Synthesis of [1,2,3]-triazolo[1,5-a][1,4]benzodiazepines via an unprecedented one-pot Cu-catalyzed azidation-cyclization reaction

Article abstract of DOI:10.1016/j.tet.2013.03.031

A novel three-step approach leading to [1,2,3]-triazolo[1,5-a][1,4] benzodiazepines in moderate to good yields has been developed. The key step is an unprecedented one-pot Cu-catalyzed azidation-cyclization reaction of ortho-bromobenzylpropargylamines.

Full text of DOI:10.1016/j.tet.2013.03.031

Tetrahedron xxx (2013) 1e7
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Tetrahedron
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Synthesis of [1,2,3]-triazolo[1,5-a][1,4]benzodiazepines via an
unprecedented one-pot Cu-catalyzed azidationecyclization reaction
*
Geert Hooyberghs, Hendrik De Coster, Dipak D. Vachhani, Denis S. Ermolat’ev ,
*
Erik V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F,
B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel three-step approach leading to [1,2,3]-triazolo[1,5-a][1,4]benzodiazepines in moderate to good
yields has been developed. The key step is an unprecedented one-pot Cu-catalyzed azidationecyclization
reaction of ortho-bromobenzylpropargylamines.
Received 10 January 2013
Received in revised form 6 March 2013
Accepted 8 March 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Medium-sized ring
Benzodiazepine
Tandem reaction
1. Introduction
Structurally novel and diverse heterocycles are very useful in
drug discovery and related fields. Among the large varieties of
heterocycles, 1,4-benzodiazepines have been integral parts of many
drugs,1 therapeutic leads,2 and bioactive naturally occurring sub-
stances.3 This structural moiety is the archetypal privileged struc-
ture as defined by Evans in 1988.4 Compounds possessing the 1,4-
benzodiazepine scaffold show a broad range of biological activi-
ties. They have been described as mimetics of b a-heli-
-turns5 and
Fig. 1. Drugs containing the [1,2,4]-triazolo-[4,3-a][1,4]benzodiazepine scaffold.
ces6 and they bind to a multitude of targets, as e.g., ligand-gated ion
channels, enzymes, and G-protein coupled receptors.7 The spectrum
of therapeutic activities has further been enhanced through the
development of heterocyclic fused 1,4-benzodiazepines. This has
resulted in the discovery of clinically and commercially successful
drugs used for the treatment of diseases of the central nervous
system (CNS) and other diseases. The most notable are the tri-
azolobenzodiazepines alprazolam (1a), estazolam (1b), and tri-
azolam (1c) (Fig. 1) showing anxiolytic (1a, b)8 or anti-depressant
(1c)9 activity.
limited to terminal or activated acetylenes. In this paper we de-
scribe the first in situ azidationecyclization process of ortho-bro-
mobenzylpropargylamines 7. The desired starting compounds can
easily be generated via A3-coupling.11 Based on our previous re-
search12 we transformed the known literature protocol for the A3-
coupling of bromobenzylamines 613 to a fast MW-assisted protocol
(Scheme 1). The implementation of a multi-component reaction
allows the rapid construction of a library of diversely substituted
propargylamines.14 The bromobenzylamines 6 are easily accessible
via reductive amination of ortho-bromoaldehyde 3 and a suitable
primary amine 2 (Scheme 1).
Recently several articles about protocols leading to nitrogen
containing rings fused with triazoles have been published.10 These
protocols are mainly based on the sequential synthesis of the tri-
azole followed by Ullmann coupling. However this strategy is
2. Results and discussion
A convenient method for the preparation of aryl azides is the
Ullmann-type coupling of aryl halides with NaN3 using CuI as
* Corresponding authors. Tel.: þ32 16 32 74 0; fax: þ32 16 32 79 90; e-mail
address: erik.vandereycken@chem.kuleuven.be (E.V. Van der Eycken).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.031
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2
G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
Table 2
Scope and limitationsa
Entry
Compd.
R1
R2
R3
Yield (%)b
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
iBu
iPr
Tolyl
Pent
Pr
Ph
82
49
53
49
58
43
48
40
54
45
77
53
71
56
57
58
58
d
iBu
CyPr
Hep
Bu
Ph
Ph
Ph
Ph
Ph
Tol
Scheme 1. Retrosynthetical analysis for the starting ortho-bromoporpargylamines.
Pent
Bu
Bn
Bn
Bn
Bn
PMB
Bn
PMB
Bn
PMB
PMB
Bn
Pr
catalyst.15 Our aim is to perform the azidation of the aryl-bromide
and to react the obtained ortho-azidobenzylpropargylamine in situ
with the acetylene to yield the [1,2,3]-triazolo[1,5-a][1,4]benzodi-
azepines (8) (Table 1). The core of this structure has previously been
described, although with a limited substitution pattern.16 Our ap-
proach would result in the introduction of various substituents at
the triazole ring, the C3- and the N4-position. The optimization of
the reaction parameters for the azidationecyclization process was
performed with ortho-bromobenzylpropargylamine 7a, using NaN3
with CuI as catalyst and DMSO as solvent. The reaction resulted in
comparable yields when performed at 120 ꢀC and 150 ꢀC (Table 1,
entries 1 and 2). Changing the solvent from DMSO to DMF (Table 1,
entry 3) resulted in similar yields, while using NMP gave lower
yields (Table 1, entry 4). When the reaction was run for a longer
time, the yields dropped (Table 1, entries 5 and 6). Subsequently we
screened different copper catalyst as CuCl, CuBr, and Cu(I)OTf. Only
CuBr gave similar yields as CuI (Table 1, entries 7e9). This is in
accordance with the observations of Shinoda et al.15 Changing the
catalyst loading from 10 mol % to 20 mol % did not alter the yield
(Table 2, entry 10). To further improve the reaction we enhanced
the nucleophilicity of the azide by addition of 15-crown-5
(2.5 equiv). Performing the reaction at 150 ꢀC resulted in an im-
proved yield (Table 1, entry 11). Though when running the reaction
for a longer time the yields dropped (Table 1, entry 13). However,
when the reaction was performed at a slightly lower temperature of
120 ꢀC but for a prolonged time (32 h), a good yield of 82% was
obtained (Table 1, entry 12). When the reaction was run under
microwave irradiation for 3 h the yield was only 28% (Table 1, entry
14). Without any catalyst no desired product is formed (Table 1,
iPr
Et
Pent
Pr
Pr
Pr
Et
9
10
11
18
13
14
15
16
17
18
Tol
p-EtPh
p-PentPh
Tol
Ph
Ph
Pr
iBu
iBu
Oct
Bu
Ph
PMB
3,4-diOMeBn
Bn
Ph
Ph
a
Reactions were run on a 0.25 mmol scale, employing the optimized conditions.
Isolated yields.
b
entry 15). We conclude that the optimal conditions for the reaction
are: sodiumazide (2.5 equiv) at 120 ꢀC for 32 h in DMSO as solvent
with CuI (20 mol %) as catalyst and 15-crown-5 (2.5 equiv) as
additive.
With these conditions in hand we started to explore the scope of
our process. A small library of [1,2,3]-triazolo[1,5-a][1,4]benzodi-
azepines was generated. At the amine position we introduced both
alkyl (Table 2, entries 1e4) and benzyl (Table 2, entries 5e17)
substituents. On the propargylic position the reaction proceeded
well with alkyl substituents (Table 2, entries 1, 3, and 5e17) and
with a phenyl substituent (Table 2, entry 2 and 4). Regarding the
acetylene substituent the reaction is tolerant to both aryl (Table 2,
entries 1, 6e17) and alkyl (Table 2, entries 2e4) groups. The desired
products are obtained in moderate to good yields as a single di-
astereoisomer. In the case of a benzyl substituent on the amine
position and an aryl residue on both other positions, no desired
products was formed and only decomposition was observed (Table
2, entry 18). This could be due to increased sterical hindrance. The
chlorine analogue of 7a failed to react.
A plausible reaction mechanism is shown in Scheme 2. Fol-
lowing pathway I an azideealkyne [3þ2] cycloaddition in the
presence of CuI takes place, resulting in the formation of the NeCu
species B, which subsequently inserts into the aryl halogen bond
via Ullmann coupling leading to the desired product 8. This path-
way occurs in the case of activated or terminal acetylenes10 and is
therefore most probably not operating in our case. Following
pathway II, the process starts with a copper-catalyzed azidation of
Table 1
Optimization of the procedurea
Entry
Catalyst
(mol %)
Solvent
Temp
(ꢀC)
Time
(h)
Additive
Yieldb
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (20)
CuCl (10)
CuBr (10)
Cu(I)OTf (10)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
d
DMSO
DMSO
DMF
NMP
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
150
120
150
150
150
150
150
150
150
150
120
150
120
150
24
24
24
24
48
32
24
24
24
24
12
32
24
3d
d
62
70
70
54
27
40
32
62
44
71
77
82
63
28
d
d
d
d
d
d
d
d
9
d
10
11
12
13
14
15
d
15-Crown-5c
15-Crown-5c
15-Crown-5c
15-Crown-5c
d
24
a
Reactions were run on a 0.25 mmol scale with NaN3 (2.5 equiv) in the indicated
solvent (1 mL).
b
c
Isolated yields.
