A new modular and flexible approach to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2007.03.121

A new synthetic route for the access to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines and other derivatives is described. This strategy is based on the cycloaddition of 2-oxoalkylidenephosphoranes to o-functionalized aryl azides followed by the reaction of the corresponding triazole intermediate with amines. This new approach presents unique properties such as regioselectivity, modularity, mild reaction conditions, and high yields.

Full text of DOI:10.1016/j.tetlet.2007.03.121

Tetrahedron Letters 48 (2007) 3495–3499
A new modular and flexible approach to
[1,2,3]triazolo[1,5-a][1,4]benzodiazepines
a,
a
a
b
*
´
´
´
Mateo Alajarın, Jose Cabrera, Aurelia Pastor and Jose M. Villalgordo
aDepartamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Murcia Campus de Espinardo, Murcia 30100, Spain
bVillapharma Research S.L., Polı´gono Industrial Oeste, c/Paraguay, Parcela 7/5-A, Mo´dulo A-1, Murcia 30169, Spain
Received 17 January 2007; revised 20 March 2007; accepted 21 March 2007
Available online 25 March 2007
Abstract—A new synthetic route for the access to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines and other derivatives is described. This
strategy is based on the cycloaddition of 2-oxoalkylidenephosphoranes to o-functionalized aryl azides followed by the reaction of the
corresponding triazole intermediate with amines. This new approach presents unique properties such as regioselectivity, modularity,
mild reaction conditions, and high yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Among the drugs used in the treatment of central ner-
vous system (CNS) disorders, 1,4-benzodiazepines have
occupied a prominent place during the last 40 years.1
Consequently, elegant and practical syntheses of these
heterocyclic systems have been developed.2 A simple
modification of the benzodiazepine core consists of the
annelation of a new heterocyclic moiety to the benzodi-
azepine framework.3 Alprazolam (A) and Estazolam (B)
belong to this family of compounds which possesses a
1,2,4-triazole ring fused to the 1,2 position of the diaze-
pine (see Fig. 1). Both are common anxiolytic agents
and have found both clinical and commercial success.4
Several approaches to this type of compounds have been
described previously in the literature, all of them based
on inter/intramolecular cycloadditions of aryl azides to
alkenes or acetylenes (Huisgen dipolar cycloaddition)
to generate the triazole ring.5 In spite of its popularity,
the Huisgen approach presents some disadvantages,
such as the high activation energies of these cycloaddi-
tions, which are very slow even at elevated temperatures,
and the lack of regioselectivity when unsymmetrical
dipolarophiles are used.6 Recently, Sharpless and others
demonstrated that these processes are catalyzed by
Cu(I)7 or Ru(II)8 with high levels of regioselection. Sur-
prisingly, alternative synthetic routes for the preparation
of the tricyclic structures C have been rarely pursued.
In this context, we directed our attention to the synthesis
of [1,2,3]triazolo[1,5-a][1,4]benzodiazepines (C in Fig. 1).
Herein, we disclose a new synthetic strategy for the syn-
thesis of [1,2,3]triazolo[1,5-a][1,4]benzodiazepines by
starting from easily available o-functionalized aryl
azides (Scheme 1). The key step is the formation of the
triazole moiety present in intermediates 3 (Scheme 1)
by the regioselective thermal cycloaddition of (3-chloro-
acetonylidene)triphenylphosphorane (2) to aryl azides
1a–d (Harvey approach).6c,9 This reaction can be visual-
ized as a 1,3-dipolar cycloaddition of the azido group to
the C@C bond of the betainic form of the ketophospho-
rane with subsequent spontaneous elimination of phos-
phine oxide.
Ph
Ph
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
H3C
(A)
(B)
(C)
Figure 1. Alprazolam (A), Estazolam (B) and structure of 4H-
[1,2,3]triazolo[1,5-a][1,4]benzodiazepine (C).
Keywords: 1,2,3-Triazole; Ketophosphorane; o-Functionalized aryl
azide; Bis-electrophile.
