A four-component synthesis of highly substituted imidazole derivatives

Article abstract of DOI:10.1055/s-2006-947318

Addition of lithiated methoxyallene 1 to imines 2 provided allenyl amines 3, which upon reaction with iodine and nitriles furnished dihydroimidazole derivatives 5. Treatment of these intermediates with strong acids such as trifluoromethane sulfonic acid a

Full text of DOI:10.1055/s-2006-947318

LETTER
1683
A Four-Component Synthesis of Highly Substituted Imidazole Derivatives
Synthesis of
H
ighly Su
a
bstituted Im
c
idazole
D
e
i
rivativ
e
es j Gwiazda, Hans-Ulrich Reissig*
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
Received 12 April 2006
Table 1 Synthesis of 1-Iodovinylimidazole Derivatives 6 from
Methoxyallene, Imines, Iodine and Nitriles
Abstract: Addition of lithiated methoxyallene 1 to imines 2 provid-
ed allenyl amines 3, which upon reaction with iodine and nitriles
furnished dihydroimidazole derivatives 5. Treatment of these inter-
mediates with strong acids such as trifluoromethane sulfonic acid
afforded tetrasubstituted imidazole derivatives 6 in good overall
yields. Subsequent base-promoted conversion of 1-iodovinyl-sub-
stituted compounds 6 into alkynyl-substituted imidazole derivatives
7 proceeded smoothly. Products 6 and 7 are versatile intermediates
for further transformations such as palladium-catalyzed coupling
reactions.
R1
H
N
OMe
R1
OMe
2
R2
THF
–40 °C to –20 °C
Li
R2HN
1
3
2.5 equiv I2
R3
C
N
Key words: methoxyallene, imine, nitrile, imidazole, alkyne
4
I
CF3SO3H
1–2.5 equiv
N
In earlier publications we have reported that lithiated
alkoxyallenes smoothly add to aldimines and that the re-
sulting allenyl amines can be cyclized to produce dihydro-
pyrrole derivatives.1 This route has been exploited for
syntheses of several natural products.2 During attempts to
prepare 4-iododihydropyrrole derivatives we detected that
the reaction of allenyl amines such as 3 with iodine in ac-
etonitrile furnished dihydroimidazole derivatives 5 in
good yields (Table 1). Apparently, an allyl cation is
formed by addition of the iodine cation to the central
allene carbon, which is subsequently trapped by the sol-
vent acetonitrile. Cyclization by attack of the amino group
to the nitrilium carbon generated the five-membered ring.
This Ritter type reaction3 proved to be rather general
allowing a new access to imidazole derivatives by a four-
component process.
N
I
OMe
R1
R3
R3
CH2Cl2
r.t., 1–2 h
R1
N
R2
N
R2
6a–6e
5
Entry
R1
Ph
Ph
Ph
R2
Ph
Ph
Ph
Ts
Ts
R3
Yield (%) Imidazole
a
b
c
d
e
Me
Et
80
40
40
63
35
6a
6b
6c
6d
6e
Ph
n-Bu
Me
Me
Ph
component synthesis is clearly the necessity to use the
corresponding nitrile in excess.
Addition of lithiated methoxyallene 1 (generated from
methoxyallene and n-BuLi) to imines 2 provided allenyl
amines 3,1c which upon reaction with iodine in different
nitriles 4 as solvent furnished dihydroimidazole deriva-
tives 5a–e as mixtures of diastereomers. Elimination of
methanol to afford the 1-iodovinyl-substituted imidazoles
6a–e was achieved by treatment with strong acids such as
trifluoromethane sulfonic acid (Table 1).4 Imine substitu-
ents R1 can be aryl or alkyl, at the nitrogen R2 = aryl and
tosyl are tolerated and as typical nitriles we successfully
employed acetonitrile, propionitrile, and benzonitrile. The
overall yields for this three-step sequence were good to
moderate (Table 1, entries a–e). It should be noted here
that experiments reducing the amount of nitriles were not
very successful. Thus, one drawback of our new four-
The 1-iodovinyl substituent of compounds 6 is a suitable
handle for further diversification, the simplest one being
base-induced elimination providing 4-alkynyl-substituted
imidazole derivatives 7 (Table 2).5 Whereas the reaction
of N-phenyl-substituted compounds 6a–c with potassium
tert-butoxide in tetrahydrofuran afforded the expected
alkynes 7a–c the N-tosyl derivative 6d suffered de-
tosylation, thus providing imidazole derivative 7d with a
free NH group in moderate yield (Table 2, entries a–d).
