Microwave-assisted regioselective synthesis of 2,4-disubstituted imidazoles: Nortopsentin D synthesized by minimal effort

Article abstract of DOI:10.1055/s-2001-10767

A two step regioselective synthesis of 2,4-disubstituted imidazoles based on the reaction of α-azidoacetyl indoles with carboxylic acids in the presence of tertiary phosphines followed by cyclization of the resulting ketoamides by the action of ammonium acetate under microwave irradiation is described. The method has successfully been applied to the synthesis of the antifungal nortopsentin D [2,4-bis(3-indolyl)imidazole].

Full text of DOI:10.1055/s-2001-10767

218
LETTER
Microwave-assisted Regioselective Synthesis of 2,4-Disubstituted Imidazoles:
Nortopsentin D Synthesized by Minimal Effort
Pilar M. Fresneda,* Pedro Molina,* Miguel A. Sanz
Departamento de Química Orgánica, Facultad de Química. Universidad de Murcia, Campus de Espinardo, 30071, Murcia, Spain
Fax +34 968 364149; E-mail: pmolina@um.es; fresneda@fcu.um.es
Received 4 December 2000
We now report an efficient and simple approach that has
Abstract: A two step regioselective synthesis of 2,4-disubstituted
sufficient flexibility to allow 2,4-disubstituted imidazoles
imidazoles based on the reaction of -azidoacetyl indoles with car-
to be conveniently generated and is suitable for the prep-
aration of nortopsentins, thus demostrating the applicabil-
boxylic acids in the presence of tertiary phosphines followed by cy-
clization of the resulting ketoamides by the action of ammonium
acetate under microwave irradiation is described. The method has ity of this method. The synthetic strategy is based on the
successfully been applied to the synthesis of the antifungal
nortopsentin D [2,4-bis(3-indolyl)imidazole].
tertiary phosphine-mediated coupling of -azidocarbonyl
compounds with carboxylic acids and cyclization of the
resulting ketoamides to 2,4-disubstituted imidazoles, us-
ing ammonium acetate as a convenient surrogate for am-
monia.
Key words: nortopsentin, 2,4-disubstituted imidazoles, microwave
chemistry, tertiary phosphines
The -azido carbonyl component of choice was a 3-( -
azidoacetyl)indole since there is a growing number of 4-
(3-indolyl)imidazole (nortopsentins, topsentins) and 5-(3-
indolyl)oxazole natural products (pimprinine, pimprin-
afine, martefragin A)11 with interesting biological proper-
ties.
The imidazole nucleus is of particular interest especially
within the realms of medicinal chemistry. This ring sys-
tem plays an important role in many biologically interest-
ing processes, and many natural products and useful
therapeutic agents contain the imidazole moiety. For ex-
ample, several classes of marine products possessing a
2,4-disubstituted imidazole ring have recently been dis-
covered and identified. Noteworthy among these bioac-
tive metabolites are nortopsentins1 and topsentins2
possessing an imidazole spacer between the two indole
residues. These compounds, isolated from caribbean
deep-sea sponges of the genus Spongorites and from the
mediterranean shallow-water sponge Topsentia genitrix,
have been shown to have antitumor activity against P388
and B16 melanoma, antiviral activity against HSV-1 and
corona virus A-59 and antifungal activity.
The starting N-benzyl-3-( -azidoacetyl)indole 1 was pre-
pared from N-benzyl-3-acetylindole in 64% overall yield
by a two-step sequence: (a) -chlorination with benzyltri-
methylammonium dichloroiodate (80%) and (b) halogen-
azide exchange with sodium azide in acetone/water
(80%). Although the reaction of -azidoketones with
triphenylphosphine to give 1,4-disubstituted pyrazines
through the intermediate iminophosphorane is a well es-
tablished reaction,12 compound 1 does not react with
triphenylphosphine even after an extended reaction time
(24 h). However, it does react with the more reactive tri-
methylphosphine to give the expected iminophosphorane
which by treatment with either acyl chorides or carboxylic
acids leads to a complex mixture.
The biological activity of this family of marine alkaloids
and the recent identification of aryl and heteroaryl disub-
stituted imidazoles as nitrogen activated protein kinase in-
hibitors,3 farnesyl-protein transferase inhibitors4 and
potentially antiinflamatory drugs,5 have generated syn-
thetic interest in the preparation of 2,4-disubstituted imi-
dazoles.6
The preparation of ketoamides 3a-d was achieved in 55-
60% yields by sequential treatment of 1 with diphenyl-
methylphosphine and acyl chlorides in THF at room tem-
perature. (Scheme). In spite of the fact that the reaction of
carboxylic acids with alkyl or arylazides to give amides in
good yields has been reported,13 very low yields of keto-
amides 3a-d were obtained when compound 1 was treated
with diphenylmethyl phosphine and the corresponding
carboxylic acid.