2.5 equiv were used.
The reaction was run under microwave irradiation at 300 W maximum power.
d
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G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
3
doublet, t¼triplet, m¼multiplet. The 13C NMR spectra are proton
decoupled. High-resolution mass spectra were recorded by using
double-focusing magnetic sector analyzer and at an ion source
temperature 150e250 ꢀC as required. High-resolution EI-mass
spectra were performed with a resolution of 10,000. The [M]þ
mass for products 7aer and 8aeq was never observed due to in-
stability of the compound in EI. For all products the [MꢁR2]þ
fragment was observed.
4.2. General procedure for the MW-assisted synthesis of or-
tho-bromobenzylpropargylamines
To a solution of amine (1 equiv) in toluene (0.5 mL) in a MW vial
with magnetic stirrer was added aldehyde (1.1 equiv), terminal
alkyne (1.5 equiv) and CuBr (10 mol %). The reaction was irradiated
at 100 ꢀC for 30 min. The reaction mixture was directly purified via
column chromatography on silica gel using a mixture of ethyl ac-
etate and heptane (5/95) as eluant.
Scheme 2. Plausible reaction pathways.
the aryl-moiety yielding intermediate A, followed by an intra-
molecular thermal [3þ2] cycloaddition leading to product 8.
An indication that the reaction is presumably running via
pathway II is given by the observation that when compound 7s (i.e.,
the debrominated analogue of 7a) is submitted to the optimized
reaction conditions, only starting material was received (Scheme 3).
4.2.1. N-(2-Bromobenzyl)-N-(propan-2-yl)-4-dimethyl-1-phenylpent-
1-yn-3-amine
(800 mg, 3.32 mmol, 1 equiv), isobutyraldehyde (328
1.1 equiv), phenylacetylene (554 l, 4.98 mmol, 1.5 equiv), and CuBr
(7a). N-(2-Bromobenzyl)-2-methylpropan-1-amine
ml, 3.65 mmol,
m
(47.5 mg, 0.332 mmol,10 mol %). The product was obtained as a yellow
oil (1.016 g, 77%). 1H NMR (CDCl3): 7.64 (1H, d, J¼7.5), 7.50 (3H, m),
7.29 (4H, m), 7.07 (1H, m), 3.80 (2H, m), 3.14 (1H, d, J¼10.2), 2.49 (1H,
dd, J¼12.6 and 4.0), 2.18 (1H, m), 1.86 (2H, m), 1.08 (3H, d, J¼6.4), 1.04
(3H, d, J¼6.4), 0.98 (3H, d, J¼6.4), 0.87 (3H, d, J¼6.8); 13C NMR (CDCl3):
139.1, 132.6, 131.8, 130.8, 128.2, 128.1, 127.7, 127.1, 124.5, 123.7, 87.7,
85.8, 61.1, 59.8, 55.8, 30.9, 26.2, 21.3, 21.04, 20.95, 20.3; HRMS (EI): m/z
calcd for C20H21NBr [MꢁCH(CH3)2]: 354.0857; found: 354.0874.
4.2.2. N-(2-Bromobenzyl)-3-cyclopropyl-N-(propan-2-yl)-1-
(4-methylphenyl)prop-2-yn-1-amine (7b). N-(2-Bromobenzyl)-2-
methylpropan-1-amine (200 mg, 0.83 mmol, 1 equiv), para-
Scheme 3. No reaction of the benzylpropargylamine lacking the bromide.
3. Conclusion
tolylaldehyde (108
ml, 0.91 mmol, 1.1 equiv), ethynylcyclopropane
(106 l, 1.25 mmol, 1.5 equiv), and CuBr (11.9 mg, 0.083 mmol,
m
In conclusion, we have elaborated a novel procedure for the
synthesis of a new class of substituted [1,2,3]-triazolo[1,5-a][1,4]
benzodiazepines employing an azidationecyclization sequence.
The resulting products are obtained in moderate to good yields.
Diversity is secured by the generation of the starting ortho-bro-
mobenzylpropargylamines via A3-coupling reaction.
10 mol %). The product was obtained as a yellow oil (281 mg, 83%).
1H NMR (CDCl3): 7.59 (1H, d, J¼7.5), 7.48 (3H, d, J¼7.2), 7.25 (1H, m),
7.07 (3H, m), 4.66 (1H, s), 3.64 (2H, m), 2.41 (1H, dd, J¼12.6, 4.0),
2.31 (3H, s), 1.99 (1H, dd, J¼12.2, 10.7), 1.76 (1H, m), 1.39 (1H, m),
0.81 (11H, m); 13C NMR (CDCl3): 139.4, 137.0, 132.9, 131.1, 128.8,
128.7, 128.4, 127.4, 124.8, 91.9, 77.7, 77.3, 76.9, 70.9, 59.0, 56.7, 55.3,
26.3, 21.4, 21.0, 9.00, 8.97, 0.31; HRMS (EI): m/z calcd for C17H21NBr
[Mꢁ(C6H5)CH3]: 318.0857; found: 318.0835.
4. Experimental part
4.1. General information
4.2.3. N-(2-Bromobenzyl)-N-pentylpentadec-7-yn-6-amine (7c). N-
(2-Bromobenzyl)pentan-1-amine (200 mg, 0.78 mmol, 1 equiv),
All solvents and reagents were purchased from commercial
sources and were used without prior purification. All microwave
irradiation experiments were carried out in a monomode micro-
wave apparatus, operating at a frequency of 2.45 GHz with con-
tinuous irradiation power from 0 to 300 W. The reactions were
carried out in 10 mL glass tubes, sealed with snap caps and placed
in the microwave cavity. The reaction mixture was irradiated at
a required ceiling temperature using maximum power for the
stipulated time, and the reaction mixture temperatures were
measured by the external IR sensor. The reaction tube was cooled to
ambient temperature with air jet cooling. TLC analysis was per-
formed on aluminum backed plates. The products were purified by
silica gel (200e300 mesh) column chromatography. NMR spectra
were recorded at 300 MHz (1H and 13C). The 1H and 13C chemical
shifts are reported in parts per million relative to tetramethylsilane
using the residual solvent signal as the internal reference. The
following abbreviation were used to designate chemical shift
multiplicities: s¼singlet, bs¼broad singlet, d¼doublet, dd¼double
hexanal (106 ml, 0.86 mmol, 1.1 equiv), 1-nonyn (192 ml, 1.172 mmol,
1.5 equiv), and CuBr (11.2 mg, 0.078 mmol, 10 mol %). The product
was obtained as a yellow oil (326 mg, 88%). 1H NMR (CDCl3): 7.57
(1H, d, J¼7.5), 7.49 (1H, m), 7.25 (1H, m), 7.06 (1H, m), 3.69 (2H,m),
3.38 (1H, t, J¼7.5), 2.46 (2H, m), 2.23 (2H, td, J¼6.6,1.9),1.52 (9H, m),
1.24 (15 H, m), 0.88 (9H, m); 13C NMR (CDCl3): 139.8, 132.5, 130.6,
127.9, 127.0, 124.2, 84.6, 78.7, 55.3, 53.3, 51.6, 34.4, 31.9, 31.5, 29.7,
29.2, 28.9, 28.8, 28.0, 26.4, 22.7, 36.4, 22.7, 22.6, 18.7, 14.12, 14.07;
HRMS (EI): m/z calcd for C22H33NBr [MꢁC5H11]: 390.1796; found:
390.1790.
4.2.4. N-(2-Bromobenzyl)-N-(3-ethoxypropyl)-1-(4-fluorophenyl)-
pent-2-yn-1-amine (7d). N-(2-Bromobenzyl)-3-ethoxypropan-1-
amine (200 mg, 0.74 mmol, 1 equiv), 4-fluorobenzaldehyde
(200 mg, 0.81 mmol, 1.1 equiv), 1-heptyn (105 mg, 1.1 mmol,
1.5 equiv), and CuBr (10.5 mg, 0.074 mmol, 10 mol %). The product
was obtained as a yellow oil (290 mg, 83%). 1H NMR (CDCl3): 7.53
(4H, m), 7.26 (1H, td, J¼7.4(ꢂ2) and J¼0.9), 7.07 (1H, td, J¼7.5 (ꢂ2)
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G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
and J¼1.5), 6.98 (2H, t, J¼8.7), 4.66 (1H, s), 3.73 (2H, m), 3.33 (4H,
m), 2.51 (2H, m), 2.37 (2H, td, J¼6.9(ꢂ2) and J¼2.1), 1.74 (2H, m),
1.63 (2H, m), 1.49 (2H, m), 1.37 (2H, m), 1.09 (3H, t, J¼7.0), 0.94 (3H,
t, J¼7.2); 13C NMR (CDCl3): 163.7, 160.5, 138.7, 135.61, 135.58, 132.8,
131.0, 129.9, 128.4, 127.2, 124.6, 114.7, 114.5, 88.9, 74.9, 68.7, 66.0,
56.1, 55.2, 47.4, 31.2, 28.8, 28.2, 22.3, 18.8, 15.2, 14.1; HRMS: m/z
calcd for C15H25NOBr [MꢁC5H4F]: 378.1433; found: 378.1421.
