A novel Zn-catalyzed hydroamination of propargylamides: A general synthesis of di- and tri-substituted imidazoles

Article abstract of DOI:10.1039/c0cc04625f

Starting from commercially available amines and propargylamides a variety of substituted imidazoles were synthesized via a novel hydroamination- cyclization sequence. The target compounds are obtained in good to excellent yields in the presence of catalytic amounts of zinc triflate.

Full text of DOI:10.1039/c0cc04625f

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COMMUNICATION
A novel Zn-catalyzed hydroamination of propargylamides: a general
synthesis of di- and tri-substituted imidazolesw
Anahit Pews-Davtyan and Matthias Beller*
Received 26th October 2010, Accepted 7th December 2010
DOI: 10.1039/c0cc04625f
Starting from commercially available amines and propargyl-
by cyclization protocols, and (b) selective functionalization
of the existing imidazole core.11a–c Most conventional
methods for the synthesis of functionalized imidazoles require
several reaction steps, sometimes harsh reaction conditions,
expensive catalysts and might be limited in terms of substrate
accessibility, generality and diversity. Therefore, the
development of novel approaches for the preparation of
imidazoles remains a challenging and interesting topic for
organic synthesis.
amides a variety of substituted imidazoles were synthesized via
a
novel hydroamination–cyclization sequence. The target
compounds are obtained in good to excellent yields in the
presence of catalytic amounts of zinc triflate.
Substituted imidazoles represent
a common scaffold in
numerous bio-active compounds.1 For example, they act as
inhibitors of serotonin 5-HT2B receptors2 and glutaminyl
cyclase,3 and as antagonists of endothelial differentiation gene
(EDG-1),4 melanocortin 4 (MC4-R)5 and histamine H3
receptors.6 Furthermore, they are known ligands for GABAA
receptors,7 and selective blockers of an NMDA (N-methyl-D-
aspartate)-receptor subtype.8 Representatives of the well
known 5-alkylsubstituted imidazoles are cimetidine (1), which
is used under the trade name Tagamet for treatment of
heartburn, peptic ulcers, the imidazole alkaloid (2),9 used for
cancer treatment, and the naturally occurring alkaloid
pilocarpine (3), which is a cholinergic agonist and useful in
the treatment of glaucoma or xerostomia (Fig. 1).
Here, we report a new, general and straightforward
synthesis of 2,5(4)-disubstituted and 1,2,5-trisubstituted
imidazoles starting from commercially available amines and
easily accessible propargylamides using catalytic amounts of
zinc triflate.
Until to date, only few examples of using alkynes for the
synthesis of imidazoles have been reported.12 More specifi-
cally, Yura described the preparation of imidazole from
halo-acetylenes and guanidine.12h Eloy and co-workers
reported the condensation of propargylamine with imido-
esters, imidoyl chlorides and amidines to give substituted
imidazoles in moderate to good yields.12c,d
In addition, imidazoles are widely used as precursors of
N-heterocyclic carbenes,10a organocatalysts,10b,c and ionic
liquids.10d Because of the importance of this class of
compounds their synthesis and functionalization reactions
have been intensively studied and continue to be an
actual subject in organic synthesis. The different synthetic
methods for the synthesis of imidazoles can be categorized
in two main types: (a) construction of an imidazole core
Moreover, palladium-catalyzed cyclizations of N-propargyl-
benzamidine and aryl halides led to imidazoles.12a Finally,
the cyclization of acetylenic ureas to imidazolidinones12g or
imidazolones has been described.12e
There are also limited examples reported for the regio-
selective ring formation of 1,2,5-trisubstituted imidazoles.13
Known procedures involve (a) the addition of aminoalcohols
to thioamides and subsequent oxidation with PDC,13a (b)
cycloaddition of thioamides with imines,13c and reactions of
(c) N-monosubstituted amidines with 2-halo-3-alkoxy-2-
propenals,13b (d) enamines13d or silyl enol ethers13f with
N-aryl-N0-chlorobenzimidine, (e) a-bromophenylacetaldehyde
with isothiosemicarbazones,13e and (f) N-tosylmethylimines
with aldimines.13g Obviously, all these approaches are rather
special or require the use of unusual reagents.
Fig. 1 Cimetidine (1), imidazole alkaloid (2) and pilocarpine (3).