As part of our program to prepare bioactive metabolites
from marine organisms possessing the imidazole ring,7 we
routinely require an efficient method that could be used to
prepare 2,4-disubstituted imidazoles. In surveying the lit-
erature, we have found that the classical general methods
for the preparation of this ring system e.g. Bredereck
reaction8 and the TOSMIC method of van Leusen9 do not
allow this kind of substitution pattern. The only general
approach for the preparation of 2,4-diaryl(heteroaryl)imi-
dazoles involves a succesive palladium-catalyzed cross-
coupling reaction of either aryl(heteroaryl) boronic acids
or aryl(heteroaryl)stannanes with halogeno-functional-
ized imidazoles.10
More interesting was the reaction of 3-( -az-
idoacetyl)indole14 2 with carboxylic acids in the presence
of trimethylphosphine to give the otherwise not readily
available ketoamides15 3d-j. (Scheme). The reaction
seems to be general and works well with aliphatic (entry
d), benzylic (entries e and f), aromatic (entry g) and het-
eroaromatic carboxylic acids (entries h - j) with yields
Synlett 2001, No. 2, 218–221 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Microwave-assisted Regioselective Synthesis of 2,4-Disubstituted Imidazoles
219
preparation of the non-naturally ocurring 8”-deoxy-
topsentin (entry f) in good yield, which may be converted
into the natural product in a straightforward manner,18 and
the efficient preparation of the antifungal nortopsentin D
(entry j) in two steps with an overall yield of 53% without
the need of using a protecting group on nitrogen show the
usefulness of the present method in organic synthesis.19
O
O
N3
N3
N
H
N
Bn
2
1
R1-COCl
PPh2Me
R1COOH
55-75%
PMe3
55-60%
In conclusion, the coupling between 3-( -azidoacetyl)in-
dole and carboxylic acids provides, by an appropriate
choice of the tertiary phosphine, an excellent and general
method for the formation of ketoamides, which undergo
cyclization in the presence of an ammonia source under
microwave irradiation to give 2,4-disubstituted imida-
zoles.
O
H
R1
N
O
N
R2
3
AcONH4, DMF
MW
50-75%
N
Acknowledgement
R1
We gratefully acknowledge the financial support of the Dirección
General de Investigación Científica y Técnica, project number
PB95-1019. M.A.S. also thanks the CARM “Fundación Séneca” for
a studentship.
N
H
N
R2
4
Scheme
References and Notes
(1) (a) Sakemi, S.; Sun, H. H. J. Org. Chem. 1991, 56, 4304.
(b) Moody, C. J.; Roffey, J. R. A. ARKIVOC 2000, Vol.1, 45.
(2) (a) Bartik, K.; Braekman, J. C.; Daloze, D.; Stoller, C.;
Huysecom, J.; Vandevyver, G.; Ottinger, R. Cand. J. Chem.
1987, 65, 2118. (b) Braekman, J. C.; Daloze, D.; Stoller, C.
Bull. Soc. Chim. Belg. 1987, 96, 809. (c) Tsuji, S.; Rinehart,
K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui, M.
S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem. 1988, 53, 5446.
(d) Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715.
(3) Lee, J. C.; Laydon, J. T.; Mc Donnell, P. C.; Gallagh, T. F.;
Green, D.; Mc Nulty, D.; Blumenthal, M. J.; Heys, J. R.;
Landvatter, S. V., Strickler, J. E.; Mc Laughlin, M. M.;
Siemens, Y. R.; Fisher, S. M., Livi, G. P.; White, J. R.; Adams,
J. L.; Young, P. R. Nature 1994, 372, 739.
ranging from 55% to 75%. It is important to note the
preparation of 3j in 70% yield, as a suitable precursor of
the nortopsentin D.
Conversion of ketoamides 3 into the corresponding 2,4-
disubstituted imidazoles 4 involved the use of ammonium
acetate (ammonia source) and heating of the resulting
mixture. Preliminary optimization of reaction conditions
was done using dry DMF as solvent and thermal heating
at 180 °C for 12-16 h (Method A) (25-75%). Optimal con-
ditions for the synthesis of 4 were found to be 10-30 min
reaction time under microwave irradiation (Method B)
(50-75%) (Table). Since there is only one reported synthe-
sis of nortopsentins,10a we thought that it could be interest-
ing to use this straightforward procedure in the
preparation of the nortopsentin D. Thus, classical heating
of ketoamide 3j in DMF at 130 °C in the presence of am-
monium acetate for 14 h, provided the nortopsentin D 4j
although in low yield (25%). However, when this mixture
was submitted to microwave irradiation the target mole-
cule was obtained in high yield (75%).
