Copper-free intramolecular alkyne-azide cycloadditions leading to seven-membered heterocycles

Article abstract of DOI:10.1021/ol201869y

Treatment of alk-2-ynyl derivatives of enantiopure phenylglycidol with NaN₃ triggers a cascade reaction consisting of stereospecific and regioselective epoxide ring opening followed by intramolecular azide-alkyne cycloaddition under strictly me

Full text of DOI:10.1021/ol201869y

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5044–5047
Copper-Free Intramolecular
AlkyneÀAzide Cycloadditions Leading to
Seven-Membered Heterocycles
†
Mıriam Sau, Carles Rodrıguez-Escrich, and Miquel A. Pericas*
†
,†,‡
ꢀ
´
´
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans, 16,
ꢀ
¨
43007 Tarragona, Spain, and Departament de Quımica Organica,
´
Universitat de Barcelona, 08080, Barcelona, Spain
mapericas@iciq.es
Received July 12, 2011
ABSTRACT
Treatment of alk-2-ynyl derivatives of enantiopure phenylglycidol with NaN3 triggers a cascade reaction consisting of stereospecific and
regioselective epoxide ring opening followed by intramolecular azideÀalkyne cycloaddition under strictly metal-free conditions. This simple
one-pot procedure allows a fast buildup of molecular complexity, generating a wide array of triazolooxazepinols, triazolodiazepinols, and
triazolothiazepinols.
The construction of triazoles by azideÀalkyne cycload-
dition (AAC) has long been known,1 but it was not until
the independent discovery by the groups of Meldal2 and
Sharpless3 that copper(I) catalyzed the process that it
became a useful tool for synthetic chemists. Indeed,
several catalysts have been developed that not only
stabilize the Cu(I) species but also accelerate the global
catalytic process,4 which has allowed application of this
transformation in fields as diverse as biotechnology and
materials science.5
For biological applications, the cytotoxicity of copper
could represent an important drawback6 and, in fact,
impressive efforts have been devoted to developing cop-
per-free protocols that have even enabled the performance
of these reactions in vivo.7 While for intermolecular pro-
cesses the strain-induced increase in reactivity of the alkyne
component has evolved into a most practical approach to
copper-free alkyne azide cyloadditions,8 intramolecular
† Institute of Chemical Research of Catalonia.
‡ Universitat de Barcelona.
(1) (a) Pioneering work: Huisgen, R. Angew. Chem., Int. Ed. Engl.
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39, 1280.
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(5) Click Chemistry for Biotechnology and Materials Science; Lahann,
J., Ed.; John Wiley & Sons: Hoboken, NJ, 2009.
(6) (a) Baskin, J. M.; Bertozzi, C. R. ‘Copper-free Click Chemistry' in
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43, 15.
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Chem. Soc. 2010, 132, 3923. (c) Jewett, J. C.; Sletten, E. M.; Bertozzi,
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Lastecoueres, D.; Diallo, A. K.; Ruiz Aranzaes, J.; Astruc, D.; Vincent,
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J.-M. Chem. Commun. 2008, 741. (c) Dıez-Gonzalez, S.; Nolan, S. P.
€
Angew. Chem., Int. Ed. 2008, 47, 9013. (d) Ozc-ubukc-u, S.; Ozkal, E.;
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Jimeno, C.; Pericas, M. A. Org. Lett. 2009, 11, 4680. (e) Shao, C.; Cheng,
G.; Su, D.; Xu, J.; Wang, X.; Hu, Y. Adv. Synth. Catal. 2010, 352, 1587.
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r
10.1021/ol201869y
Published on Web 09/02/2011
2011 American Chemical Society