2-Azidobenzyl chloride (1b)10 and 2-azidobenzaldehyde
(1c)11 could be obtained in good yields from 2-azidobenz-
yl alcohol (1a)12 by treatment with thionyl chloride or
*
Corresponding author. Tel.: +34 968367497; fax: +34 968364149;
e-mail: alajarin@um.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.121

3496
M. Alajarı´n et al. / Tetrahedron Letters 48 (2007) 3495–3499
O
N
N
N
4 (80%)
toluene
reflux
2
CHO
COOMe
N3
PCC
SOCl2
OH
N3
Cl
N3
1b (97%)
CH2Cl2
25 ºC
CH2Cl2
25 ºC
N3
1c (98%)
1d
1a
O
toluene
reflux
toluene
80 ºC
CH2Cl2
25 ºC
toluene
reflux
Ph3P
OH
Cl
2
2
2
2
Cl
COOMe
Cl
CHO
N
PCC
Cl
Cl
Cl
N
CH2Cl2
25 ºC
N
N
N
N
N
N
N
N
N
N
3b (90%)
3a (90%)
3c (60% from
3d (90%)
both 1c and 3a)
Scheme 1. Reaction of the o–functionalized aryl azides1a–d with (3-chloroacetonylidene)triphenylphosphorane (2) to give triazoles 3a–d and 4H,6H-
[1,2,3]triazolo[1,5-a][4,1]benzoxazepine 4.
PCC, respectively (Scheme 1). The reaction of 1a–c with
2 led to triazoles 3a–c in good yields (60–90%)13
although experimental conditions, that is, temperature
and solvent, were crucial for the formation of 3 (see
Scheme 1). Thus, an increase of temperature, from
80 ꢁC to reflux, in the reaction of 1a with 2 led to
4H,6H-[1,2,3]triazolo[1,5-a][4,1]benzoxazepine (4) (80%)
instead of to 3a. On the other hand, the reaction of azide
1c with 2 in toluene at 90 ꢁC led to a mixture of
compounds resulting from the Wittig reaction of the
phosphorane with the formyl group of 1c before or after
the formation of the triazole ring (not shown in Scheme
1). Triazole 3c could be alternatively obtained from 3a
by treatment with PCC (60%). Finally, the reaction of
methyl 2-azidobenzoate14 (1d) with 2 in refluxing tolu-
ene led to triazole 3d in 90% yield.
polycyclic structures 5a–c could be prepared also from
triazole 3c through an alternative route depicted in
Scheme 3. Thus, the reaction of 3c with ammonia in
acetonitrile led to 4H-[1,2,3]triazolo[1,5-a][1,4]benzo-
diazepine (6a) in 87% yield. The subsequent treatment
of 6a with NaBH4 gave 5a (86%). On the other hand,
3c was allowed to react with benzylamine or p-toluidine
and subsequently with NaBH4 to give 5b–c (50–53%).
4H-[1,2,3]Triazolo[1,5-a][1,4]benzodiazepin-6-ones 5d–f
(Table 1, entries 4–6) were prepared by the reaction of
triazole 3d with ammonia, benzylamine or p-toluidine
respectively in yields ranging 52–87%. Finally, ethanol-
amine and two other optically active amino alcohols
were used as bis-nucleophiles. While the reaction of 3c
and ethanolamine led to the chiral tetracyclic structure
5g (Table 1, entry 7), the reaction of 3c with (S)-phenyl-
glycinol and (S)-phenylalaninol gave u-5h and u-5i in
excellent yields and high levels of diastereoselection
(entries 8–9).16,17
The triazole intermediates 3 can act as bis-electrophilic
species reacting with different amines to form the benzo-
diazepine nucleus (Scheme 2 and Table 1). Triazole 3b
was reacted with ammonia, benzylamine or p-toluidine
to give the corresponding 4H,6H-[1,2,3]triazolo[1,5-a]-
[1,4]benzodiazepines 5a–c in excellent yields (Scheme 2
and Table 1, entries 1–3). In the two latter cases, the
presence of triethylamine was necessary.15 The hetero-
In summary, our methodology provides a new and
clean synthetic access to [1,2,3]triazolo[1,5-a][1,4]benzo-
diazepines and other derivatives of pharmacological
interest using readily available and inexpensive starting
materials derived from anthranilic acid. These complex
structures can be rapidly assembled using a short
sequence of transformations. This new strategy, based
on the Harvey approach to the synthesis of triazoles,
presents unique properties such as regioselectivity,
modularity, mild reaction conditions, and high yields.
