Intramolecular azide-Alkyne for the fast assembly of structurally diverse, tricyclic 1,2,3-triazoles

Article abstract of DOI:10.1021/ol800291t

The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure comp

Full text of DOI:10.1021/ol800291t

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1617-1619
Intramolecular Azide−Alkyne
Cycloaddition for the Fast Assembly of
Structurally Diverse, Tricyclic
1,2,3-Triazoles
Ana I. Oliva,† Ute Christmann,† Daniel Font,† Fe´lix Cuevas,† Pablo Ballester,‡
Helmut Buschmann,# Antoni Torrens,# Susana Yenes,# and Miquel A. Perica`s*,§
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans, 16, 43007
Tarragona, Spain, Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona (UB),
08028 Barcelona, Spain, ICREA and Laboratorios Dr. EsteVe, S.A., AV. Mare de Deu
de Montserrat, 221, 08041 Barcelona, Spain
mapericas@iciq.es
Received February 8, 2008
ABSTRACT
The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar
cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported.
Some of these compounds exhibit significant affinity for the sigma-1 receptor.
In recent years, the 1,3-dipolar cycloaddition between azides
and alkynes has witnessed a renewed interest since the
introduction by Sharpless of the Click Chemistry concept.1
In most cases, the 1,2,3-triazole system resulting from the
cycloaddition represents an almost universal ligation element
allowing the fast connection of properly functionalized
components of very diverse natures with quite different
functions/activities.2 In addition, the 1,2,3-triazole unit can
itself exhibit interesting properties, either catalytic or phar-
macological, among others.3
azide-alkyne cycloaddition appears as a most promising
alternative for the fast assembly of drug-like, tricyclic 1,2,3-
triazoles. However, either the fact that the involved dipolar
cycloaddition does not adjust to the structural requirements
of the click chemistry paradigm or the belief that the trans
arrangement in the cycloaddition substrate would play a
negative role on the cycloaddition process have hampered
the exploration of this possibility until now.
We report herein that cyclic epoxides, when submitted to
sequential azidolysis plus propargylation, lead to stereode-
fined azidoalkynes that readily undergo purely thermal 1,3-
dipolar cycloaddition leading to tricyclic [1,2,3]triazolo[1,5-
d][1,4]oxazines. The introduction of structural diversity at
two key points in these tricyclic structures is also demon-
The versatility of this cycloaddition has driven the
development of tandem processes involving it as the key step,
as a ready access to molecular diversity.4 Among these
multicomponent constructions, the combination of epoxide
ring-opening with azide, O-propargylation and intramolecular
(3) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8,
1128. (b) Whiting, M.; Mudoon, J.; Lin, Y. C.; Silverman, S. M.; Lindstrom,
W.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.;
Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 1435. (c) Luo, S.; Xu, H.;
Mi, X.; Li, J.; Zheng, X.; Cheng, J. P. J. Org. Chem. 2006, 71, 9244. (d)
Detz, R. J.; Arevalo, S.; De Gelder, R.; van Leeuwen, P. W. N. M.; Hiemstra,
H.; Reek, J. N. H.; van Maarseven, J. H. Org. Lett. 2006, 8, 3227.
(4) (a) Thomas, A. W. Bioorg. Med. Chem. Lett. 2002, 12, 1881. (b)
Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6, 884.
(c) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 8439. (d) Gracias, V.; Darczak, D.; Gasiecki, A. F.; Djuric, S.
W. Tetrahedron Lett. 2005, 46, 9053.
† ICIQ.
‡ ICREA and ICIQ.
# Laboratorios Dr. Esteve, S. A.
§ ICIQ and UB.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Rostovsev, V. V.; Gree, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(2) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007, 36, 1249.
(b) Lutz, J. F. Angew. Chem., Int. Ed. 2007, 46, 1018.
10.1021/ol800291t CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/19/2008