For some years we have been interested in alkyne hydro-
amination reactions,14,15 more recently especially Zn-catalyzed
syntheses towards indoles.16 Based on this work, we investi-
gated the hydroamination reaction of N-benzoyl propargyl-
amine with primary aliphatic amines in the presence of zinc
salts. To our surprise instead of the expected imine, we
obtained N-butyl-2-phenyl-5-methyl imidazole as the major
product. Apparently, the initial hydroamination reaction is
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V.,
¨
¨
Albert-Einstein-Str. 29a, D-18059 Rostock, Germany.
E-mail: matthias.beller@catalysis.de; Tel: +49 381 1281 113
w Electronic supplementary information (ESI) available: Procedures
and characterisation data for imidazoles and new compounds, scans of
NMR spectra. See DOI: 10.1039/c0cc04625f
c
2152 Chem. Commun., 2011, 47, 2152–2154
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Table 2 Reaction of propargylamides with aromatic and aliphatic
amines to functionalized imidazolesa
Yieldc
[%]
Entry Amine
R2b
Product
Scheme
1 Zn-catalyzed reaction of N-acylpropargylamides and
amines.
1
4a Me
5a17d
618
73
followed by a Zn-promoted intramolecular cyclization and
dehydration reaction (Scheme 1).
Preliminary experiments showed that this novel reaction
sequence took place either by conventional thermal heating or
under microwave irradiation. Because the microwave-assisted
synthesis led to reduction of reaction time and suppression of
side products, we performed most of the optimization experi-
ments under the latter conditions. Notably, the success of the
cyclocondensation reaction is strongly dependent on the
selection of the Zn-source, its amount, temperature, and
solvent. In Table 1 selected results of the influence of critical
parameters on our model reaction using N-benzoylpropargyl-
amine (5b) and n-butylamine (4b) are shown. Optimal results
are observed using 5 mol% of Zn(OTf)2 in toluene at 140 1C.
Next, the optimized reaction conditions were used to
demonstrate the scope and limitations of our protocol. All
amines (4a–j) are commercially available. Propargylamides
(5a–g) were readily synthesized from propargyl amine and
suitable acylchlorides using known one step multigram
procedures.17 As shown in Table 2, a variety of primary
amines and acylated propargylamines gave the desired
products (6–18) in good to excellent yields (Table 2).
Functional groups like alkyloxy, hydroxyl, halogen, and
olefins are well tolerated (Table 2, entries 4, 5, 7, 8, and 10).
Both aromatic and aliphatic amines react equally well and give
in some cases nearly quantitative yield of the corresponding
imidazole (Table 2, entries 3–5). Moderate to good yields were
2
4a
5b17d
712d,13f 87
3
4
5
4b
4c
4d
5b
5b
5b
812d
95
96
96
9
10
6
7
4e
4f
5c17d
11
12
78
81
5d17d
Table 1 Selection of reaction conditions for our benchmark reactiona
8
9
4g
4e
5d
5e
13
14
55
78
Catalyst
Entry Zn source (mol%) Solvent T/1C Time/h [%]
Conv. Yieldb
[%]
1
2
3
4
5
6
7
8
Zn(OTf)2
ZnCl2
ZnBr2
Zn(ClO4)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2 15
Zn(OTf)2 10
Zn(OTf)2
Zn(OTf)2
TfOH
5
5
5
5
5
5
5
5
Toluene 140
Toluene 140
Toluene 140
Toluene 140
Dioxane 120 1.5
Heptane 120 1.5
1
1
1
1
100
94
84
86
86
91
18
20
55
83
98
95
24
95c
38
23
64
62
65
3
THF
CH2Cl2
100 1.5
80 1.5
1
10
11
4h
4a
5f17b
15
16
38
61
9
Toluene 100
Toluene 120
Toluene 130
Toluene 140
Toluene 140
1
1
1
1
1
35
74
85
86
4
10
11
12
13
5
3
5
a
5g17e,g
Reaction conditions: alkyne (0.25 mmol), amine (1.5 eq.), solvent
b
(1 mL), 100 W, microwave irradiation. GC yield. Isolated yield.
c
c
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Table 2 (continued )
R2b
9 (a) B. Cui, B. L. Zheng, K. He and Q. Y. Zheng, US 20040034079,
Hogan & Hartson LLP, 2004; (b) B. Cui, B. L. Zheng, K. He and
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10 For selected reviews see: (a) J. C. Y. Lin, R. T. W. Huang,
C. S. Lee, A. Bhattacharyya, W. S. Hwang and I. J. B. Lin, Chem.
Rev., 2009, 109, 3561; (b) S. Mukherjee, J. W. Yang, S. Hoffmann
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2002, 102, 3667.