7.29 (6H, m), 7.04 (1H, m), 6.84 (2H, m), 3.82 (3H, m), 3.74 (3H, s),
3.63 (1H, t, J¼7.5), 3.52 (1H, d, J¼13.6), 1.73 (2H, m), 1.46 (2H, m),
0.83 (3H, t, J¼7.3); 13C NMR (CDCl3): 158.8, 139.1, 132.8, 132.0, 131.6,
130.7, 130.2, 128.4, 128.3, 128.0, 127.4, 124.7, 123.7, 113.8, 88.3, 85.5,
55.3, 55.0, 54.5, 52.5, 36.1, 20.0, 13.9; HRMS: m/z calcd for
C24H21NOBr [MꢁC3H7]: 418.0807; found: 418.0819.
4.2.10. N-Benzyl-N-(2-bromobenzyl)-4-(4-methylphenyl)hex-5-yn-
4-amine (7j). N-Benzyl-1-(2-bromophenyl)methanamine (300 mg,
1.1 mmol, 1 equiv), butanal (86 mg, 1.2 mmol, 1.1 equiv), p-tolyla-
cetylene (189 mg, 1.6 mmol, 1.5 equiv), and CuBr (15.7 mg,
0.11 mmol, 10 mol %). The product was obtained as a yellow oil
(421 mg, 87%). 1H NMR (CDCl3): 7.66 (1H, m), 7.48 (1H, d, J¼7.9),
7.41 (4H, d, J¼7.9), 7.24 (4H, m), 7.10 (2H, d, J¼7.9), 7.03 (1H, m), 3.86
(3H, m), 3.61 (2H, m), 2.32 (3H, m), 1.73 (2H, m), 1.47 (2H, dq,
J¼14.5, 7), 0.82 (3H, t, J¼7.3); 13C NMR (CDCl3): 139.5, 138.9, 137.8,
132.6, 131.7, 130.5, 129.0, 128.8, 128.2, 128.1, 127.2, 126.9, 124.5,
120.5, 87.2, 85.4, 55.4, 54.5, 52.6, 36.0, 21.4; 19.8; 13.8; HRMS: m/z
calcd for C24H21NBr [MꢁC3H7]: 402.0857; found: 402.0839.
4.2.5. N-Benzyl-N-(2-bromobenzyl)-4-phenylhex-5-yn-4-
amine (7e). N-Benzyl-1-(2-bromophenyl)methanamine (400 mg,
1.45 mmol, 1 equiv), butanal (115 mg, 1.6 mmol, 1.1 equiv), phe-
nylacetylene (222 mg, 2.2 mmol, 1.5 equiv), and CuBr (20.7 mg,
0.15 mmol, 10 mol %). The product was obtained as a yellow oil
(512 mg, 82%). 1H NMR (CDCl3): 7.63 (1H, m), 7.51 (3H, m), 7.42 (2H,
m), 7.29 (7H, m), 7.07 (1H, m), 3.88 (3H, m), 3.58 (2H, m), 1.75 (2H,
m), 1.47 (2H, m), 0.83 (3H, m); 13C NMR (CDCl3): 139.9, 139.5, 138.8,
132.7, 132.6, 131.8, 130.5, 128.9, 128.8, 128.3, 128.22, 128.19, 127.9,
127.2, 126.9, 126.8, 124.5, 123.6, 88.0, 85.4, 55.4, 54.5, 52.6, 36.0,
19.8, 19.7, 13.8, 13.7; HRMS: m/z calcd for C23H19NBr [MꢁC3H7]:
388.0701; found: 388.0701.
4.2.11. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-4-(4-
4.2.6. N-Benzyl-N-(2-bromobenzyl)-4-methyl-1-phenylpent-1-yn-3-
amine (7f). N-Benzyl-1-(2-bromophenyl)methanamine (400 mg,
1.45 mmol,1 equiv), isobutyraldehyde (115 mg,1.6 mmol,1.1 equiv),
phenylacetylene (222 mg, 2.2 mmol, 1.5 equiv), and CuBr (20.7 mg,
0.15 mmol, 10 mol %). The product was obtained as a yellow oil
(330 mg, 67%). 1H NMR (CDCl3): 7.69 (1H, m), 7.52 (3H, m), 7.44 (2H,
d, J¼7.5), 7.30 (7H, m), 7.08 (1H, m), 3.87 (3H, m), 3.51 (1H, m), 3.14
(1H, m), 2.0 (1H, m), 1.05 (6H, d, J¼6.4); 13C NMR (CDCl3): 139.8,
139.4, 138.7, 132.7, 131.8, 130.5, 129.0, 128.9, 1283, 128.2, 128.21,
128.17, 127.8, 127.3, 127.0, 126.8, 124.6, 123.6, 87.3, 86.2, 60.1, 55.6,
54.6, 31.0, 21.0, 20.2; HRMS: m/z calcd for C23H19NBr [MꢁC3H7]:
388.0701; found: 388.0698.
methylphenyl)hex-5-yn-4-amine
(7k). 1-(2-Bromophenyl)-N-(4-
methoxybenzyl)methanamine (300 mg, 0.98 mmol, 1 equiv),
butanal (78 mg, 1.1 mmol, 1.1 equiv), p-tolylacetylene (171 mg,
1.5 mmol, 1.5 equiv), and CuBr (14.0 mg, 0.1 mmol, 10 mol %). The
product was obtained as a yellow oil (387 mg, 83%). 1H NMR
(CDCl3): 7.64 (1H, m), 7.46 (1H, m), 7.41 (2H, d, J¼8.3), 7.31 (2H, d,
J¼8.3), 7.25 (1H, t, J¼7.0), 7.09 (2H, d, J¼7.9), 7.01 (1H, td, J¼5.0, 1.5),
6.82 (2H, d, J¼8.7), 3.84 (3H, m), 3.70 (3H, s), 3.63 (1H, t, J¼7.5), 3.52
(1H, d, J¼13.6), 2.30 (3H, s), 1.73 (2H, m), 1.46 (2H, sxt, J¼7.5), 0.82
(3H, t, J¼7.3); 13C NMR (CDCl3): 158.6, 139.0, 137.8, 132.6, 131.7,
131.5, 130.5, 130.0, 129.0, 128.1, 127.2, 124.5, 120.5, 113.6, 87.3, 85.4,
55.1, 54.8, 54.3, 52.4, 36.0, 21.4, 19.8, 13.8; HRMS: m/z calcd for
C25H23NOBr [MꢁC3H7]: 432.0963; found: 432.0974.
4.2.7. N-Benzyl-N-(2-bromobenzyl)-4-phenylpent-4-yn-3-
amine (7g). N-Benzyl-1-(2-bromophenyl)methanamine (200 mg,
0.73 mmol, 1 equiv), propanal (46 mg, 0.8 mmol, 1.1 equiv), phe-
nylacetylene (111 mg, 1.1 mmol, 1.5 equiv), and CuBr (10.4 mg,
0.07 mmol, 10 mol %). The product was obtained as a yellow oil
(237 mg, 78%). 1H NMR (CDCl3): 7.64 (1H, m), 7.51 (3H, m), 7.42 (2H,
m), 7.29 (7H, m), 7.07 (1H, td, J¼7.5, 1.5), 3.88 (3H, m), 3.53 (2H, m),
1.78 (2H, m), 1.00 (3H, t, J¼7.3); 13C NMR (CDCl3): 139.9, 139.6,
138.8, 132.6,131.8, 130.5,128.84, 128.00, 128.3,128.22, 128.0,128.18,
127.9, 127.2, 126.9, 126.8, 124.5, 123.5, 87.8, 85.5, 55.5, 54.7, 54.5,
27.0, 11.4; HRMS: m/z calcd for C23H19NBr [MꢁC2H5]: 388.0701;
found: 388.0691.