strated, and access to enantiopure products is secured by
catalytic desymmetrization of the starting epoxide with azide
delivering reagents.
Our strategy to prepare the tricyclic compounds starting
from benzylpyrroline epoxide 1 is outlined in Scheme 1. The
afford compounds 4 (Table 1). As anticipated, only 1,5-
regioisomers were obtained. The cycloaddition was also
attempted using copper-catalyzed conditions with unsubsti-
tuted propargyl compound 3a, but no adduct was formed
probably due to geometry restrictions in the formation of
the 1,4-regioisomer.
To increase structural diversity in the new compounds
prepared, we thought that the nitrogen of the pyrroline
subunit was good to derivatize. Thus, we studied the
palladium catalyzed N-arylation reaction with aryl halides
(Scheme 2).6 The hydrogenolysis of compounds 4 with Pd/C
Scheme 1. Synthetic Sequence
Scheme 2. Debenzylation of 4 and Derivatization by the
N-Arylation Reaction
combination of the opening reaction with NaN3, alkylation
of the resulting alcohol with propargyl bromides and the
subsequent intramolecular cycloaddition of the alkynyl-azido
compound afforded the tricyclic triazoles as racemic mixture
of trans-fused compounds 4.
Thus, the reaction of the epoxide 1 with NaN3 in the
presence of LiClO4 in acetonitrile at reflux conditions5
afforded the racemic trans-azidoalcohol 2 in 90% yield. The
alkylation of 2 with different propargyl bromides with NaH
as base and tetrabutylammonium iodide as catalyst in THF,
gave the alkynyl-azido compounds 3 in moderate to excellent
yields (Table 1).
Table 1. Synthesis of Tricyclic Triazole Derivatives
in methanol or THF afforded the secondary amine in good
yields. For the N-arylation reaction, we found that 1 mol %
of precatalyst 7 was able to mediate the coupling between 5
and different aryl halides in presence of NaOtBu in THF at
room temperature in good yields.7
Moreover, this novel synthetic approach can be applied
to the synthesis of enantiopure tricyclic triazoles. For the
asymmetric version, we used the enantiomerically pure Boc-
protected azido alcohol 8 as key intermediate. This inter-
mediate can be prepared by asymmetric ring opening of the
N-trifluoroacetamide pyrroline epoxide with TMSN3 cata-
lyzed by the chiral (salen)Cr(III) complex (R,R)-L, and
subsequently N-Boc protection according to described pro-
cedures (Table 2).8 In our hands, the azido alcohol was
obtained in 94% ee from the corresponding N-trifluoro-
entry
R
3 (yield, %)
4 (yield, %)
1
2
3
4
5
6
7
8
H
3a (99)
3b (77)
3c (90)
3d (84)
3e (50)
3f (47)
3g (61)
3h (35)
4a (87)
4b (93)
4c (79)
4d (85)
4e (66)
4f (85)
4g (77)
4h (86)
Me
Et
Ph
2-F-C6H4
3-F-C6H4
4-Cl-C6H4
4-CF3-C6H4
(6) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144. (b)
Wentland, M. P.; Xu, G.; Cioffi, C. L.; Ye, Y.; Duan, W.; Cohen, D. J.;
Colasurdo, A. M.; Bidlack, J. M. Bioorg. Med. Chem. Lett. 2000, 10, 183.
(c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158.
(7) (a) Christmann, U.; Vilar, R.; White, A. J. P.; Williams, D. J. Chem.
Commun. 2004, 1294. (b) Christmann, U.; Pantazis, D. A.; Benet-Buchholz,
J.; McGrady, J.; Maseras, F.; Vilar, R. J. Am. Chem. Soc. 2006, 128, 6376.
(8) (a) Mart´ınez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N.
J. Am. Chem. Soc. 1995, 117, 5897. (b) Schaus, S. E.; Larrow, J. F.;
Jacobsen, E. N. J. Org. Chem. 1997, 62, 4197.
The intramolecular azide-alkyne cycloaddition was per-
formed in good yields upon heating in toluene or xylene to
(5) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J. Org. Chem. 1993, 58, 1221.
1618
Org. Lett., Vol. 10, No. 8, 2008

Table 2. Synthesis of Enantiomerically Pure Tricyclic
Triazoles
Figure 1. X-ray structure of (S,S)-5a (2HCl).
compounds 4 bearing a benzyl-substituted pyrroline showed
activity for sigma-1, and interestingly, the affinity increased
when R2 is an aryl group (Table 3). Compound 4f, wherein
Table 3. Affinity for the Sigma-1 Receptor
% displacement
compound
Ki (nM)
(10-6 M)
4a
4b
4c
4d
4e
4f
<50
>1000
375 ( 1.6
26.9 ( 4.4
27.4 ( 4.9
15.8 ( 0.3
entry
R
9 (yield, %)
10 (yield, %)
4g
4h
87
1
2
3
4
H
Me
Ph
9a (92)
9b (96)
9c (80)
9d (91)
10a (96)
10b (47)
10c (57)
10d (86)
31.3 ( 8.7
3-F-C6H4
R2 is a meta-fluorine-substituted aryl, had the highest affinity
(Ki 15.8 ( 0.3 nM).
In summary, we have developed a straightforward prepa-
ration of new structurally diverse tricyclic 1,2,3-triazoles
based on a sequential epoxide ring-opening with azide,
O-propargylation and intramolecular azide-alkyne cycload-
dition. Furthermore, we have described the derivatization of
these compounds by an N-arylation reaction and the synthesis
of enantiomerically pure analogues. Preliminary screening
results indicated that some of these compounds exhibited a
high affinity for the sigma-1 receptor. More detailed SAR
studies and the biological evaluation of the enantiomerically
pure compounds are underway in our laboratories.
acetamide epoxide. The alkylation of 8 in the conditions
described above and the intramolecular cycloaddition of the
alkyne-azido compounds gave a variety of enantiopure
triazoles 10 in good yields (Table 2 and Supporting Informa-
tion). Finally, the deprotection of the N-Boc group and the
subsequent N-derivatization will provide enantiomerically
pure compounds. In the case of 10a, the deprotection of the
Boc group afforded the enantiopure amino derivative 5a as
dihydrochloride salt form, where the (S,S) configuration of
the fused rings was confirmed by X-ray crystallographic
analysis (Figure 1).
Quite interestingly, this strategy to access enantiopure
tricyclic triazoles could be applied to other azido alcohols
prepared by desymmetrization of the corresponding epoxides.
Acknowledgment. We thank the Torres-Quevedo pro-
gram for contracts to F.C. and U.C.
Supporting Information Available: Detailed description
of experimental procedures, 1H and 13C NMR spectra of the
compounds, and X-ray crystalographic file (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Representative compounds from the triazole library were
tested in a wide biological screening against 160 receptors.
These results revealed that some of the novel tricyclic
compounds prepared exhibit high affinity and selectivity for
the sigma-1 receptor. The sigma-1 receptor is of great interest
in pharmacology in view of its possible physiological role
in processes related to analgesia, anxiety, addiction, amnesia,
and depression among others.9 In addition, some preliminary
structure-activity relationships (SARs) were found. Tricyclic
OL800291T
(9) (a) Walker, J. M.; Bowen, W. D.; Walker, F. O.; Matsumoto, R. R.;
De Costa, B.; Rice, K. C. Pharmacol. ReV. 1990, 42, 355. (b) Bowen, W.
D. Pharm. Acta HelV. 2000, 74, 211.
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