Alkynes 7 are suitable substrates for Sonogashira reac-
tions. Under standard conditions6 precursors 7a or 7c
reacted in the presence of iodobenzene to generate phen-
yl-substituted products 8a or 8c, respectively, in good
yields (Scheme 1).
We expected that the acidic alkyne hydrogen could be
used to introduce other substituents at the terminal carbon
of compounds 7. Deprotonation of 7a with 2.2 equivalents
of n-butyllithium followed by reaction with chlorotri-
methylsilane provided the bissilylated product 9 in 72%
SYNLETT 2006, No. 11, pp 1683–1686
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947318; Art ID: G12506ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.0
7
.2
0
0
6

1684
M. Gwiazda, H.-U. Reissig
LETTER
Other cross-coupling experiments were even less success-
ful. These observations may reflect the considerable steric
hindrance at the reacting carbon due to the highly substi-
tuted imidazole core. We also successfully performed the
Stille coupling of 6a with tributylvinyltin, which provided
the expected 2-imidazolyl-1,3-diene derivative. However,
this compound rapidly polymerized and therefore it could
not be completely characterized. Trapping of the crude
product with tetracyanoethylene (TCNE) furnished
Diels–Alder adduct 14 in 32% overall yield. Other dieno-
philes examined were not sufficiently reactive.
Table 2 Synthesis of 4-Alkynyl-Substituted Imidazole Derivatives 7
t-BuOK
1–2 equiv
N
I
N
R3
R3
THF, 0 °C,
1–2 h
R1
N
R2
R1
N
R2
6a–6d
7
Entry
R1
R2
R3
Yield (%) Alkyne
a
b
c
d
Ph
Ph
Ph
Ph
Ts
Me
Et
50
60
72
54
7a
7b
7c
Ph
Ph
Ph
Me
N
N
I
Ph
n-Bu
7d
(R2 = H)
Ph
CuI, PdCl2(PPh3)2
DMF, Et3N, r.t., 15 h
N
N
Ph
Ph
Ph
Ph
6a
12 57%
Ph
I
N
N
(HO)2B
OMe
R3
R3
N
N
N
I
PdCl2(PPh3)2, CuI,
DMF, Et3N,
N
N
Ph
Ph
OMe
MeCN, K3PO4, Bu4NBr
PdCl2(dppf), 80 °C, 4 h
N
Ph
Ph
Ph
6a
Ph
13 26%
r.t., 15 h
Ph
Ph
7a, c
8a, c
R3 = Me
3 = Ph
77%
52%
R
CN
CN
NC
SnBu3
Pd(OAc)2, PPh3
DMF, 50 °C,15 h
1.
CN
Scheme 1 Sonogashira reactions of 7 with iodobenzene leading to
disubstituted alkynes 8
N
N
I
2.
TCNE
MeCN, 50 °C,
15 h
N
N
Ph
Ph
yield (Scheme 2). Hence the base is also able to depro-
tonate at the C-2 methyl group. This was confirmed when
methyl iodide was employed as electrophile, which
furnished dimethylated compound 10 in moderate yield.
Similar reaction conditions using methyl chloroformate as
electrophile gave the monosubstituted product 11 in low
yield.
Ph
Ph
6a
14 32%
Scheme 3 Cross-coupling reactions of 1-iodovinyl imidazole
derivative 6a
In this communication we present a new four-component
synthesis7 involving an alkoxyallene, an imine, a nitrile,
and iodine, which furnished highly substituted imidazole
derivatives in moderate to good yields.8 Due to the func-
tional groups these can be further transformed into several
higher substituted and functionalized heterocycles. In par-
ticular, imidazole derivatives with different aryl substitu-
ents are easily accessible. Since imidazole derivatives are
of considerable interest in medicinal chemistry and also in
material science our new method – although restricted in
scope – should establish a valuable new approach to this
important class of heterocycles.9 These results once again
demonstrate the high synthetic versatility and value of
lithiated alkoxyallenes,10 which have served as an iodo-
vinyl carbene synthon in this new application leading to
imidazole derivatives.
The reactivity of the 1-iodovinyl group of compound 6a
was also examined in typical palladium-catalyzed reac-
tions. Sonogashira reaction with phenylacetylene provid-
ed coupling product 12 in acceptable yield whereas the
Suzuki reaction of 6a with an aryl boronic acid led to the
expected compound 13 in lower efficacy (Scheme 3).