4.2.12. N-Benzyl-N-(2-bromobenzyl)-4-(2-ethylphenyl)pent-4-yn-3-
amine (7l). N-Benzyl-1-(2-bromophenyl)methanamine (300 mg,
1.1 mmol, 1 equiv), propanal (70 mg, 1.2 mmol, 1.1 equiv), 2-
ethylphenylacetylene (212 mg, 1.6 mmol, 1.5 equiv), and CuBr
(15.7 mg, 0.11 mmol, 10 mol %). The product was obtained as
a yellow oil (428 mg, 98%). 1H NMR (CDCl3): 7.66 (1H, d, J¼7.5), 7.44
(5H, m), 7.26 (3H, m), 7.18 (1H, m), 7.11 (2H, d, J¼7.9), 6.99 (1H, m),
3.87 (3H, m), 3.56 (2H, m), 2.59 (2H, q, J¼7.5), 1.77 (2H, m), 1.19 (3H,
t, J¼7.5), 0.98 (3H, t, J¼7.3); 13C NMR (CDCl3): 144.4, 139.8, 139.1,
132.9, 132.1, 130.8, 129.1, 128.4, 128.4, 128.1, 127.5, 127.1, 124.6, 121.0,
87.2, 85.9, 55.7, 55.0, 54.8, 29.0, 27.3, 15.7, 11.7; HRMS: m/z calcd for
C25H23NBr [MꢁC2H5]: 416.1014; found: 416.1007.
4.2.8. N-Benzyl-N-(2-bromobenzyl)-4-phenyloct-7-yn-6-
amine (7h). N-Benzyl-1-(2-bromophenyl)methanamine (300 mg,
1.086 mmol, 1 equiv), hexanal (120 mg, 1.2 mmol, 1.1 equiv), phe-
nylacetylene (163 mg, 1.6 mmol, 1.5 equiv), and CuBr (16 mg,
0.1086 mmol, 10 mol %). The product was obtained as a yellow oil
(434.5 mg, 84%). 1H NMR (CDCl3): 7.63 (1H, m), 7.51 (3H, d, J¼6.8),
7.41 (2H, m), 7.28 (7H, m), 7.07 (1H, t, J¼2ꢂ7.5), 3.87 (3H, m), 3.56
(2H, m), 1.75 (2H, m), 1.46 (2H, m), 1.24 (4H, m), 0.84 (3H, m); 13C
NMR (CDCl3): 139.9, 139.6, 138.9, 132.6, 131.8, 128.91, 128.85, 128.3,
127.9, 127.2, 126.9, 123.6, 88.1, 85.4, 55.4, 55.0, 54.6, 52.8, 33.8, 31.4,
26.2, 26.0, 22.6, 14.0; HRMS: m/z calcd for C23H19NBr [MꢁC5H11]:
388.0701; found: 388.0695.
4.2.13. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-4-(2-
pentylphenyl)hex-5-yn-4-amine (7m). 1-(2-Bromophenyl)-N-(4-
methoxybenzyl)methanamine (300 mg, 0.98 mmol, 1 equiv),
butanal (78 mg, 1.1 mmol, 1.1 equiv), 2-pentylphenylacetylene
(253 mg, 1.5 mmol, 1.5 equiv), and CuBr (14.0 mg, 0.1 mmol,
10 mol %). The product was obtained as a yellow oil (434.6 mg, 83%).
1H NMR (CDCl3): 7.64 (1H, m), 7.48 (1H, d, J¼7.9, 7.43 (2H, d, J¼7.9),
7.30 (2H, m), 7.25 (1H, m), 7.12 (2H, d, J¼8.3), 7.04 (1H, td, J¼7.6,1.3),
6.83 (2H, d, J¼8.7), 3.82 (3H, m), 3.74 (3H, s), 3.62 (1H, t, J¼7.5), 3.52
(1H, d, J¼13.6), 2.58 (1H, t, J¼7.7), 1.75 (2H, m), 1.57 (2H, m), 1.45 6H,
m), 1.29 (12H, m), 0.88 (3H, t, J¼6.8), 0.82 (3H, t, J¼7.3); 13C NMR
(CDCl3): 158.6, 142.9, 139.0, 123.6, 131.7, 131.5, 130.5, 130.0, 128.4,
1128.1,127.2,124.5,120.7,113.6, 87.3, 85.4, 55.1, 54.8, 54.4, 52.4, 36.1,
35.8, 31.4, 31.0, 22.5, 19.8, 14.0, 13.8; HRMS: m/z calcd for
4.2.9. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-4-phenylhex-5-yn-
4-amine (7i). 1-(2-Bromophenyl)-N-(4-methoxybenzyl)methan-
amine (300 mg, 0.98 mmol, 1 equiv), hexanal (77.6 mg, 1.1 mmol,
1.1 equiv), phenylacetylene (143 mg, 1.5 mmol, 1.5 equiv), and CuBr
(14.0 mg, 0.1 mmol,10 mol %). The product was obtained as a yellow
oil (364 mg, 80%). 1H NMR (CDCl3): 7.65 (1H, d, J¼7.9), 7.50 (3H, m),
C29H31NOBr [MꢁC3H7]: 488.1589; found: 488.1608.
4.2.14. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-5-methyl-1-(4-
methylphenyl)hex-1-yn-3-amine (7n). 1-(2-Bromophenyl)-N-(4-
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G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
5
methoxybenzyl)methanamine (300 mg, 0.98 mmol, 1 equiv), iso-
butyraldehyde (93 mg, 1.1 mmol, 1.1 equiv), p-tolylacetylene
(171 mg, 1.5 mmol, 1.5 equiv), and CuBr (14.0 mg, 0.1 mmol,
10 mol %). The product was obtained as a yellow oil (408 mg, 85%).
1H NMR (CDCl3): 7.63 (1H, dd, J¼7.7, 1.3), 7.49 (1H, d, J¼7.9), 7.41
(2H, d, J¼7.9), 7.31 (2H, d, J¼8.7), 7.25 (1H, m), 7.11 (2H, J¼7.9), 7.04
(1H, td, J¼7.7, 1.5), 6.83 (2H, d, J¼8.7), 3.83 (2H, d, J¼3.0), 3.71 (5H,
m), 3.50 (1H, d, J¼13.6), 2.33 (3H, s), 1.89 (1H, m), 1.70 (1H, m), 1.55
(1H, m), 0.81 (3H, d, J¼6.8), 0.73 (3H, d, J¼6.8); 13C NMR (CDCl3):
158.6, 139.0, 137.9, 132.6, 131.7, 131.5, 130.7, 130.1, 129.0, 128.2, 127.2,
124.6, 120.5, 113.6, 87.4, 85.3, 65.9, 55.2, 54.8, 54.4, 50.6, 43.0, 24.8,
22.7, 22.2, 21.5, 15.3; HRMS: m/z calcd for C25H23NOBr [MꢁC4H9]:
432.0963; found: 432.0960.
127.1, 124.7, 123.3, 88.8, 84.7, 56.5, 55.0, 54.0; HRMS: m/z calcd for
23H19NOBr [MꢁC6H5]: 388.0701; found: 388.0691.
C
4.3. General procedure for the azidationecyclization reaction
An oven-dried 10 mL screwcap reaction vial was loaded with
ortho-bromobenzylpropargylamine (1 equiv), sodiumazide
(2.5 equiv), 15-crown-5 (2.5 equiv), CuI (20 mol %), DMSO (1 mL),
and a magnetic stirring bar. The vial was evacuated and then put
under Argon atmosphere. The reaction was heated in oilbath at
120 ꢀC for 32 h. After cooling down to ambient temperature
diethylether (25 mL) was added. The resulting mixture was washed
with water (3ꢂ25 mL) and brine (25 mL), dried over MgSO4, fil-
tered and concentrated in vacuo. The crude product was purified
via Silica gel column chromatography using a mixture of heptane/
ethyl acetate (8/2) as eluant.
4.2.15. N-Benzyl-N-((2-bromobenzyl)-5-methyl-1-phenyl)hex-1-yn-
3-amine (7o). N-Benzyl-1-(2-bromophenyl)methanamine (300 mg,
1.1 mmol, 1 equiv), isobutyraldehyde (102 mg, 1.2 mmol, 1.1 equiv),
phenylacetylene (167 mg, 1.6 mmol, 1.5 equiv), and CuBr (15.7 mg,
0.11 mmol, 10 mol %). The product was obtained as a yellow oil
(467 mg, 96%). 1H NMR (CDCl3): 7.64 (1H, d, J¼7.5), 7.51 (3H, m),
7.41 (2H, m), 7.26 (7H, m), 7.03 (1H, td, J¼7.6, 1.3), 3.87 (3H, m), 3.70
(1H, t, J¼7.3), 3.58 (1H, d, J¼13.6), 1.91 (1H, m), 1.71 (1H, m), 1.57
(1H, m), 0.81 (3H, d, J¼6.8), 0.73 (3H, d, J¼6.8); 13C NMR (CDCl3):
139.5, 138.8, 132.6, 131.8, 130.7, 129.0, 128.2, 127.9, 127.2, 127.0,
124.6, 123.6, 88.1, 85.3 65.9, 55.5, 54.6, 50.8, 433.0, 24.8, 22.7, 22.2,
15.3; HRMS: m/z calcd for C23H19NOBr [MꢁC4H9]: 388.0701; found:
388.0691.