(4) Anthony, N. J.; U.S. Patent 5854265A, 1998, Chem. Abstr.
1998, 130, 95548.
(5) Boehm, J. C.; Smietana, J. M.; Sorenson, M. E.; Garigipati, R.
S.; Gallagher, T. F.; Sheldrake, P. L.; Bradbeer, J.; Badger, A.
M.; Laydon, J. T.; Lee, J. C.; Hilegass, L. M.; Griswold, D. E.;
Breton, J. J.; Chabot-Fletcher, M. C.; Adams, J. L. J. Med.
Chem. 1996, 39; 3929.
(6) (a) Molina, P.; Diaz, I.; Tarraga, A. Synlett 1995, 1031. (b)
Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1995, 2615.
(c) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino,
S. J. Org. Chem. 1995, 5899. (d) Kawasaki, I; Taguchi, T;
Yamamoto, M.; Yamashita, M.; Otha, S. Tetrahedron Lett.
1995, 8251.
To the best of our knowledge, the microwave-assisted
synthesis of 2,4-disubstituted imidazoles has not been re-
ported, although several papers describing other micro-
wave-assisted synthesis of substituted imidazoles have
been published.16
(7) Fresneda, P. M.; Molina, P.; Sanz, M. A. Synlett 2000, 1190.
(8) Bredereck, H.; Theilig, G. Chem. Ber. 1953, 86, 88.
(9) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org.
Chem. 1977, 42, 1153.
(10) (a) Kawasaki, I; Yamashita, M.; Otha, S. Chem. Pharm. Bull.
1996, 40, 1831. (b) Revesz, L.; Bonne, F.; Makaron, P.
Tetrahedron Lett. 1998, 5171.
(11) Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito, H.;
Nakagawa, M. Tetrahedron Lett. 2000, 4791 and references
cited therein.
(12) Zbiral, E.; Ströh, J. Liebigs Ann. Chem. 1969, 727, 231.
(13) (a) García, J.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1984,
4841. (b) Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1986, 4623.
The structures of all 2,4-disubstituted imidazoles 4 were
determined from their analytical and spectral (1H, 13C
NMR and MS) data.17 The results are summarized in the
Table. Inspection of the data shows that the method is ap-
plicable to a variety of 4-(3-indolyl)-2-substituted imida-
zoles in moderate to good yields. Only the 2-(4-
pyridyl)derivative (entry 4i) gave under microwave irra-
diation somewhat lower yields than classical heating. The
Synlett 2001, No. 2, 218–221 ISSN 0936-5214 © Thieme Stuttgart · New York

220
P. M. Fresneda et al.
LETTER
Table Ketoamides 3 and 2,4-disubstitued imidazoles 4 prepared.
a) Isolated yields of the products obtained after silica gel column chromatography.
b) Thermal heating in DMF at 130 °C for 12-16h.
c) Microwave irradiation for 10-35 min.
d) The reaction product was found to be 3-(3-indolyl)-5-(N-benzylindol-3-yl)pyrazin-2-one.
(14) (a) Moody, C. J.; Ward, J. G. J. Chem. Soc., Perkin Trans 1
1984, 2903. (b) Molina, P.; Fresneda, P. M.; Almendros, P.
Synthesis 1993, 54.
(15) Recently related ketoamides, used as precursors of 5-(3-
indolyl)oxazole alkaloids, have been prepared from Fmoc-
tryptophan in four steps: esterification, deprotonation,
acylation using the system Ph3P/NCS and finally oxidation of
the methylene group with DDQ.11
(16) (a) Reddy, A. C. S.; Rao, P. S.; Ventaratham, R. V.
Tetrahedron 1997, 53, 5847. (b) Bougrin, K.; Soufiaoui, M.
Tetrahedron Lett. 1995, 36, 3683. (c) Ben-Alloum, A.;
Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1998, 39, 4481.
(d) Glas, H.; Thiel, W. R. Tetrahedron Lett. 1998, 39, 3509.
(e) Martin-Aranda, R. M.; Vicente-Rodriguez, M. A.; Lopez-
Pestana, J. M.; Lopez-Peinado, A. J.; Jerez, A.; Lopez-
Gonzalez, J. D.; Banares-Muñoz, M. A. J. Mol. Cat. A. 1997,
124, 115. (f) Bogdal, D.; Pielichowski, J.; Jaskot, K.
