C
Ph
Ph
Ph
Ph
7
6
50%
Scheme 2 Preparation of 4-ethynyl-substituted imidazole deriva-
tive 7
SYNTHESIS 2008, No. 6, pp 0990–0994
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.11.2007
DOI: 10.1055/s-2007-990933; Art ID: Z19907SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Highly Substituted Imidazole Derivatives
991
CO2Et
The imidazole derivatives obtained could be further elab-
orated by functionalizations of the 1-iodoethenyl side
chain. For example, elimination of 6 by treatment with po-
tassium tert-butoxide provided alkyne 7 (Scheme 2). This
compound may be used in Sonogashira reactions, substi-
tutions at the terminal alkyne carbon or even cycloaddi-
tions at the C≡C bond.
1) EtMgBr
THF, r.t.
N
N
N
N
Me
Me
2) NCCO2Et, r.t.
Ph
Ph
Ph
Ph
7
11
92%
As illustrated in Scheme 3, Sonogashira reactions11 of
alkyne 7 occurred cleanly under standard conditions. Cou-
pling with phenyl iodide gave triphenyl-substituted com-
pound 8 in good yield and reaction with highly substituted
pyridyl nonaflate 95a provided the pyridine-imidazole hy-
brid 10 in 63% yield. Notably, 9 itself derives from yet an-
other novel multicomponent reaction of lithiated
methoxyallene with nitriles and is accessible in just two
steps from 1, pivalonitrile and trifluoroacetic acid.5
Alkyne 10 therefore contains six carbon atoms derived
from methoxyallene (without counting the methoxy
group). Disubstituted alkynes similar to 10 bearing 4-im-
idazolyl and 4-pyridyl substituents are potent mGluR5a
receptor antagonists.12
Scheme 4 Preparation of alkynyl carboxylic ester 11
N
N
N
N
Ph
I
Me
Me
Ph
PdCl2(PPh3)2
CuI, DMF, Et3N
r.t.
Ph
Ph
Ph
Ph
6
12
57%
Scheme 5 Sonogashira reaction of 6 with phenylacetylene provi-
ding coupling product 12
The protocols presented in this PSP are simple and syn-
thetically useful for the preparation of new imidazole de-
rivatives. The route via our novel four-component
reaction is flexible and short and should be of general in-
terest. Imidazoles are important lead structures in medici-
nal chemistry13 as well as components for material-
oriented research,14,15 thus new entries to this class of het-
erocycles are highly desirable.16,17
Ph
N
N
N
N
PhI
Me
Me
PdCl2(PPh3)2
CuI, DMF, Et3N
r.t.
Ph
Ph
Ph
Ph
7
8
77%
t-Bu
For general information concerning experimental setup and analyt-
ical methods, see ref.6c
t-Bu
MeO
MeO
N
N
4-(1-Iodoethenyl)-2-methyl-1,5-diphenylimidazole (6)
CF3
NfO
CF3
A solution of methoxyallene 1 (2.80 g, 39.9 mmol) in anhyd THF
(50 mL) under argon was treated at –40 °C with n-BuLi (2.5 M in
hexane, 14.4 mL, 35.9 mmol, deprotonation time 5–10 min). Imine
2 (5.10 g, 28.1 mmol) dissolved in anhyd THF (10 mL) was added
within 5 min. The mixture was stirred for 2 h at –20 °C and
quenched with H2O (100 mL). Warming to r.t. was followed by ex-
traction with Et2O (3 × 100 mL), drying (Na2SO4), and concentra-
tion in vacuo, which led to the crude product 3; yield: 7.00 g (99%).
N
N
N
9
Me
Me
Pd(OAc)2, PPh3
CuI, DMF
i-Pr2NH, r.t.
N
Ph
Ph
Ph
Ph
7
10
63%
Scheme 3 Sonogashira reactions of 7 with iodobenzene and pyridyl
nonaflate 9 leading to disubstituted alkynes 8 and 10
I2 (2.54 g, 10.0 mmol) was dissolved in freshly distilled MeCN (50
mL) at 45 °C and stirred for 10 min. A solution of the crude allenyl-
amine 3 (1.00 g, 3.98 mmol) dissolved in MeCN (10 mL) was added
within 5 min and the mixture was stirred for 15 h at r.t. Aq 10%
Na2S2O3 (30 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 50 mL), dried (Na2SO4), and concentrated in vacuo fur-
nishing crude 5 (1.95 g).