TMS
1. n-BuLi, 2.2 equiv
THF, –50 °C,
0.5 h
N
N
TMS
2. ClSiMe3, 2.5 equiv
–35 °C 0.5 h
N
N
Ph
Ph
Ph
Ph
to r.t., 15 h
7a
9
72%
CO2Me
Acknowledgment
N
N
Support by the Deutsche Forschungsgemeinschaft (Graduierten-
kolleg ‘Hydrogen Bridges and Hydrogen Transfer’), the Fonds der
Chemischen Industrie and the Schering AG is most gratefully
acknowledged. We also thank Dr. M. G. Okala Amombo for pre-
liminary results in this area and Dr. R. Zimmer for discussions as
well as his assistance during preparation of this manuscript.
N
N
Ph
Ph
Ph
Ph
for MeI 10 55%
for ClCO2Me 11 30%
Scheme 2 Deprotonation of imidazole derivative 7a and reactions
with electrophiles
Synlett 2006, No. 11, 1683–1686 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Substituted Imidazole Derivatives
1685
0 °C for 1 h. The mixture was quenched with sat. aq NH4Cl
solution (3 mL) and extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried over Na2SO4 and the
crude product was purified by column chromatography
(silica gel, hexane–EtOAc = 4:1), which provided 50 mg
(50%) of 7a as yellow crystals.
References and Notes
(1) Reviews: (a) Zimmer, R.; Reissig, H.-U. Modern Allene
Chemistry, Vol. 2; Krause, N.; Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004, 847–876. (b) Reissig, H.-U.;
Hormuth, S.; Schade, W.; Okala Amombo, M. G.;
Watanabe, T.; Pulz, R.; Hausherr, A.; Zimmer, R. J.
Heterocycl. Chem. 2000, 37, 597 . Original publications:
(c) Okala Amombo, M. G.; Hausherr, A.; Reissig, H.-U.
Synlett 1999, 1871. (d) Flögel, O.; Reissig, H.-U. Synlett
2004, 895.
(2) (a) Synthesis of the g-amino acid (–)-detoxinine: Flögel, O.;
Okala Amombo, M. G.; Reissig, H.-U.; Zahn, G.; Brüdgam,
I.; Hartl, H. Chem. Eur. J. 2003, 9, 1405. (b) Synthesis of
(–)-preussin: Hausherr, A. Dissertation; Freie Universität
Berlin: Berlin, 2002. (c) Synthesis of both enantiomers of
anisomycin: Kaden, S.; Brockmann, M.; Reissig, H.-U.
Helv. Chem. Acta 2005, 88, 1826. (d) Synthesis of
codonopsinine: Chowdhury, M. A.; Reissig, H.-U.
manuscript in preparation for Synlett.
Analytical Data for 4-Ethynyl-2-methyl-1,5-
diphenylimidazole (7a).
Mp 163–164 °C. 1H NMR (500 MHz, CDCl3): d = 2.28 (s,
3 H, Me), 3.07 (s, 1 H, ≡CH), 7.09–7.41 (m, 10 H, Ph) ppm.
13C NMR (126 MHz, CDCl3): d = 14.2 (q, Me), 78.3 (s, ≡C),
78.4 (d, H–C≡), 127.7, 127.8, 128.2, 128.9, 129.0, 129.7 (6
d, Ph), 128.8, 137.2 (2 s, Ph), 120.3 (s, C-4), 136.6 (s, C-5),
146.0 (s, C-2) ppm. IR (KBr): 3290–2850 (C-H), 2105
(C≡C), 1595 (C=C) cm–1. 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, 80 eV,
40 °C): m/z calcd for C18H14N2: 258.1157. Found: 258.1163.
(6) Typical Procedure for Sonogashira Reaction 7a → 8a.
To a solution of Et3N (0.8 mL) and DMF (0.4 mL) under Ar
were added iodobenzene (0.08 mL, 0.69 mmol), alkyne 7a
(150 mg, 0.58 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol),
and CuI (2 mg, 0.012 mmol). The mixture was stirred at r.t.
for 16 h, then quenched with sat. aq NH4Cl solution (3 mL)
and extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried over Na2SO4 and the resulting
crude product was purified by column chromatography
(silica gel, toluene–EtOAc = 4:1) to give 150 mg (77%) of
8a as pale yellow crystals.
(3) For a review of the Ritter reaction, see: Krimen, L. I.; Cota,
D. J. Org. React. 1969, 17, 213.
(4) Typical Procedure for the Preparation of Imidazole 6a.
A solution of methoxyallene (2.80 g, 39.9 mmol) in dry THF
(50 mL) under Ar 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 2a (5.10 g, 28.1 mmol) dissolved in dry THF (10
mL) was added within 5 min. The mixture was stirred for 2
h at –20 °C and quenched with H2O (100 mL). Warm up to
r.t. was followed by extraction with Et2O (3 × 100 mL),
drying (Na2SO4), and concentration in vacuo, which led to
crude product 3a, yield 7.00 g (99%).