Heterocycles 1997, 45, 715. (g) Usyatinsky, A. Ya.;
Khmelnitsky, Y. L. Tetrahedron Lett. 2000, 5031.
(17) Compound 4d: m.p. 111-114 °C. 1H NMR (300 MHz,
MeOD-d4) : 2.41 (s, 3H, CH3), 7.09 (td, 1H, J = 7.05, 1.21
Hz, H-5’), 7.15 (td, 1H, J = 7.35, 1.21 Hz, H-6’), 7.15 (s, 1H,
H-5), 7.40 (dd, 1H, J = 7.45, 1.21 Hz, H-7’), 7.54 (s, 1H,
H-2’), 2.77 (dd, 1H, J = 7.25, 1.21 Hz, H-4’). 13C NMR (75
MHz, MeOD-d4) : 14.3 (CH3), 110.4 (C-3’), 113.4 (C-7’),
117.5 (C-5), 121.28 (C-4’) 121.38 (C-5’), 123.5 (C-2’), 123.6
(C-6’), 127.1 (C-3’a), 133.4 (C-4), 139.0 (C-7’a), 146.0 (C-2).
EIMS (70 eV); m/z (%): 198 (M++1, 31), 197 (M+, 100), 196
(29), 155 (36), 129 (36).
Compound 4f: m.p. 257-260 °C. 1H NMR (300 MHz,
DMSO-d6) : 4.17 (s, 2H, CH2), 6.95 (t, 1H, J = 6.8 Hz, H-5”),
7.05 (t, 2H, J = 7.7 Hz, H-5’ and H-6”), 7.12 (t, 1H, J = 6.4 Hz,
H-6’), 7.24 (s, 1H, H-5), 7.26 (s, 1H, H-2”), 7.35 (d, 1H,
J = 8.11Hz, H-7’’), 7.40 (d, 1H, J = 8.11 Hz, H-7’), 7.61 (d,
1H, J = 7.7, Hz, H-4”), 7.68 (s, 1H, H-2’), 7.86 (d, 1H, J = 7.3
Synlett 2001, No. 2, 218–221 ISSN 0936-5214 © Thieme Stuttgart · New York

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Microwave-assisted Regioselective Synthesis of 2,4-Disubstituted Imidazoles
221
Hz, H-4’). 13C NMR (75 MHz, DMSO-d6)) : 24.3 (CH2),
NH4OAc (5g) and dry DMF (25 mL) was treated in sealed
glass tube at 130 °C for 16 h. After cooling, the mixture was
poured in brine (50 mL) and then extracted with EtOAc
(5 20 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated to dryness. The
crude product was chromatographed on a silica gel column
using EtOAc/EtOH (8:2) as eluent to give nortopsentin D 4j
(74.5 mg, 25% yield). M.p. 197-220 °C, (lit.10a m.p. 195-
227 °C).
108.5 (C-3”), 110.9 (C-3’), 111.4 (C-7”), 111.6 (C-7’), 114.8
(C-5), 118.3 (C-5”), 118.7 (C-4”), 119.1 (C-5’), 119.8 (C-4’),
120.9 (C-6”), 121.3 (C-6’), 121.9 (C-2’), 123.4 (C-2”), 124.5
(C-3”a), 127.0 (C-3’a), 131.0 (C-4), 136.2 (C-7’’a), 136.3 (C-
7’a), 146.5 (C-2). EIMS (70 eV); m/z (%): 313 (M++1, 43),
312 (M+, 100), 311 (34), 196 (54), 195 (60), 156 (30), 130
(41), 117 (66).
Compound 4g: m.p. 147-150 °C. 1H NMR (300 MHz,
MeOD-d4) 2.45 (s, 3H, CH3), 7.16 (t, 1H, J = 6.9 Hz, H-5’),
7.21 (t, 1H, J = 6.6 Hz, H-6’), 7.26-7.39 (m, 2H), 7.40-7.51
(m, 2H), 7.58 (s, 1H, H-2’), 7.73-7.85 (m, 3H). 13C NMR (75
MHz, MeOD-d4) : 22.3 (CH3), 106.8 (C-3’), 113.7 (C-7’),
118.0 (C-5), 121.0 (C-4’), 122.1 (C-5’), 124.2 (C-6’), 125.3,
(C-6”), 125.4 (C-2’), 127.0 (C-3’a), 128.6 (C-5”), 131.1 (C-
2”), 133.1 (C-4”), 133.4 (C-4), 139.1 (C-1”), 141.3 (C-7’a and
C-3”). EIMS (70 eV); m/z (%): 274 (M++1, 39), 273 (M+,
100), 272 (21), 155 (30), 129 (28).