alkyneÀazide cycloadditions can take place under mild
conditions in the absence of copper thanks to favorable
entropy effects on the corresponding transition states.9
different strategies: deprotonation of phenylglycidol fol-
lowed by substitution on the corresponding propargyl
halide (Scheme 2, route A) or attack of a propargyl alkoxide
to the tosylate ester of phenylglycidol (Scheme 2, route B).
Scheme 1. Aims of the Present Work
Scheme 2. Preparation of Phenyglycidyl Propargyl Ethers 1aÀg
Herein, we report that enantiopure compounds invol-
ving triazole rings fused to seven-membered heterocycles
(oxepanes, thiepanes, and azepanes) can be easily obtained
from the corresponding propargyl derivatives (ethers,
thioethers, and amines) of phenylglycidol in a two-step,
one-pot operation, which is not mediated by any metallic
source (Scheme 1). Despite the potential interest of these
heterocyclic systems in medicinal chemistry,10 arising from
its close structural similarity with benzodiazepine drugs
such as Triazolam, Alprazolam (Trankimazin, Xanax),
and Estazolam (Figure 1), synthetic methods for their
preparation are scarce,9c,f,10b,11 and all chiral approaches
to these compounds rely on the construction of the mole-
cules on carbohydrate educts.12
The results obtained in the preparation of these ethers
are summarized in Table 1.
Table 1. Preparation of Phenyglycidyl Propargyl Ethers 1aÀg
entry
R
method
yield [%]
product
1
2
3
4
5
6
7
H
A
A
A
A
A
B
Ba
86
80
78
80
85
53
74
1a
1b
1c
1d
1e
1f
Me
Ph
2-naphthyl
n-pent
CH2OPMB
CH2OH
1g
a Obtained by deprotection of 1f with DDQ.
With ethers 1aÀg in hand, the stage was set to search for
the optimal reaction conditions for the planned cascade
process, which was carried out with 1a as the model
substrate. At this point, it is worth mentioning that since
the very beginning it became apparent that the kinetics
governing the two consecutive reactions rendered isolation
of the intermediate azido alcohol 2a a hopeless task. Thus,
no reaction conditions could be found where 2a could be
formed without concomitant generation of significant
amounts of the cyclization product 3a.13 Nevertheless, this
only played to our advantage, since fine-tuning of reaction
conditions for the two consecutive processes would allow
the transformation to be carried out in a one-pot manner,
thus avoiding the isolation of potentially dangerous
organic azides.
Figure 1. Benzodiazepine drugs involving triazole substructures.
For the preparation of oxepane-type products, propar-
gyl ethers of phenylglycidol (1aÀg) were prepared by two
(9) (a) Oliva, A. I.; Christmann, U.; Font, D.; Cuevas, F.; Ballester,
ꢀ
P.; Buschmann, H.; Torrens, A.; Yenes, S.; Pericas, M. A. Org. Lett.
2008, 10, 1617. (b) Balducci, E.; Belluci, L.; Petricci, E.; Taddei, M.; Tafi,
A. J. Org. Chem. 2009, 74, 1314. (c) Declerck, V.; Toupet, L.; Martinez,
J.; Lamaty, F. J. Org. Chem. 2009, 74, 2004. (d) Chowdhury, C.;
Mukherjee, S.; Das, B.; Achari, B. J. Org. Chem. 2009, 74, 3612. (e)
Li, R.; Jansen, D. J.; Datta, A. Org. Biomol. Chem. 2009, 7, 1921. (f)
Brawn, R. A.; Welzel, M.; Lowe, J. T.; Panek, J. S. Org. Lett. 2010, 12,
336.
(10) (a) Hein, C. D.; Liu, X. M.; Wang, D. Pharm. Res. 2008, 25,
2216. (b) Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852.
(11) (a) Padwa, A.; Ku, A.; Ku, H.; Mazzu, A. J. Org. Chem. 1978, 43,
66. (b) Orlek, B. S.; Sammes, P. G.; Weller, D. J. Tetrahedron 1993, 49,
8179. (c) Orlek, B. S.; Sammes, P. G.; Weller, D. J. J. Chem. Soc., Chem.
Commun. 1993, 607. (d) Garanti, L.; Molteni, G.; Zecchi, G. Heterocycles
1994, 38, 291. (e) Alajarın, M.; Cabrera, J.; Pastor, A.; Villalgordo, J. M.
Tetrahedron Lett. 2007, 48, 3495.
The first efforts toward optimization focused on the
solvent. Here, the choice was quite narrow since we wanted
(12) (a) Tripathi, S.; Singha, K.; Achari, B.; Mandal, S. Tetrahedron
2004, 60, 4959. (b) Hotha, S.; Anegundi, R. I.; Natu, A. A. Tetrahedron
Lett. 2005, 46, 4585. (c) Chandrasekhar, S.; Rao, C. L.; Nagesh, C.; Reddy,
C. R.; Sridhar, B. Tetrahedron Lett. 2007, 48, 5869. (d) Anegundi, R. I.;
Puranik, V. G.; Hotha, S. Org. Biomol. Chem. 2008, 6, 779. (e) Jarosz, S.;
Lewandowski, B.; Listkowski, A. Synthesis 2008, 913.
(13) Throughout the rest of the work no intermediates were isolated
other than 2a. For the complete characterization of 2a, see Supporting
Information.
Org. Lett., Vol. 13, No. 19, 2011
5045