The rich array of functionalities displayed by the
intermediate products 3 provides opportunities for its
application in the preparation of combinatorial
libraries.
X
Cl
ZNH2
5
N
N
Et3N (or NH3)
N
3b-d
Scheme 2. Triazoles 3b–d were reacted with different amines to give
[1,2,3]triazolo[1,5-a][1,4]benzodiazepines
5 (see also Table 1 and
Scheme 3).

M. Alajarı´n et al. / Tetrahedron Letters 48 (2007) 3495–3499
3497
Table 1. [1,2,3]Triazolo[1,5-a][1,4]benzodiazepines 5a–i produced via the reaction depicted in Scheme 2
Entry Starting material
X
Z
Reaction conditions
Product
Yielda (%)
NH
1
3b
CH2Cl
H
Acetonitrile,b 25 ꢁC, 16 h
85
N
N
N
5a
Bn
N
N
N
2
3
3b
3b
CH2Cl
Bn
Et3N, CH2Cl2, 25 ꢁC, 48 h
90
72
N
5b
Tol-
p
N
N
N
CH2Cl
p–Tol
Et3N, CH2Cl2, reflux, 36 h
N
5c
O
NH
4
3d
COOMe
H
Acetonitrile,b 80 ꢁC, 12 h
87
N
N
N
5d
O
Bn
N
5
6
7
3d
3d
3c
COOMe Bn
Et3N, toluene, reflux, 5 days
80
52
93
N
N
N
5e
O
Tol-
p
N
COOMe p-Tol
Et3N, toluene, 140 ꢁC, 14 days
N
N
N
5f
O
N
CHO
HOCH2CH2 Et3N, CH2Cl2, 25 ꢁC, 8 h
N
N
N
5g
O
O
Ph
Ph
N
N
HO
8
9
3c
CHO
CHO
Et3N, CH2Cl2, 25 ꢁC, 72 h
83 (dr 10:1)c
N
N
N
N
Ph
N
N
u
-5h
l
-5h
O
O
Bn
Bn
N
N
HO
3c
Et3N, CH2Cl2, 25 ꢁC, 48 h
80 (dr 10:1)c
N
N
N
N
Bn
N
N
u
-5i
l
-5i
a After purification by chromatography.
b In this case the addition of Et3N was not necessary.
c Determined by 1H NMR analysis of characteristic signals directly on the crude product (error 5% of the stated value).

3498
M. Alajarı´n et al. / Tetrahedron Letters 48 (2007) 3495–3499
Broggini, G.; De Marchi, I.; Martinelli, M.; Paladino, G.;
Pilati, T.; Terraneo, A. Synthesis 2005, 2246–2252.
N
CHO
N
NH3
Cl
CH3CN
25 °C
N
N
6. (a) L’abbe, G. Chem. Rev. 1969, 69, 345–363; (b) L’abbe,
´
´
N
G.; Galle, J. E.; Hassner, A. Tetrahedron Lett. 1970, 303–
N
N
´
306; (c) L’abbe, G. Angew. Chem., Int. Ed. Engl. 1975, 14,
3c
6a
775–782.
7. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057–3064; (c) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51–68; (d) Lipshutz, B. H.; Taft, B. R. Angew.
Chem., Int. Ed. 2006, 45, 8235–8238.