4.3.1. 3-Phenyl-5-(2-methylpropyl)-4-(propan-2-yl)-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine
(8a). ortho-Bromobenzyl-
propargylamine 7a (100 mg, 0.251 mmol, 1 equiv), sodiumazide
(40.7 mg, 0.63 mmol, 2.5 equiv), 15-crown-5 (138.0 mg, 0.63 mmol,
2.5 equiv), and CuI (9.5 mg, 0.05 mmol, 20 mol %). The product was
obtained as an orange oil (81.9 mg, 82%). 1H NMR (CDCl3): 7.90 (1H,
d, J¼7.9), 7.74 (2H, m), 7.47 (6H, m), 3.75 (1H, d, J¼11.7), 3.58 (1H, d,
J¼10.5), 3.19 (1H, d, J¼11.7), 2.59 (1H, dd, J¼11.9 and 6.6), 2.37 (1H,
dd, J¼12.1 and 7.9),1.84 (1H, m),1.06 (1H, m), 0.97 (6H, d, J¼6.4), 0.89
(3H, d, J¼6.4), 0.22 (3H, d, J¼6.8); 13C NMR (CDCl3): 147.2, 137.8,
133.0, 131.0, 129.0, 128.7, 128.1, 121.7, 77.5, 76.6, 67.8, 65.0, 54.7, 33.2,
26.7, 21.1, 19.4; HRMS (EI): m/z calcd for C20H21N4 [MꢁCH(CH3)2]:
317.1766; found: 317.1770.
4.2.16. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-4-phenylundec-10-
yn-9-amine (7p). 1-(2-Bromophenyl)-N-(4-methoxybenzyl)meth-
anamine (300 mg, 0.98 mmol, 1 equiv), nonal (153 mg, 1.1 mmol,
1.1 equiv), phenylacetylene (143, 1.5 mmol, 1.5 equiv), and CuBr
(14.0 mg, 0.1 mmol, 10 mol %). The product was obtained as a yellow
oil (348 mg, 67%). 1H NMR (CDCl3): 7.64 (1H, d, J¼7.5), 7.50 (3H, m),
7028 (6H, m), 7.04 (1H, m), 6.83 (2H, d, J¼8.7), 3.82 (3H, m), 3.74 (3H,
s), 3.61 (1H, t, J¼7.5), 3.52 (1H, d, J¼13.6), 1.75 (2H, m), 1.44 (2H, m),
1.24 (10H, m), 0.87 (3H, t, J¼6.8); 13C NMR (CDCl3): 158.8, 139.1, 132.7,
131.9, 131.6, 130.7, 130.1, 128.4, 128.2, 127.9, 127.3, 124.6, 123.7, 88.3,
85.4, 55.3, 54.9, 54.5, 52.7, 33.9, 32.0, 29.6, 29.4, 29.3, 26.6, 22.8, 14.2;
HRMS: m/z calcd for C24H22NOBr [MꢁC8H17]: 418.0807; found:
418.0819.
4.3.2. 3-Cyclopropyl-4-(40-methylphenyl)-5-(2-methylpropyl)-
5,6-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8b). ortho-
Bromobenzylpropargylamine 7b (100 mg, 0.244 mmol, 1 equiv),
sodiumazide (39.7 mg, 0.61 mmol, 2.5 equiv),15-crown-5(134.2 mg,
0.61 mmol, 2.5 equiv), and CuI (9.5 mg, 0.05 mmol, 20 mol %). The
product was obtained as an orange oil (51.2 mg, 49%). 1H NMR
(CDCl3): 7.85 (1H, d, J¼7.5), 7.37 (1H, m), 7.29 (2H, m), 7.12 (2H, m),
6.99 (2H, d, J¼7.5); 4.83 (1H, s), 3.72 (2H, m), 2.39 (1H, m), 2.26 (4H,
m), 1.95 (1H, m), 1.21 (1H, ddd, J¼13.0, 8.5, 4.9), 0.98 (4H, d, J¼6.4),
0.91 (4H, d, J¼6.4), 0.74 (2H, m); 13C NMR (CDCl3): 147.3, 137.1,
136.92, 136.90, 133.9, 130.3, 129.5, 128.8, 128.4, 128.2, 127.9, 122.2,
32.1, 60.9, 52.7, 26.5, 21.03, 21.00, 7.22, 7.19, 5.9.; HRMS (EI): m/z calcd
for C17H21N4 [MꢁC6H5CH3]þ: 281.1766; found: 281.1742.
4.2.17. N-(2-Bromobenzyl)-N-(3,4-dimethoxybenzyl)-4-phenylhept-
6-yn-5-amine (7q). 1-(2-Bromophenyl)-N-(3,4-dimethoxybenzyl)
methanamine (300 mg, 0.91 mmol, 1 equiv), hexanal (86 mg,
1.0 mmol, 1.1 equiv), phenylacetylene (139 mg, 1.4 mmol, 1.5 equiv),
and CuBr (13.0 mg, 0.09 mmol,10 mol %). The product was obtained
as a yellow oil (414 mg, 90%). 1H NMR (CDCl3): 7.63 (1H, dd, J¼7.5,
1.5), 7.51 (3H, m), 7.31 (4H, m), 7.09 (1H, td, J¼7.5, 1.5), 6.98 (1H, d,
J¼1.5), 6.92 (1H, m), 6.80 (1H, m), 3.87 (3H, s), 3.86 (3H, s), 3.82 (3H,
m), 3.62 (1H, t, J¼7.5), 3.52 (1H, d, J¼13.9), 1.78 (2H, m), 1.45 (2H,
m), 1.26 (2H, m), 0.86 (3H, t, J¼7.3); 13C NMR (CDCl3): 148.8, 148.0,
138.9, 132.7, 132.2, 131.8, 130.7, 128.3, 127.9, 127.2, 124.6, 123.6,
120.8, 112.0, 110.9, 88.1, 85.3, 55.9, 55.8, 55.1, 54.7, 53.0, 33.6, 28.9,
22.4, 14.1; HRMS: m/z calcd for C25H23NO2Br [MꢁC4H9]: 448.0912;
found: 448.0880.
4.3.3. 3-Heptyl-4-pentyl-5-pentyl-5,6-dihydro-4H-[1,2,3]triazolo
[1,5-a][1,4]benzodiazepine (8c). ortho-Bromobenzylpropargylamine
7c (100 mg, 0.216 mmol, 1 equiv), sodiumazide (35.1 mg,
0.54 mmol, 2.5 equiv), 15-crown-5 (118.8 mg, 0.54 mmol,
2.5 equiv), and CuI (8.2 mg, 0.043 mmol, 20 mol %). The product was
obtained as an orange oil (48.8 mg, 53%). 1H NMR (CDCl3): 7.86 (1H,
d, J¼7.9), 7.45 (3H, m), 3.86 (1H, br s), 3.72 (1H, d, J¼11.7), 3.30 (1H,
d, J¼12.4), 2.66 (4H, m), 1.74 (3H, m), 1.34 (13H, m), 1.05 (6H, m),
0.91 (7H, m), 0.75 (4H, t, J¼2ꢂ7.0); 13C NMR (CDCl3): 137.5, 130.7,
129.3, 128.8, 121.7, 58.1, 56.1, 55.0, 31.8, 31.2, 30.2, 29.5, 29.1, 27.4,
26.0, 25.0, 22.7, 22.6, 22.3, 14.1, 13.9; HRMS (EI): m/z calcd for
C
22H33N4 [MꢁC5H11]þ: 353.2705; found: 353.2696.