the reaction to take place under homogeneous conditions.
Thus, onlyMeCN, DMF, andt-BuOH/H2O werefound to
fulfill the above condition and were subsequently tested
(Table 2). Very disappointing results were recorded with
polar aprotic solvents (entries 1 and 2) under both purely
thermal and microwave promoted reaction conditions.
Even the attempt of promoting epoxide ring opening in
acetonitrile with Lewis acid catalysis (LiClO4)14 led to
impractical reaction mixtures after prolonged reaction
times (entry 3).
Table 3. Preparation of (7R,8R)-8-Phenyl-4,6,7,8-tetrahydro-
[1,2,3]triazolo[5,1-c][1,4]oxazepin-7-ols 3bÀg by Cascade
Epoxide Ring Opening plus AAC Reaction from
Phenyglycidyl Propargyl Ethers 1bÀg
On the contrary, reaction in t-BuOH/H2O occurred
under mild conditions to afford 3a, but it required 18 h
at 100 °C for complete conversion (entry 4). Interestingly,
reaction times could be significantly reduced by perform-
ing the cascade process under microwave irradiation (entry 5).
The reaction conditions employed in this experiment
(3 equiv of NaN3 in t-BuOH/H2O under MW irradiation)
were considered optimal and were used for the rest of this
study.
time
[h]
yield
[%]
entry
R
product
1
2
3
4
5
6
Me
Ph
2.5
1.5
2
60
80
68
70
63
60
3b
3c
3d
3e
3f
1-naphthyl
n-pentyl
1.5
1.5
2
CH2OPMB
CH2OH
3g
as single diastereoisomers having the trans configuration,
as indicated by NMR analysis (the diagnostic methine
proton R to phenyl appeared in all cases as a doublet at ca.
6.5 ppm with J = 4.6À4.7 Hz).15 This stereochemical
assignment could be confirmed by X-ray diffraction in
the case of 3f (Figure 2). Given the very close similarity
between the relevant parts of the NMR spectra of 3aÀg
(see above), the trans configuration was confirmed for the
rest of the series.
Table 2. Optimization of the Reaction Conditions for the
Cascade Process Leading to 3a
temp
time
[h]
entry
solvent
DMF
[°C]
1a/2a/3a
1
95
100
75
0.5
12
24
18
3
100:0:0 (MW)
100:0:0
2
MeCN
3a
4
MeCN
13:46:41
t-BuOH/H2O
t-BuOH/H2O
100
100
0:0:100
5b
0:0:100 (MW)
Figure 2. X-ray structure of (7R,8R)-3f.
a Reaction performed with NaN3 (2.0 equiv) and LiClO4 (1.2 equiv).
b With the optimal conditions, 3a was isolated in 70% isolated yield.
The glycidyl propargylamines and thioethers 4aÀd re-
quired for the preparation of the analogous azepane and
thiepane systems 5aÀd (Table 4) were easily prepared from
phenylglycidyl p-toluenesulfonate (see Supporting Infor-
mation). As expected, substrates 4aÀd underwent regiose-
lective epoxide ring opening with concomitant AAC to
afford 5aÀd when submitted to microwave heating with
3 equiv of NaN3, as shown in Table 4.
As already noted for the formation of 3aÀg, the cascade
process triggered by the ring opening of 4aÀd with azide
took place in a stereospecific manner involving inversion
at the benzylic carbon. Thus, reaction products 5aÀd
were again obtained as single trans diastereomers accord-
ing to NMR analysis. For the preparation of drug-like
With these optimized conditions the scope of the reac-
tion with internal alkynes was investigated. However,
although the reaction proved quite general with respect
to substrate modification at the alkyne fragment, higher
temperatures were required to achieve full conversion of
internal alkynes in reasonable reaction times. In fact, this
parameter had to be fine-tuned for each substrate to
preclude formation of decomposition products. The best
conditions found for the two-step azide substitutionÀAAC
of substrates 1bÀg are outlined in Table 3.
As can be seen, good yields were obtained in all cases for
the considered two-step process (yields per individual step
are in the 80À90% range). It is worth mentioning that all
products obtained in the course of this study were formed
(14) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J. Org. Chem. 1993, 58, 1221.
(15) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L.
Tetrahedron 1994, 50, 9471.
5046
Org. Lett., Vol. 13, No. 19, 2011