BnNH2 or
p
-TolNH2
NaBH4
MeOH
Na2SO4
CH2Cl2, 25 °C
0
25 °C
NaBH4
MeOH
R
N
0
25 °C
N
N
8. (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams,
I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem.
Soc. 2005, 127, 15998–15999; (b) Majireck, M. M.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 8680–8683.
9. (a) Harvey, G. R. J. Org. Chem. 1966, 31, 1587–1590; (b)
N
5a-c
Scheme 3. Alternative route to that shown in Table 1 (entries 1–3) for
the synthesis of 5a–c by starting from triazole 3c.
´
Ykman, P.; Mathys, G.; L’abbe, G.; Smets, G. J. Org.
Chem. 1972, 37, 3213–3216.
10. Eguchi, S.; Goto, S. Heterocycl. Commun. 1994, 1, 51–54.
11. Ardakani, M. A.; Smalley, R. K.; Smith, R. H. J. Chem.
Soc., Perkin Trans. 1 1983, 2501–2506.
Acknowledgements
12. Smolinsky, G. J. Org. Chem. 1961, 26, 4108–4110.
13. Experimental procedure for the synthesis of 3b: A solution
of 1b (1.42 g; 8.50 mmol) and phosphorane 2 (2.00 g;
5.67 mmol) in toluene (50 mL) was stirred under reflux for
6 h. After removal of the solvent under reduced pressure,
the residue was purified by silica gel chromatography
eluting with 1:2 AcOEt/hexane (Rf = 0.23); yield 90%; mp
68–69 ꢁC (colorless prisms, Et2O); IR (Nujol) 1503, 1282,
´
We are grateful to the ‘Ministerio de Educacion y Cien-
cia’ (MEC) of Spain and FEDER funds (Project
CTQ2005-02323/BQU) as well as to the ‘Fundacion
Seneca-CARM’ (Project PI-1/00749/FS/01) for funding.
J.C. and A.P. are also grateful to the MEC for a fellow-
´
´
´
ship and for a contract in the frame of the ‘Ramon y
Cajal’ Program, respectively.
1
1268, 1232, 1113, 1103, 980, 840, 776, 725, 671 cmÀ1; H
NMR (CDCl3) d 4.37 (s, 2H), 4.51 (s, 2H), 7.45 (d, 1H,
J = 7.7 Hz), 7.56 (td, 1H, J = 7.6 Hz, J = 1.7 Hz), 7.60–
7.68 (m, 2H), 7.91 (s, 1H); 13C NMR (CDCl3) d 32.0 (t),
41.3 (t), 127.8 (d), 129.7 (d), 131.2 (d), 131.4 (d), 133.7 (s),
133.8 (d), 135.2 (s), 135.5 (s); MS (EI, 70 eV) m/z (rel int)
245 (M++4, 13), 243 (M++2, 21), 241 (M+, 29), 230 (32),
180 (34), 178 (100), 143 (63), 142 (60), 125 (59), 116 (28),
115 (34), 89 (56), 63 (25). Anal. Calcd for C10H9Cl2N3
(242.11): C, 49.61; H, 3.75; N, 17.36. Found: C, 49.84; H,
3.93; N, 17.36.
References and notes
1. (a) Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10,
34–43; (b) Lancel, M.; Steiger, A. Angew. Chem., Int. Ed.
1999, 111, 2852–2854.
2. (a) Sharp, J. T. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 7, pp 608–620; (b) Ellman, J. A. Acc. Chem.
´
Res. 1996, 29, 132–143; (c) Cepanec, I.; Litvic, M.;
Pogorelic, I. Org. Process Res. Dev. 2006, 10, 1192–1198.
14. Purvis, R.; Smalley, R. K.; Suschitzky, H.; Alkhader, M.
A. J. Chem. Soc., Perkin Trans. 1 1984, 249–254.
´
3. (a) Meguro, K.; Kuwada, Y. Tetrahedron Lett. 1970,
4039–4042; (b) Hester, J. B., Jr.; Duchamp, D. J.;
Chidester, C. G. Tetrahedron Lett. 1971, 1609–1612; (c)
Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.;
Veber, D. F.; Freidinger, R. M.; Chang, R. S. L.; Lotti, V.