Alkyne 7 could also be metalated at the terminus and
trapped with electrophiles. For example, treatment of 7
with ethylmagnesium bromide followed by addition of
ethyl cyanoformate cleanly gave carboxylic ester 11
(Scheme 4). Compounds 7 and 11 should both be of value
in cycloadditions and lead to a diverse set of interesting
new bicyclic derivatives.
Crude 5 was dissolved in anhyd CH2Cl2 (4 mL) under argon, and
CF3SO3H (0.5 mL, 5.59 mmol) was added dropwise. The mixture
was stirred for 1 h at r.t., treated with dilute NaHCO3 solution (30
mL), then with 10% aq Na2S2O3 (10 mL), and extracted with
CH2Cl2 (3 × 50 mL). The combined organic phases were washed
with H2O (1 × 30 mL) and dried (Na2SO4). The crude product was
purified by column chromatography (silica gel, hexane–
EtOAc, 4:1) to yield 1.22 g (80% overall yield) of 6 as yellow crys-
tals; mp 104–105 °C.
IR (KBr): 3185–2870 (=C–H, C–H), 1600 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 5.96, 6.14 (2
d, J = 1.4 Hz, 1 H each, =CH2), 7.07–7.36 (m, 10 H, C6H5).
The 1-iodoethenyl group of compound 6 was also exploit-
ed in palladium-catalyzed reactions. Whereas Suzuki and
Stille couplings were not yet very efficient and further op-
timization is ahead, the Sonogashira reaction with phe-
nylacetylene provided cross-conjugated imidazole
derivative 12 in acceptable yield (Scheme 5).
Synthesis 2008, No. 6, 990–994 © Thieme Stuttgart · New York

992
M. Gwiazda, H.-U. Reissig
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (126 MHz, CDCl3): d = 14.1 (q, CH3), 98.9 (s, =CI),
127.8, 127.9, 128.3, 128.7, 129.4, 130.5 (6 d, C6H5), 128.9
(t, =CH2), 129.1 (s, C6H5), 129.8 (s, C-5), 136.5 (s, C6H5), 138.0 (s,
C-4), 144.4 (s, C-2).
with CH2Cl2 (3 × 30 mL). The combined organic phases were dried
(Na2SO4) and the resulting crude product was purified by column
chromatography (silica gel, hexane–EtOAc, 3:2) to give 95 mg
(63%) of 10 as colorless crystals; mp 178–179 °C.
MS (EI, 80 eV, 40 °C): m/z (%) = 386 (17, [M]+), 259 (100, [M –
IR (KBr): 3055–2870 (=C–H, C–H), 2210 (C≡C), 1600 cm–1
(C=C).
I]+), 218 (50), 184 (18), 77 (26, [C6H5]+), 43 (21), 28 (13).
HRMS (EI): m/z calcd for C18H15IN2: 386.0280; found: 386.0267.
1H NMR (500 MHz, CDCl3): d = 1.38 (s, 9 H, t-C4H9), 2.34 (s, 3 H,
CH3), 3.94 (s, 3 H, OCH3), 7.15–7.44 (m, 10 H, C6H5), 7.55 (s, 1 H,
C-5).
Anal. Calcd for C18H15IN2 (386.2): C, 55.98; H, 3.91; N, 7.25.
Found: C, 56.28; H, 3.62; N, 6.98.
13C NMR (126 MHz, CDCl3): d = 14.1 (q, CH3), 60.8 (q, OCH3),
28.9, 38.3 [q, s, C(CH3)3], 84.8, 94.5 (2 s, C≡C), 120.2 (s, C-4¢),
121.4 (q, JC,F = 273 Hz, CF3), 122.7 (dq, JC,F = 2.8 Hz, C-5), 127.6,
128.2, 128.3, 129.0, 129.1, 129.6 (6 d, C6H5), 128.5, 138.1 (2 s,
C6H5), 136.2 (s, C-5¢), 139.7 (q, JC,F = 34 Hz, C-6), 146.7 (s, C-2¢),
124.2, 157.2, 162.2 (3 s, C-2,3,4).