In conclusion, a straightforward procedure for the
generation in enantiopure form of bicyclic systems
featuring a triazole ring fused to a seven-membered
heterocycle (oxepane, azepane, or thiepane) through a
cascade process involving regioselective and stereo-
specific epoxide ring opening with azide plus a cop-
per-free intramolecular AAC reaction has been
developed.16 The highly modular character of the re-
sulting bicyclic systems, which offer up to four readily
fine-tunable points of diversity, together with its po-
tential as enantiopure benzodiazepine analogs, pro-
vides these substances with additional interest.
Table 4. Preparation of [1,2,3]Triazolo[5,1-c][1,4]diazepin-7-ols
and [1,2,3]Triazolo[5,1-c][1,4]thiazepin-7-ols 5aÀd by Cascade
Epoxide Ring Opening plus AAC Reaction from Derivatives
4aÀd
temp
t
yield
[%]
Acknowledgment. This work was funded by MICINN
(Grant CTQ2008-00947/BQU), DIUE (Grant 2009SGR623),
Consolider Ingenio 2010 (Grant CSD2006-0003), and the
ICIQ Foundation. The authors gratefully acknowledge
ꢁ
M. Martınez Belmonte, Eduardo Escudero-Adan, and
J. Benet-Buchholz (X-ray diffraction unit, ICIQ) as well as
entry
R
X
[°C]
[h]
product
1
2
3
4
H
NH
NBn
NBu
S
110
130
130
140
2.5
3
60
70
85
53
5a
5b
5c
5d
H
H
3
Ph
1.5
ꢁ
ꢁ
G. Gomez Castresana and G. Gonzalez (NMR spectro-
scopy unit, ICIQ) for their invaluable help with X-ray
diffraction and NMR techniques.
[1,2,3]triazolo[5,1-c][1,4]diazepin-7-ols, such as 5bÀc, the
unsubstituted NÀH derivative 5a could be considered as a
convenient relay; however, purification of this compound
is problematic (see Supporting Information) and, although
crude 5a has been successfully converted into 5b by
alkylation, it is advisible to prepare derivatives 5 using
phenylglycidylp-toluenesulfonateasthesourceofdiversity
(see Scheme 2, route B).
Supporting Information Available. Detailed experi-
mental procedures, characterization data, and copies
of H and 13C NMR spectra of all new compounds.
X-ray crystalographic data (CIF) for 3f. This material
is available free of charge via the Internet at http://
pubs.acs.org.
1
(16) Patent pending.
Org. Lett., Vol. 13, No. 19, 2011
5047