J. J. Med. Chem. 1988, 31, 176–181.
4. (a) Hester, J. B., Jr.; Rudzik, A. D.; Kamdar, B. V. J.
Med. Chem. 1971, 14, 1078–1081; (b) Schweitzer, P. K.;
Koshorek, G.; Muehlbach, M. J.; Morris, D. D.; Roehrs,
T.; Walsh, J. K.; Roth, T. Hum. Psychopharmacol. Clin.
Exp. 1991, 6, 99–107; (c) Levine, J.; Cole, D. P.; Roy
Chengappa, K. N.; Gershon, S. Depress. Anxiety 2001, 14,
94–104; (d) Snyder, P. J.; Werth, J.; Giordani, B.;
Caveney, A. F.; Feltner, D.; Maruff, P. Hum. Psycho-
pharmacol. Clin. Exp. 2005, 20, 263–273.
15. Experimental procedure for the synthesis of 5a: A slow
stream of ammonia gas was continually bubbled through a
solution of 3b (0.20 g; 0.83 mmol) in acetonitrile (10 mL)
at 25 ꢁC for 10 min. The reaction mixture was kept in a
sealed tube and stirred at the same temperature for 16 h.
After removal of the solvent under reduced pressure, the
residue was treated with 5%, aqueous NaHCO3 (20 mL)
and extracted with CH2Cl2 (3 · 20 mL). The combined
extracts were dried (MgSO4), the solvent was evaporated,
and the residue was purified by chromatography with
Et3N-deactivated silica gel eluting with 5:1 AcOEt/MeOH
(Rf = 0.30); yield 85%; mp 124–125 ꢁC (colorless prisms,
Et2O); IR (nujol) 3312, 1492, 1228, 1132, 977, 835,
1
764 cmÀ1; H NMR (CDCl3) d 2.61 (broad s, 1 H, NH),
3.81 (s, 2H), 4.02 (s, 2H), 7.41–7.47 (m, 2H), 7.53 (ddd,
1H, J = 7.8 Hz, J = 7.1 Hz, J = 2.0 Hz), 7.70 (s, 1H), 7.92
(dd, 1H, J = 7.8 Hz, J = 1.0 Hz); 13C NMR (CDCl3) d
38.8 (t), 48.6 (t), 122.7 (d), 129.1 (d), 129.2 (d), 130.0 (d),
131.2 (s), 132.0 (d), 135.3 (s), 136.6 (s); MS (EI, 70 eV) m/z
(rel int) 186 (M+, 12), 157 (100), 130 (22), 103 (22), 102
(25). Anal. Calcd for C10H10N4 (186.21): C, 64.50; H, 5.41;
N, 30.09. Found: C, 64.26; H, 5.80; N, 30.04.
5. (a) Coffen, D. L.; Fryer, R. I.; Katonak, D. A.; Wong, F.
J. Org. Chem. 1975, 40, 894–897; (b) Broggini, G.;
Molteni, G.; Zecchi, G. Synthesis 1995, 647–648; (c)
Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G.
Tetrahedron 1999, 55, 14803–14806; (d) Garanti, L.;
Molteni, G.; Broggini, G. J. Chem. Soc., Perkin Trans. 1
2001, 1816–1819; (e) Thomas, A. W. Bioorg. Med. Chem.