4.2.18. N-Benzyl-N-(2-bromobenzyl)- 1,3-diphenylprop-2-yn-1-
amine (7r). N-Benzyl-1-(2-bromophenyl)methanamine (300 mg,
1.1 mmol, 1 equiv), benzaldehyde (173 mg, 1.6 mmol, 1.5 equiv),
phenylacetylene (167 mg, 1.6 mmol, 1.5 equiv), and CuBr (15.6 mg,
0.11 mmol, 10 mol %). The product was obtained as a yellow oil
(424 mg, 85%). 1H NMR (CDCl3): 7.73 (1H, d, J¼7.5), 7.64 (3H, m),
7.50 (1H, d, J¼7.9), 7.32 (12H, m), 7.08 (1H, m), 4.94 (1H, s), 4.0 (1H,
d, J¼14.3), 3.70 (3H, m); 13C NMR (CDCl3): 139.2, 138.9, 138.5, 132.7,
132.0, 130.8, 129.0, 128.40, 128.36, 128.29, 128.26, 128.1, 127.6, 127.3,
4.3.4. 3-Pentyl-4-(40-fluorophenyl)-5-(30-ethoxypropyl)-5,6-dihydro-
4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8d). ortho-Bromobenzyl-
propargylamine 7d (100 mg, 0.21 mmol, 1 equiv), sodiumazide
(34.5 mg, 0.53 mmol, 2.5 equiv), 15-crown-5 (117 mg, 0.53 mmol,
2.5 equiv), and CuI (8.0 mg, 0.04 mmol, 20 mol %). The product was
obtained as an orange oil (38.5 mg, 49%). 1H NMR (CDCl3): 7.77 (1H, d,
J¼7.9), 7.38 (1H, m), 7.31 (2H, d, J¼4.1), 7.14 (2H, dd, J¼8.3 and J¼5.7),
6.86 (2H, m), 4.76 (1H, s), 3.78 (1H, d, J¼13.6), 3.49 (4H, m), 2.65 (2H, t,
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6
G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
J¼7.2), 2.40 (1H, m), 2.23 (1H, m), 1.88 (2H, quin, J¼6.7), 1.59 (2H, m),
1.29 (4H, m), 0.18 (3H, t, J¼7.0), 0.87 (3H, t, J¼7.0); 13C NMR (CDCl3):
160.3, 146.8, 137.0, 135.6, 135.5, 132.5, 130.4, 129.3, 129.2, 128.6, 122.3,
115.0, 114.7, 68.2, 66.3, 59.7, 52.8, 51.3, 31.7, 19.9, 28.4, 25.0, 22.4, 15.2,
14.0; HRMS (EI): m/z calcd for C21H29N4O [MꢁC6H4F]þ: 353.2341;
found: 353.2352.
3.37 (1H, d, J¼12.1), 12.7 (1H, m), 1.02 (2H, m), 0.81 (1H, m), 0.48
(3H, t, J¼7.0); 13C NMR (CDCl3): 158.9, 146.3, 137.6, 133.6, 130.9,
130.7, 130.3, 130.2, 129.2, 129.0, 128.7, 128.23, 128.20, 122.0, 113.7,
61.6, 55.2, 55.0, 54.4, 38.0, 19.3, 13.4; HRMS (EI): m/z calcd for
C
24H21N4O [MꢁC3H7]þ: 381.1715; found: 381.1738.
4.3.10. 3-(40-Methylphenyl)-4-propyl-5-benzyl-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8j). ortho-Bromobenzyl-
propargylamine 7j (100 mg, 0.23 mmol, 1 equiv), sodiumazide
(36 mg, 0.56 mmol, 2.5 equiv), 15-crown-5 (124 mg, 0.56 mmol,
2.5 equiv), and CuI (8.6 mg, 0.045 mmol, 20 mol %). The product was
obtained as an orange oil (41.4 mg, 45%). 1H NMR (CDCl3): 7.94 (1H,
d, J¼7.9), 7.52 (3H, m), 7.41 (2H, m), 7.26 (7H, m), 4.22 (1H, t, J¼7.5),
3.82 (2H, m), 3.68 (1H, m), 3.39 (1H, d, J¼12.4), 2.43 (3H, s), 1.28
(2H, m), 1.0 (2H, m), 0.83 (2H, m), 0.47 (3H, t, J¼7); 13C NMR
(CDCl3): 146.4, 138.3, 137.6, 133.3, 130.6, 130.4, 129.4, 129.3, 129.1,
128.9, 128.3, 128.1, 128.0, 127.4, 122.0, 62.3, 55.00, 54.96, 38.0, 35.4,
21.3, 19.3, 13.8; HRMS (EI): m/z calcd for C24H21N4 [MꢁC3H7]þ:
365.1766; found: 365.1763.
4.3.5. 3-Phenyl-4-propyl-5-benzyl-5,6-dihydro-4H-[1,2,3]triazolo
[1,5-a][1,4]benzodiazepine (8e). ortho-Bromobenzylpropargylamine
7e (100 mg, 0.23 mmol, 1 equiv), sodiumazide (38 mg, 0.58 mmol,
2.5 equiv), 15-crown-5 (127 mg, 0.58 mmol, 2.5 equiv), and CuI (8.
mg, 0.046 mmol, 20 mol %). The product was obtained as an orange
oil (53.7 mg, 58%). 1H NMR (CDCl3): 7.94 (1H, d, J¼7.9), 7.66 (2H, dd,
J¼7.9, 1.5), 7.47 (6H, m), 7.25 (5H, m), 4.23 (1H, t, J¼7.5), 3.83 (2H,
m), 3.67 (1H, m), 3.40 (1H, d, J¼12.4),1.28 (1H, m),1.01 (2H, m), 0.80
(1H, m), 0.47 (3H, t, J¼7); 13C NMR (CDCl3): 146.3, 138.2, 137.6,
133.5, 130.9, 130.7, 129.3, 129.1, 129.0, 128.7, 128.4, 128.2, 127.5,
122.0, 62.2, 55.0, 54.8, 38.0, 19.3, 13.4; HRMS (EI): m/z calcd for
C
23H19N4 [MꢁC3H7]þ: 351.1610; found: 351.1610.
4.3.6. 3-Phenyl-4-(propan-2-yl)-5-benzyl-5,6-dihydro-4H-[1,2,3]tri-
azolo[1,5-a][1,4]benzodiazepine (8f). ortho-Bromobenzylpropargyl-
amine 7f (100 mg, 0.23 mmol, 1 equiv), sodiumazide (38 mg,
0.58 mmol, 2.5 equiv), 15-crown-5 (127 mg, 0.58 mmol, 2.5 equiv),
and CuI (8.8 mg, 0.046 mmol, 20 mol %). The product was obtained
as an orange oil (39.2 mg, 43%). 1H NMR (CDCl3): 7.9 (1H, d, J¼7.9),
7.73 (2H, dd, J¼8.1, 1.3), 7.37 (11H, m), 3.78 (4H, m), 3.24 (1H, d,
J¼11.7),1.13 (1H, m), 0.83 (3H, d, J¼6.4), 0.27 (3H, d, J¼6.4); 13C NMR
(CDCl3): 147.3, 138.3, 137.8, 132.9, 131.0, 132.9, 131.0, 130.8, 130.4,
129.34, 129.27, 128.8, 128.4, 128.30, 128.25, 127.5, 121.8, 63.6, 63.0,
4.3.11. 3-(40-Methylphenyl)-4-propyl-5-(40-methoxybenzyl)-5,6-
dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8k). ortho-Bro-
mobenzylpropargylamine 7k (100 mg, 0.21 mmol, 1 equiv), sodiu-
mazide (34 mg, 0.53 mmol, 2.5 equiv), 15-crown-5 (116 mg,
0.53 mmol, 2.5 equiv), and CuI (8.0 mg, 0.042 mmol, 20 mol %). The
product was obtained as an orange oil (71.3 mg, 77%). 1H NMR
(CDCl3): 7.93 (1H, d, J¼7.9), 7.51 (2H, m), 7.40 (2H, m), 7.27 (2H, d,
J¼7.9), 7.12 (2H, d, J¼8.7), 6.80 (2H, d, J¼8.7), 4.22 (1H, t, J¼7.5), 3.78
(5H, m), 3.60 (1H, m), 3.36 (1H, d, J¼12.4), 2.43 (3H, s), 1.25 (1H, m),
1.01 (2H, m), 0.82 (1H, m), 0.48 (3H, t, J¼7.0); 13C NMR (CDCl3): 158.9,
146.3, 138.0, 137.6, 133.3, 130.7, 130.4, 130.3, 129.4, 129.2, 128.9, 128.1,
128.0, 121.9, 113.7, 61.6, 55.2, 54.9, 54.5, 38.0, 21.3, 19.3, 13.4; HRMS
(EI): m/z calcd for C25H23N4O [MꢁC3H7]þ: 395.1872; found: 395.1875.
54.6, 33.2, 20.8, 19.5; HRMS (EI): m/z calcd for
C23H19N4
[MꢁCH(CH3)2]þ: 351.1610; found: 351.1659.