Method B : A mixture of ketoamide 3j (0.32 g, 1 mmol),
NH4OAc (5g) and dry DMF (20 mL) was placed in a
cylindrical quartz tube. Then the tube was introduced into a
Synthewave 402 Prolabo microwave reactor (2.45 GHz,
adjustable power within the range 0.300 W) and irradiated at
20% power for 5 min intervals. After this heating a period of
2 min was allowed for cooling to prevent excess of heating,
and NH4OAc (2g) was added. This process was repeated 7
times. After completation of the reaction, the cooled mixture
was poured on brine (20 mL) and 5% NaOH aqueous solution
was added until pH = 8. The resultant mixture was extracted
with EtOAc (5 10 mL). The combined organic layers were
dried on anhydrous MgSO4, filtered and concentrated to
dryness. The solid residue was chromatographed on a silica
gel column using EtOAc/EtOH (8:2) as eluent to give
nortopsentin D 4j (0.223g, 75% yield). 1H NMR (300 MHz,
MeOD-d4) 7.10-7.24 (m, 4H, H-5’, H-6’, H-5”and H-6”),
7.41 (1H, H-5), 7.4-7.5 (m, 2H, H-7’ and H-7”), 7.72 (s, 1H,
H-2’), 7.84 (dd, 1H, J = 6.5, 1.41 Hz, H-4”), 7.87 (s, 1H, H-
2”), 8.10 (dd, 1H, J = 6.7, 1.8 Hz, H-4’). 13C NMR (75 MHz,
MeOD-d4) : 107.2 (C-3”), 109.0 (C-3’), 113.5 and 113.7 (C-
7’ or C-7”), 117.8 (C-5), 121.2 (C-5”), 121.6 (C-4”), 121.7 (C-
5’), 122.4 (C-4’), 123.8 (C-6”), 124.4 (C-6’ and C-2’), 126.9
(C-3”a), 127.0 (C-2”), 127.3 (C-3’a), 132.7 (C-4), 139.0 and
139.1 (C-7”a or C-7’a), 145.1 (C-2). EIMS (70 eV); m/z (%):
298 (M+, 100), 183 (26), 149 (53), 129 (27). HREIMS
C19H14N4 cald 298.1218 found 298.1227.
Compound 4i: m.p. 153-156 °C. 1H NMR (300 MHz,
DMSO-d6) : 7.11 (t, 1H, J = 6.0 Hz, H-5’), 7.16 (t, 1H,
J = 6.83 Hz, H-6’), 7.45 (d, 1H, J = 7.27 Hz, H-7’), 7.60 (s,
1H, H-5), 7.91-8.5 (m, 2H, H-4’ and H-2’), 8.07 (d, 2H,
J = 6.0 Hz, H-3”), 8.62, J = 6.0 Hz, H-2”), 11.40 (s, 1H, H-1’).
13C NMR (75 MHz, DMSO-d6) : 111.7 (C-7’), 112.2 (C-3’),
114.8 (C-5); 118.8 (C-3”), 119,3 (C-5’), 199.9 (C-4’), 121.4
(C-6’), 122.9 (C-2’), 124.7 (C-3’a), 136.4 (C-4), 137.4 (C-
7’a), 142.3 (C-2), 150 (C-2”), 150.3 (C-4”). EIMS (70 eV);
m/z (%): 260 (M+, 100), 232 (47), 183 (43), 155 (50), 144
(62), 101 (86).
(18) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(19) Typical Procedure for the Preparation of Nortopsentin D 4:
To a solution of 3-( -azidoacetyl)indole 2 (1g, 5 mmol) and 3-
indolecarboxylic acid (0.97 g, 6 mmol) in dry THF (50 mL),
trimethylphosphine (5 mL, 1M toluene solution) was added
dropwise under N2. The reaction mixture was stirred at r.t. for
12 h and then heated at reflux temperature for 1 h. After
cooling, EtOAc (30 mL) was added and the resulting solution
was washed with 5% NaOH aqueous (20 mL). The organic
layer was dried over anhydrous MgSO4, filtered and the
solvent removed under reduced pressure. The remaining solid
was slurried with Et2O (30 mL) and the separated solid was
filtered and air-dried to give 3j (70%) in pure form.
Article Identifier:
1437-2096,E;2001,0,02,0218,0221,ftx,en;L19300ST.pdf
Method A : A mixture of ketoamide 3j (0.32 g, 1 mmol),
Synlett 2001, No. 2, 218–221 ISSN 0936-5214 © Thieme Stuttgart · New York