MS (EI, 80 eV, 160 °C): m/z (%) = 490 (34), 489 (100, [M+]), 488
(23), 474 (27, [M+ – CH3]), 458 (12), 447 (12), 446 (20), 259 (19),
246 (12), 245 (44), 180 (14), 118 (22), 97 (11), 87 (19), 85 (14), 84
(15), 83 (15), 81 (12), 77 (43), 73 (29), 71 (17), 70 (13), 69 (27), 67
(13), 60 (44), 58 (11), 57 (44), 56 (17), 55 (52), 45 (22), 44 (14), 43
(94), 42 (24), 41 (73), 39 (24).
4-Ethynyl-2-methyl-1,5-diphenylimidazole (7)
To a solution of imidazole 6 (152 mg, 0.39 mmol) in anhyd THF (2
mL) at 0 °C under argon was added dropwise a solution of t-BuOK
(88 mg, 0.78 mmol, 2 equiv) in THF (1 mL). The flask was sealed
and allowed to stir at 0 °C for 1 h. The mixture was quenched with
sat. aq NH4Cl (3 mL) and extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried (Na2SO4) and the crude prod-
uct was purified by column chromatography (silica gel, hexane–
EtOAc, 4:1) to give 50 mg (50%) of 7 as yellow crystals; mp 163–
164 °C.
IR (KBr): 3290–2850 (C–H), 2105 (C≡C), 1595 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.07 (s, 1 H,
≡CH), 7.09–7.41 (m, 10 H, C6H5).
HRMS (EI): m/z calcd for C29H26F3N3O: 489.2028; found:
489.2017.
13C NMR (126 MHz, CDCl3): d = 14.2 (q, CH3), 78.3 (s, ≡C), 78.4
(d, HC≡), 120.3 (s, C-4), 127.7, 127.8, 128.2, 128.9, 129.0, 129.7 (6
d, C6H5), 128.8, 137.2 (2 s, C6H5), 136.6 (s, C-5), 146.0 (s, C-2).
Anal. Calcd for C29H26F3N3O (489.5): C, 71.15; H, 5.35; N, 8.58.
Found: C, 71.14; H, 5.10; N, 8.47.
Ethyl 2-Methyl-1,5-diphenylimidazol-4-ylpropynoate (11)
To a solution of alkyne 7 (80 mg, 0.31 mmol) in THF (2 mL) under
argon was added dropwise a solution of EtMgBr (0.18 mL, 0.52
mmol, 1.7 equiv, 3.0 M solution in Et2O) and the mixture was
stirred at r.t. for 30 min. Then ethyl cyanoformate (0.15 mL, 0.76
mmol, 2.5 equiv) was added and the mixture was allowed to stir for
15 h at r.t. The mixture was quenched with sat. aq NH4Cl solution
(10 mL) and extracted with EtOAc (3 × 30 mL). The combined or-
ganic phases were dried (Na2SO4) and the crude product was puri-
fied by column chromatography (aluminum oxide, hexane–
EtOAc, 1:1) to afford 94 mg (92%) of 11 as colorless crystals; mp
138–139 °C.
MS (EI, 80 eV, 40 °C): m/z (%) = 258 (71, [M]+), 216 (30), 181 (5,
[M – C6H5]+), 114 (23), 91 (25), 77 (55, [C6H5]+), 51 (28), 28 (100).
HRMS (EI): m/z calcd for C18H14N2: 258.1157; found: 258.1163.
4-Phenylethynyl-2-methyl-1,5-diphenylimidazole (8)
To a solution of Et3N (0.4 mL) and DMF (0.8 mL) under argon were
added alkyne 7 (150 mg, 0.58 mmol), iodobenzene (0.08 mL, 0.69
mmol, 1.2 equiv), PdCl2(PPh3)2 (20 mg, 0.029 mmol, 0.05 equiv),
and CuI (3 mg, 0.015 mmol, 0.025 equiv). The mixture was stirred
at r.t. for 15 h, then quenched with sat. aq NH4Cl (3 mL), and ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic phases
were dried (Na2SO4) and the resulting crude product was purified by
column chromatography (silica gel, toluene–EtOAc, 4:1) to give
150 mg (77%) of 8 as pale yellow crystals; mp 189–190 °C.