Analytical Data for 4-Phenylethynyl-2-methyl-1,5-
diphenylimidazole (8a).
Mp 189–190 °C. 1H NMR (500 MHz, CDCl3): d = 2.30 (s,
3 H, Me), 7.11–7.46 (m, 15 H, Ph) ppm. 13C NMR (126
MHz, CDCl3): d = 14.2 (q, Me), 84.3 (s, ≡C), 90.4 (s, Ph-
C≡), 127.7, 127.8, 127.9, 128.2, 128.3, 128.8, 128.9, 129.6,
131.4 (9 d, Ph), 121.4 (s, C-4), 123.7, 129.1, 136.8 (3 s, Ph),
136.4 (s, C-5), 146.3 (s, C-2) ppm. IR (KBr): 3055–2855
(=CH, CH), 2570 (C≡C), 1600 (C=C) cm–1. 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). HRMS
(EI, 80 eV, 40 °C): m/z calcd for C24H18N2: 334.1470.
Found: 334.1464.
Iodine (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 crude allenyl amine 3a (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. 10% Na2S2O3 solution (30 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 50
mL), dried over Na2SO4 and concentrated in vacuo
furnishing crude 5a (1.95 g).
Crude 5a was dissolved in dry CH2Cl2 (4 mL) under Ar, 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% Na2S2O3 solution
(10 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic phases were washed with H2O (1 × 30
mL) and dried over Na2SO4. The crude product was purified
by column chromatography (silica gel, hexane–
(7) (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (b) Dömling, A. Chem. Rev.
2006, 106, 17. (c) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(d) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168; Angew. Chem. 2000, 112, 3300.
(8) For an interesting alternative approach to highly substituted
imidazoles, which employs a dilithiated allene derivative
and nitriles, see: Langer, P.; Döring, M.; Seyferth, D.; Görls,
H. Eur. J. Org. Chem. 2003, 1948.
EtOAc = 4:1) to yield 1.22 g (80% overall yield) of 6a as
yellow crystals.
Analytical Data for 4-(1-Iodoethenyl)-2-methyl-1,5-
diphenylimidazole (6a).
Mp 104–105 °C. 1H NMR (500 MHz, CDCl3): d = 2.30 (s,
3 H, Me), 5.96, 6.14 (2 d, J = 1.4 Hz, each 1 H, =CH2), 7.07–
7.36 (m, 10 H, Ph) ppm. 13C NMR (126 MHz, CDCl3):
d = 14.1 (q, Me), 98.9 (s, =C–I), 127.8, 127.9, 128.3, 128.7,
129.4, 130.5 (6 d, Ph), 128.9 (t, =CH2), 129.1 (s, Ph), 129.8
(s, C-5), 136.5 (s, Ph), 138.0 (s, C-4), 144.4 (s, C-2) ppm. IR
(KBr): 3185–2870 (=CH, CH), 1600 (C=C) cm–1. MS (EI,
80 eV, 40 °C): m/z (%) = 386 (17) [M]+, 259 (100) [M – I]+,
218 (50), 184 (18), 77 (26) [C6H5]+, 43 (21), 28 (13). HRMS
(EI, 80 eV, 40 °C): m/z calcd for C18H15IN2: 386.0280.
Found: 386.0267.
(9) (a) Reviews: Grimmett, M. R. Comprehensive Heterocyclic
Chemistry, Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: London, 1984, 374–498. (b) Grimmet, M.
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Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
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publications: (c) Applications in medicinal chemistry:
Lambardino, J. G.; Wiesman, E. H. J. Med. Chem. 1974, 17,
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Gallagher, T. F.; Kumar, S.; Green, D.; McNulty, D.;
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J. E.; Mclaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi,
G. P.; White, J. R.; Adams, J. L.; Young, P. R. Nature
(5) Typical Procedure for the Preparation of Alkyne 7a.
To a solution of imidazole 6a (152 mg, 0.39 mmol) in dry
THF (2 mL) was added at 0 °C dropwise a solution of
potassium tert-butoxide (88 mg, 0.78 mmol) in THF (1 mL).
The flask was flushed with Ar, sealed and allowed to stir at
Synlett 2006, No. 11, 1683–1686 © Thieme Stuttgart · New York

1686
M. Gwiazda, H.-U. Reissig
LETTER
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Synlett 2006, No. 11, 1683–1686 © Thieme Stuttgart · New York