4.3.7. 3-Phenyl-4-ethyl-5-benzyl-5,6-dihydro-4H-[1,2,3]triazolo[1,5-a]
[1,4]benzodiazepine (8g). ortho-Bromobenzylpropargylamine 7f
(100 mg, 0.24 mmol, 1 equiv), sodiumazide (39 mg, 0.60 mmol,
2.5 equiv), 15-crown-5 (132 mg, 0.6 mmol, 2.5 equiv), and CuI (9.1 mg,
0.048 mmol, 20 mol %). The product was obtained as an orange oil
(43.2 mg, 48%). 1H NMR (CDCl3): 7.94 (1H, d, J¼7.9), 7.66 (2H, m), 7.46
(6H, m), 7.24 (5H, m), 4.14 (1H, t, J¼7.9), 3.83 (2H, m), 3.67 (1H, m),
4.3.12. 3-(40-Ethyl-phenyl)-4-propyl-5-benzyl-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8l). ortho-Bromobenzyl-
propargylamine 7l (100 mg, 0.22 mmol, 1 equiv), sodiumazide
(36 mg, 0.56 mmol, 2.5 equiv), 15-crown-5 (123 mg, 0.56 mmol,
2.5 equiv), and CuI (8.6 mg, 0.045 mmol, 20 mol %). The product was
obtained as an orange oil (48.3 mg, 53%). 1H NMR (CDCl3): 7.93 (1H,
d, J¼7.9), 7.58 (2H, d, J¼7.9), 7.51 (1H, m), 7.4 (2H, m), 7.26 (7H, m),
4.13 (1H, t, J¼8.1), 3.82 (2H, m), 3.68 (1H, m), 3.39 (1H, d, J¼12.1),
2.73 (2H, q, J¼7.5), 1.31 (4H, m), 1.07 (1H, dt, J¼14.1, 7.3), 0.49 (3H, t,
J¼7.3); 13C NMR (CDCl3): 146.6, 144.4, 138.3, 137.6, 133.0, 130.7,
130.4, 129.3, 129.1, 128.9, 128.3, 128.31, 128.25, 128.20, 127.4, 122.0,
62.3, 56.8, 54.9, 29.0, 28.7, 15.6, 10.9; HRMS (EI): m/z calcd for
3.40 (1H, d, J¼12.1), 1.28 (1H, m), 1.08 (1H, m), 0.48 (3H, t, J¼7.3); 13
C
NMR (CDCl3): 146.6,138.2,137.6,133.3,130.9,130.7,130.5,129.3,129.0,
128.8, 128.4, 128.3, 127.5, 122.0, 62.4, 56.8, 55.0, 29.0, 10.9; HRMS (EI):
m/z calcd for C23H19N4 [MꢁC2H6]þ: 351.1610; found: 351.1575.
4.3.8. 3-Phenyl-4-pentyl-5-benzyl-5,6-dihydro-4H-[1,2,3]triazolo[1,5-
a][1,4]benzodiazepine (8h). ortho-Bromobenzylpropargylamine 7h
(100 mg, 0.22 mmol, 1 equiv), sodiumazide (35 mg, 0.54 mmol,
2.5 equiv), 15-crown-5 (119 mg, 0.54 mmol, 2.5 equiv), and CuI
(8.2 mg, 0.043 mmol, 20 mol %). The product was obtained as an
orange oil (36.7 mg, 40%). 1H NMR (CDCl3): 7.94 (1H, d, J¼7.5), 7.65
(2H, d, J¼7.5), 7.47 (6H, m), 7.24 (5H, m), 4.20 (1H, m), 3.83 (2H, m),
3.67 (1H, m), 3.41 (1H, d, J¼12.1),1.28 (2H, m), 0.98 (4H, m), 0.75 (2H,
m), 0.64 (3H, m); 13C NMR (CDCl3): 146.4, 138.2, 137.6, 133.5, 130.9,
130.7, 130.5, 129.3, 129.1, 129.0, 128.7, 128.3, 128.2, 127.5, 62.2, 55.1,
54.9, 35.6, 30.9, 25.6, 22.2, 13.8; HRMS (EI): m/z calcd for C23H19N4
[MꢁC5H11]þ: 351.1610; found: 351.1628.
C
25H23N4 [MꢁC2H5]þ: 379.1923; found: 379.1949.
4.3.13. 3-(40-Pentyl-phenyl)-4-propyl-5-(40-methoxybenzyl)-5,6-
dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8m). ortho-
Bromobenzylpropargylamine 7m (100 mg, 0.19 mmol, 1 equiv),
sodiumazide (31 mg, 0.47 mmol, 2.5 equiv), 15-crown-5 (103 mg,
0.47 mmol, 2.5 equiv), and CuI (7.2 mg, 0.038 mmol, 20 mol %). The
product was obtained as an orange oil (65.6 mg, 71%). 1H NMR
(CDCl3): 7.93 (1H, d, J¼7.5), 7.57 (2H, d, J¼7.9), 7.50 (1H, m), 7.27
(2H, m), 7.1 (2H, d, J¼8.3), 6.80 (2H, d, J¼8.7), 4.22 (1H, t, J¼7.3), 3.77
(5H, m), 3.58 (1H, d, J¼12.8), 3.36 (1H, d, J¼12.1), 2.69 (2H, t, J¼7.7),
1.69 (2H, m), 1.38 (4H, m), 1.25 (1H, m), 1.01 (2H, m), 0.92 (3H, t,
J¼6.6), 0.81 (1H, m), 0.48 (3H, t, J¼7.0); 13C NMR (CDCl3): 158.9,
146.4, 143.1, 137.7, 133.3, 130.7, 130.5, 130.4, 130.3, 129.2, 128.9,
128.8, 128.2, 128.1, 122.0, 113.7, 61.6, 55.2, 55.0, 54.4, 38.0, 35.7, 31.5,
31.2, 22.6, 19.3, 14.1, 13.4; HRMS (EI): m/z calcd for C29H31N4O
[MꢁC3H7]þ: 451.2498; found: 451.2540.
4.3.9. 3-Phenyl-4-propyl-5-(40-methoxybenzyl)-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8i). ortho-Bromobenzyl-
propargylamine 7i (100 mg, 0.22 mmol, 1 equiv), sodiumazide
(35.1 mg, 0.54 mmol, 2.5 equiv), 15-crown-5 (119 mg, 0.54 mmol,
2.5 equiv), and CuI (8.2 mg, 0.043 mmol, 20 mol %). The product was
obtained as an orange oil (50.0 mg, 54%). 1H NMR (CDCl3): 7.93 (1H,
d, J¼7.5), 7.66 (2H, dd, J¼7.9, 1.5), 7.47 (6H, m), 7.1 (2H, d, J¼8.7), 6.8
(2H, d, J¼8.7), 4.23 (1H, t, J¼7.5), 3.79 (5H, m), 3.58 (1H, d, J¼12.8),
4.3.14. 3-(40-Methyl-phenyl)-4-(20-metylpropyl)-5-(40-methox-
ybenzyl)-5,6-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepine
Please cite this article in press as: Hooyberghs, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.031

G. Hooyberghs et al. / Tetrahedron xxx (2013) 1e7
7
(8n). ortho-Bromobenzylpropargylamine 7n (100 mg, 0.20 mmol,
1 equiv), sodiumazide (33 mg, 0.51 mmol, 2.5 equiv), 15-crown-5
(112 mg, 0.51 mmol, 2.5 equiv), and CuI (7.6 mg, 0.04 mmol,
20 mol %). The product was obtained as an orange oil (51.5 mg, 56%).
1H NMR (CDCl3): 7.94 (1H, d, J¼7.5), 7.52 (3H, m), 7.41 (2H, d), 7.27
(2H, d, J¼8.3); 7.13 (2H, d, J¼8.7), 6.83 (2H, m), 4.28 (1H, t, J¼7.5), 3.8
(5H, m), 3.62 (1H, m), 3.39 (1H, d, J¼12.4), 2.44 (3H, s), 1.20 (3H, m),
0.88 (1H, m), 0.44 (3H, d, J¼2.3), 0.42 (3H, d, J¼2.3); 13C NMR
(CDCl3): 159.0, 146.2, 138.0, 133.6, 130.7, 130.4, 130.33, 130.27, 129.4,
129.2, 128.9, 128.0, 128.2, 122.0, 113.7, 61.5, 55.3, 55.0, 52.9, 45.0,
HRMS (EI): m/z calcd for C25H23N4O2 [MꢁC4H9]þ: 411.1821; found:
411.1814.
Acknowledgements
Support was provided by the Research Fund of the University of
Leuven (KU Leuven), the Industrial Research Fund (IOF) and by the
FWO (Fund for Scientific ResearchdFlanders (Belgium)). D.E. is
grateful to the University of Leuven (KU Leuven) for obtaining
a postdoc fellowship. The authors thank Ir. B. Demarsin for HRMS
measurements.
24.5, 22.4, 22.0, 21.3; HRMS (EI): m/z calcd for
C25H23N4O
[MꢁCH2CH(CH3)]þ: 395.1872; found: 395.1897.