IR (KBr): 3055–2855 (=C–H, C–H), 2205 (C≡C), 1600 cm–1
(C=C).
1H NMR (500 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 7.11–7.46 (m,
15 H, C6H5).
13C NMR (126 MHz, CDCl3): d = 14.2 (q, CH3), 84.3 (s, ≡C), 90.4
(s, C6H5C≡), 127.7, 127.8, 127.9, 128.2, 128.3, 128.8, 128.9, 129.6,
131.4 (9 d, C6H5), 121.4 (s, C-4), 123.7, 129.1, 136.8 (3 s, C6H5),
136.4 (s, C-5), 146.3 (s, C-2).
MS (EI, 80 eV, 40 °C): m/z (%) = 335 (31), 334 (100, [M]+), 333
(32), 292 (29), 291 (32), 189 (27), 167 (17), 145 (23), 139 (12), 126
(11), 125 (16), 123 (22), 105 (19), 91 (13), 57 (13).
IR (KBr): 3070–2870 (=C–H, C–H), 2200 (C≡C), 1690 (C=O),
1600 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3),
2.29 (s, 3 H, CH3), 4.22 (q, J = 7.2 Hz, 2 H, OCH2), 7.12–7.43 (m,
10 H, C6H5).
13C NMR (126 MHz, CDCl3): d = 14.0, 14.1 (2 q, CH3), 61.6 (t,
CH2), 82.0, 82.6 (2 s, C≡C), 118.2 (s, C-4), 127.5, 128.3, 128.4,
128.8, 129.0, 129.6 (6 d, C6H5), 127.6, 140.7 (2 s, C6H5), 136.0 (s,
C-5), 146.9 (s, C-2), 154.1 (s, C=O).
Anal. Calcd for C21H18N2O2 (330.4): C, 76.34; H, 5.49; N, 8.48.
Found: C, 76.44; H, 5.22; N, 8.56.
2-Methyl-4-(1-methylene-3-phenylprop-2-ynyl)-1,5-diphenyl-
imidazole (12)
To a solution of iodoethenylimidazole 6 (171 mg, 0.44 mmol), phe-
nylacetylene (54 mg, 0.53 mmol, 1.2 equiv), and PdCl2(PPh3)2 (16
mg, 0.022 mmol, 0.05 equiv) in Et3N (1 mL) and DMF (0.4 mL) un-
der argon was added CuI (2 mg, 0.01 mmol, 0.025 equiv). The mix-
ture was stirred at r.t. for 15 h, then quenched with sat. aq NH4Cl (3
mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organ-
ic phases were dried (Na2SO4) and the resulting crude product was
purified by column chromatography (aluminum oxide, hexane–
EtOAc, 4:1) to afford 91 mg (57%) of 12 as pale yellow crystals; mp
145–146 °C.
HRMS (EI): m/z calcd for C24H18N2: 334.1470; found: 334.1464.
2-tert-Butyl-3-methoxy-4-(2-methyl-1,5-diphenylimidazol-4-yl-
ethynyl)-6-trifluoromethylpyridine (10)
To a solution of i-Pr2NH (0.4 mL) and DMF (0.5 mL) containing
alkyne 7 (80 mg, 0.31 mmol, 1.2 equiv), Pd(OAc)2 (4 mg, 0.018
mmol, 0.07 equiv), and PPh3 (13 mg, 0.05 mmol, 0.2 equiv) under
argon was added dropwise a solution of nonaflate 95a (133 mg, 0.25
mmol, 1 equiv, dissolved in 0.5 mL of DMF). After the addition of
CuI (3 mg, 0.013 mmol, 0.05 equiv), the mixture was stirred at r.t.
for 15 h, then quenched with sat. aq NH4Cl (3 mL) and extracted
Synthesis 2008, No. 6, 990–994 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Highly Substituted Imidazole Derivatives
993
IR (KBr): 3055–2855 (=C–H, C–H), 1600 cm–1 (C=C).