Lett. 2002, 12, 1881–1884; (f) Akritopoulou-Zanze, I.;
Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004, 45,
8439–8441; (g) Gracias, V.; Darczak, D.; Gasiecki, A. F.;
Djuric, S. W. Tetrahedron Lett. 2005, 46, 9053–9056; (h)
16. The sense and level of stereocontrol observed in the
formation of 5h,i follow similar trends to those previously
reported for the reactions of the chiral amino alcohols

M. Alajarı´n et al. / Tetrahedron Letters 48 (2007) 3495–3499
3499
1
with other aldehydes (a) Yamato, M.; Hashigaki, K.;
Ishikawa, S.; Qais, N. Tetrahedron Lett. 1988, 29, 6949–
6950; (b) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa,
S. Tetrahedron 1990, 46, 5909–5920; (c) Hatano, K.;
Kurono, Y.; Kuwayama, T.; Tamaki, H.; Yashiro, T.;
Ikeda, K. J. Chem. Soc., Perkin Trans. 2 1992, 621–628;
(d) Penhoat, M.; Leleu, S.; Dupas, G.; Papamicae¨l, C.;
Marsais, F.; Levacher, V. Tetrahedron Lett. 2005, 46,
8385–8389.
647 cmÀ1; H NMR (CDCl3) d 3.27 (d, 1H, J = 13.5 Hz,
Hu), 3.81–3.87 (m, 2H, Hu + Hl), 3.97–4.03 (m, 3H,
2Hu + Hl), 4.16 (dd, 1H, J = 15.8 Hz, J = 0.7 Hz, Hl),
4.22 (dd, 1H, J = 9.2 Hz, J = 6.6 Hz, Hl), 4.34 (dd, 1 H,
J = 7.6 Hz, J = 6.6 Hz, Hl), 4.45 (dd, 1H, J = 7.8 Hz,
J = 6.9 Hz, Hu), 5.45 (s, 1H, Hl), 5.66 (s, 1H, Hu), 7.32–
7.62 (m, 15H, 7Hu + 8Hl), 7.77 (s, 1H, Hu), 7.74–7.70 (m,
2H, Hu + Hl), 7.88 (dd, 1H, J = 7.8 Hz, J = 1.4 Hz, Hu),
8.22 (dd, 1H, J = 8.1 Hz, J = 1.2 Hz, Hl); 13C NMR
(CDCl3) d 41.1 (t, Cu), 43.5 (t, Cl), 65.9 (d, Cu), 69.1 (d,
Cl), 72.9 (t, Cl), 74.7 (t, Cu), 92.1 (d, Cu), 92.7 (d, Cl), 122.8
(d, Cl), 123.3 (d, Cu), 125.3 (d, Cl), 127.4 (2 · d, Cu), 127.8
(2 · d, Cl), 128.28 (d, Cu), 128.30 (d, Cl), 128.5 (d, Cl),
128.7 (d, Cu), 128.8 (2 · d, Cl), 128.9 (2 · d, Cu), 129.0 (d,
Cu), 129.3 (d, Cl), 129.9 (s, Cu), 130.2 (d, Cu), 131.5 (s, Cl),
131.8 (d, Cl), 132.2 (d, Cu), 133.7 (s, Cu), 134.1 (s, Cu),
134.2 (s, Cl), 134.4 (s, Cl), 136.0 (s, Cl), 137.3 (s, Cu); MS
(EI, 70 eV) m/z (rel int) 304 (M+, 33), 303 (100), 275 (90),
245 (40), 155 (32), 104 (40), 103 (32), 91 (55), 77 (33).
HRMS-EI m/z: [M+–H] Calcd for C18H15N4O,
303.124586; found, 303.123934.
17. Experimental procedure for the synthesis of u-5h and l-5h:
(S)–phenylglycinol (0.09 g; 0.68 mmol) was added to a
solution of 3c (0.15 g; 0.68 mmol) and Et3N (0.21 g,
2.03 mmol) in CH2Cl2 (15 mL). The reaction mixture
was stirred at 25 ꢁC for 72 h, then washed with 5%,
aqueous NaHCO3 (10 mL), and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue
was purified by chromatography with silica gel eluting
with 1:1 AcOEt/hexane (Rf = 0.44) to give a mixture of u-
5h and l-5h in a 10:1 ratio (83% overall yield); colorless oil;
IR (neat) 1608, 1588, 1487, 1454, 1372, 1340, 1280, 1232,
1189, 1133, 1088, 1038, 980, 911, 840, 762, 734, 702,