Supplementary data
4.3.15. 3-Phenyl-4-(20metylpropyl)-5-benzyl-5,6-dihydro-4H-[1,2,3]
triazolo[1,5-a][1,4]benzodiazepine (8o). ortho-Bromobenzylpro-
Characterization for all compounds. Supplementary data related
to this article can be found online at http://dx.doi.org/10.1016/
j.tet.2013.03.031.
pargylamine 7o (100 mg, 0.22 mmol, 1 equiv), sodiumazide
(36 mg, 0.56 mmol, 2.5 equiv), 15-crown-5 (123 mg, 0.56 mmol,
2.5 equiv), and CuI (8.5 mg, 0.045 mmol, 20 mol %). The product
was obtained as an orange oil (59.4 mg, 57%). 1H NMR (CDCl3):
7.95 (1H, d, J¼7.5), 7.66 (2H, m), 7.46 (6H, m), 7.25 (5H, m), 4.28
(1H, t, J¼7.5), 3.85 (2H, m), 3.68 (1H, m), 3.42 (1H, d, J¼12.4), 1.20
(2H, m), 0.92 (1H, m), 0.41 (3H, s), 0.389 (3H, s); 13C NMR (CDCl3):
146.2, 138.1, 133.7, 130.9, 130.6, 130.5, 129.3, 123.2, 128.9, 128.8,
128.3, 128.24, 128.17, 127.5, 62.1, 55.1, 23.0, 44.9, 24.5, 22.6, 21.9;
HRMS (EI): m/z calcd for C23H19N4 [MꢁCH2CH(CH3)]þ: 351.1610;
found: 351.1599.
References and notes
1. Greenblatt, D. J.; Shader, R. I. Benzodiazepines in Clinical Practice; Raven: New
York, NY, 1974.
2. (a) Mohiuddin, G.; Reddy, P. S.; Ahmed, K.; Ratnam, C. V. Heterocycles 1986, 24,
3489; (b) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433; (c) Patchet, A. A.;
Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
3. (a)Witt, A.;Bergman, J. J. Org.Chem.2001, 66, 2748;(b)Eguchi, S. ARKIVOC2005, 98.
4. Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.; Freidinger, R. M.; Whitter, W.
L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D.
J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem.
1988, 31, 2235.
4.3.16. 3-Phenyl-4-octyl-5-(40-methoxybenzyl)-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8p). ortho-Bromobenzyl-
propargylamine 7p (100 mg, 019 mmol, 1 equiv), sodiumazide
(31 mg, 0.47 mmol, 2.5 equiv), 15-crown-5 (103 mg, 0.47 mmol,
2.5 equiv), and CuI (6.9 mg, 0.036 mmol, 20 mol %). The product was
obtained as an orange oil (53.7 mg, 58%). 1H NMR (CDCl3): 7.93 (1H,
d, J¼7.9), 7.66 (2H, dd, J¼7.7, 1.3), 7.52 (1H, m), 7.46 (2H, d, J¼7.5),
7.42 (2H, m), 7.10 (2H, d, J¼8.7), 6.80 (2H, d, J¼8.7), 4.21 (1H, m),
3.79 (5H, m), 3.58 (1H, d, J¼12.4), 1.22 (3H, m), 1.01 (8H, m), 0.8 (7H,
m); 13C NMR (CDCl3): 158.9, 146.4, 137.6, 133.5, 131.0, 130.8, 130.5,
130.3, 130.2, 129.2, 129.0, 128.7, 128.3, 128.2, 122.0, 113.7, 61.5, 55.2,
55.0, 54.4, 35.6, 31.7, 29.1, 29.0, 28.7, 25.9, 22.6, 14.0; HRMS (EI): m/z
calcd for C24H21N4O [MꢁC8H17]þ: 381.1715; found: 381.1693.
5. Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.; Blaney, J. M.
Tetrahedron 1993, 49, 3593.
6. Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.; Carver, T. E.; Koblish, H. K.;
Cummings, M. D.; LaFrance, L. V.; Milkiewicz, K. L.; Calvo, R. R.; Maguire, D.;
Lattanze, J.; Franks, C. F.; Zhao, S.; Ramachandren, K.; Bylebyl, G. R.; Zhang, M.;
Mathney, C. L.; Petrella, E. C.; Pantoliano, M. W.; Deckman, I. C.; Spurlino, J. C.;
Maroney, A. C.; Tomczuk, B. E.; Molloy, C. J.; Bone, R. F. J. Med. Chem. 2005, 48, 909.
7. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
8. (a) Snyder, P. J.; Werth, J.; Giordani, B.; Caveney, A. F.; Feltner, D.; Maruff, P. Hum.
Psychopharmacol. Clin. Exp. 2005, 20, 263; (b) Levine, J.; Cole, D. P.; Roy Chen-
gappa, K. N.; Gerson, S. Depression Anxiety 2001,11, 94; (c) Post, G. L.; Patrick, R. O.;
Pearlman, H. G.; Shu, V. S.; Pierce, M. W. J. Clin. Psychopharmacol. 1991, 11, 249.
9. Greenblatt, D. J.; Harmatz, J. S.; Shapira, L.; Engelhardt, N.; Gouthro, T. A.;
Shader, T. A. N. Engl. J. Med. 1991, 324, 1691.
10. (a) Yan, J.; Zhou, F.; Qin, D.; Cai, T.; Ding, K.; Cai, Q. Org. Lett. 2012, 14, 1262; (b)
Cai, Q.; Yan, J.; Ding, K. Org. Lett. 2012, 14, 3332; (c) Guggenheim, K. G.; Toru, H.;
Kurth, M. J. Org. Lett. 2012, 14, 3732.
4.3.17. 3-Phenyl-4-butyl-5-(30,40-dimethoxybenzyl)-5,6-dihydro-4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (8q). ortho-Bromobenzyl-
propargylamine 7q (100 mg, 0.20 mmol, 1 equiv), sodiumazide
(32 mg, 0.50 mmol, 2.5 equiv), 15-crown-5 (109 mg, 0.50 mmol,
2.5 equiv), and CuI (7.6 mg, 0.04 mmol, 20 mol %). The product was
obtained as an orange oil (53.6 mg, 58%). 1H NMR (CDCl3) 7.94 (1H,
d, J¼7.5), 7.65 (2H, m), 7.52 (1H, m), 7.46 (1H, m), 7.43 (3H, m), 6.89
(1H, d, J¼1.5), 6.74 (1H, m), 6.64 (1H, m), 4.22 (1H, m), 3.88 (3H, s),
3.82 (5H, m), 3.58 (1H, d, J¼12.8), 3.40 (1H, d, J¼12.1), 1.28 (1H, m),
1.03 (2H, m), 0.86 (2H, m), 0.73 (1H, m), 0.58 (3H, t, J¼7.9); 13C NMR
(CDCl3): 7.94 (1H, d, J¼7.5), 7.65 (2H, m), 7.47 (6H, m), 6.89 (1H, d,
J¼1.5), 6.64 (1H, m), 4.22 (1H, m), 3.83 (8H, m), 3.58 (1H, d, J¼12.1),
1.28 (1H, m), 1.03 (2H, m), 0.88 (2H, m), 0.73 (1H, m), 0.58 (3H, m);
11. (a) Wei, W.; Li, Z.; Li, C.-J. Synlett 2004, 1472; (b) Yoo, W. J.; Zhao, L.; Li, C.-J.
Aldrichimica Acta 2011, 44, 43; (c) Peshkov, V. A.; Pereshivko, O. P.; Van der
Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790.
12. (a) Bariwal, J. B.; Ermolat0ev, D. S.; Van der Eycken, E. V. Chem.dEur. J. 2010, 16,
3281; (b) Bariwal, J. B.; Ermolat0ev, D. S.; Glasnov, T. N.; van Hecke, K.; Mehta, V.
P.; van Meervelt, L.; Kappe, C. O.; van der Eycken, E. V. Org. Lett. 2010, 12, 2774;
(c) Peshkov, V. A.; Pereshivko, O. P.; Donets, P. A.; Mehta, V. P.; van der Eycken,
E. V. Eur. J. Org. Chem. 2010, 4861; (d) Feng, H.; Ermolat0ev, D. S.; Song, G.; Van
der Eycken, E. V. Org. Lett. 2012, 14, 1942.
13. Nandakumar, A.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2011, 52, 1644.
14. De Moliner, F.; Crosignani, S.; Galatini, A.; Riva, R.; Basso, A. ACS Comb. Sci. 2011,
13, 453; (b) Vachhani, D. D.; Kumar, A.; Modha, S. G.; Sharma, S. K.; Parmar, V.
S.; Van der Eycken, E. V. Eur. J. Org. Chem. 2013, 1233.
15. Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Chem. Soc. Jpn. 1980, 53, 1765.
16. (a) Alajarín, M.; Cabrera, J.; Pastor, A.; Villalgordo, J. M. Tetrahedron Lett. 2007,
48, 3495; (b) Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852; (c) Donald, J. R.;
Wood, R. R.; Martin, S. F. ACS Comb. Sci. 2012, 14, 135.
Please cite this article in press as: Hooyberghs, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.031