(5) (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig,
H.-U. Chem. Eur. J. 2004, 10, 4283. (b) Flögel, O.; Reissig,
H.-U. German Patent DE 10336497, 2005.
1H NMR (500 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 5.67, 6.27 (2
d, J = 2.1 Hz, 1 H each, =CH2), 6.86–7.32 (m, 15 H, C6H5).
(6) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632. (b) Pulz,
R.; Cicchi, S.; Brandi, A.; Reissig, H.-U. Eur. J. Org. Chem.
2003, 1153. (c) Helms, M.; Schade, W.; Pulz, R.; Watanabe,
T.; Al-Harrasi, A.; Fisera, L.; Hlobilová, I.; Zahn, G.;
Reissig, H.-U. Eur. J. Org. Chem. 2005, 1003. For an
alternative approach to synthetically very versatile 1,2-
oxazine derivatives, see: (d) Zimmer, R.; Reissig, H.-U.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1518; Angew. Chem.
1988, 100, 1576. (e) Hippeli, C.; Zimmer, R.; Reissig, H.-U.
Liebigs Ann. Chem. 1990, 469. (f) Hippeli, C.; Reissig,
H.-U. Liebigs Ann. Chem. 1990, 475. (g) Reissig, H.-U.;
Hippeli, C.; Arnold, T. Chem. Ber. 1990, 123, 2403.
(7) For a review on Nazarov cyclizations of alkoxyallene
derived compounds, see: Tius, M. A. Eur. J. Org. Chem.
2005, 2193.
13C NMR (126 MHz, CDCl3): d = 14.0 (q, CH3), 88.6, 90.3 (2 s,
C≡C), 121.9 (t, =CH2), 123.0, 130.2, 134.3, 136.5 (4 s, C6H5), 123.9
(s, C-4), 127.4, 127.5, 127.6, 127.7, 127.8, 128.3, 129.1, 131.1,
131.4 (9 d, C6H5), 130.8 (s, C-5), 144.8 (s, C-2).
MS (EI, 80 eV, 130 °C): m/z (%) = 361 (16), 360 (58, [M+]), 359
(58), 317 (20), 215 (10), 180 (11), 118 (11), 105 (36), 86 (12), 85
+
(12), 84 (21), 83 (10), 77 (70, [C6H5 ]), 73 (12), 71 (15), 69 (14), 60
(19), 58 (12), 57 (18), 55 (22), 51 (19), 45 (13), 43 (43), 41 (24), 39
(11), 32 (20), 29 (19), 28 (100).
HRMS (EI): m/z calcd for C26H20N2: 360.1626; found: 360.1636.
Acknowledgment
Support of this work by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg ‘Hydrogen Bridges and Hydrogen Transfer’),
the Fonds der Chemischen Industrie, the Schering AG, and the Bay-
er AG is gratefully acknowledged. We also thank Dr. M. G. Okala
Amombo for preliminary results in this field, and Dr. R. Zimmer
and Dr. M. Brasholz for their assistance during the preparation of
this manuscript.
(8) Gwiazda, M.; Reissig, H.-U. Synlett 2006, 1683; see also:
Snieckus, V.; Zhao, Y. Synfacts 2006, 1110.
(9) Accounts on multicomponent reactions: (a) Dömling, A.;
Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168; Angew. Chem.
2000, 112, 3300. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(c) Zhu, J.; Bienaymé, H. In Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (d) Doemling, A. Chem.
Rev. 2006, 106, 17.
(10) For a review on the Ritter reaction, see: Krimen, L. I.; Cota,
D. J. Org. React. 1969, 17, 213.
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Synthesis 2008, No. 6, 990–994 © Thieme Stuttgart · New York

994
M. Gwiazda, H.-U. Reissig
PRACTICAL SYNTHETIC PROCEDURES
(15) Several of the imidazole derivatives of type 6 are highly
fluorescent: Gwiazda, M.; Reissig, H.-U., unpublished
results.
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Synthesis 2008, No. 6, 990–994 © Thieme Stuttgart · New York