Yieldc
[%]
Entry Amine
Product
12
4i
4j
5g
5b
17
43
91
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(b) S. Kamijo and Y. Yamamoto, Chem.–Asian J., 2007, 2, 568;
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4571.
13
NH3
1819
a
Reaction conditions: alkyne (0.5 or 1 mmol), amine (1.5 eq.), toluene
b
12 (a) G. Abbiati, A. Arcadi, V. Canevari and E. Rossi, Tetrahedron
Lett., 2007, 48, 8491; (b) P. Molina, A. Arques and M. V. Vinader,
Liebigs Ann. Chem., 1987, 103; (c) J.-P. Maffrand, J.-M. Pereillo,
F. Eloy, D. Aubert, F. Rolland and G. Barthelemy, Eur. J. Med.
Chem., 1978, 13, 469; (d) F. Eloy, A. Deryckere and
J.-P. Maffrand, Eur. J. Med. Chem., 1974, 9, 602; (e) F. Eloy and
A. Deryckere, Actual. Chim. Ther., 1973, 4, 437; (f) R. Fuks,
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(1 or 2 mL), 140 1C, 1 h, 100 W, microwave irradiation. Dashed line
points out the bond position to carbonyl group and to imidazole.
c
Isolated yield.
observed in the case of halogenated aromatic amine 4h,
heteroaromatic amine 4i and sterically hindered systems
(Table 2, entries 10–12). Moreover, we were able to
show the generality of our approach for the synthesis of
2,5(4)-disubstituted imidazoles. Here, the method was success-
fully used with gaseous ammonia instead of amines in an
autoclave to yield the desired imidazole 18 in 91% yield
(Table 2, entry 13). Thus, our approach allows for regio-
specific introduction of various substituents into the imidazole
ring just by choosing the proper combination of starting
materials.
14 For reviews see: (a) R. Severin and S. Doye, Chem. Soc. Rev., 2007,
36, 1407; (b) M. Beller, J. Seayad, A. Tillack and H. Jiao, Angew.
Chem., 2004, 116, 3448 (Angew. Chem., Int. Ed., 2004, 43, 3368);
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(d) F. Alonso, I. P. Beletskaya and M. Yus, Chem. Rev., 2004,
In conclusion, we have developed a new, effective one-step
approach for the synthesis of 2,5(4)-disubstituted and
1,2,5-trisubstituted imidazoles from commercially available
amines and propargylamides. These reactions constitute the
first examples of Zn-catalyzed one-pot synthesis of imidazoles.
Advantageously, a broad tolerance of various functional
groups is observed and the targeted products were obtained
in good to excellent yields as stable solid compounds.
This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF, and the DFG (Leibniz-price;
GRK 1113). We thank our analytical department for their
excellent technical and analytical support. We are also thank-
104, 3079; (e) T. E. Muller and M. Beller, Chem. Rev., 1998, 98,
675.
¨
15 Some examples from our group: (a) K. Alex, A. Tillack,
N. Schwarz and M. Beller, ChemSusChem, 2008, 1, 333;
(b) A. Tillack, V. Khedkar, J. Jiao and M. Beller, Eur. J. Org.
Chem., 2005, 5001; (c) V. Khedkar, A. Tillack, C. Benisch,
J.-P. Melder and M. Beller, J. Mol. Catal. A: Chem., 2005, 241,
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Tetrahedron Lett., 2004, 45, 3123; (e) A. Tillack, H. Jiao,
I. Garcia Castro, C. G. Hartung and M. Beller, Chem.–Eur. J.,
2004, 10, 2409; (f) V. Khedkar, A. Tillack and M. Beller, Org.
Lett., 2003, 5, 4767.
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¨
and students S. Werkmeister, K. Volpert and J. Schranck for
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M. J. Frech, A. Rolfs and M. Beller, Org. Biomol. Chem., 2010,
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