An expedient and facile route for the general synthesis of 3-aryl substituted 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-ones and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones

Article abstract of DOI:10.1039/c0ob00217h

We describe herein a convenient approach for the general synthesis of novel tricyclic scaffolds incorporating a fusion of the 1,2,3-triazole ring with difficultly obtainable medium sized rings such as [1,4]benzodiazepin-5-ones and [1,5]benzodiazocin-6-ones through Sonogashira coupling of an aryl iodide with 2-amino-N-methyl-N-(prop-2-ynyl)benzamide or homologue followed by in situ diazotisation, azidation and cycloaddition reactions. The strategy also allows easy accessibility of the corresponding amide-reduced analogues. The operational simplicity and easy substrate availability make the process cost effective and practical.

Full text of DOI:10.1039/c0ob00217h

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
An expedient and facile route for the general synthesis of 3-aryl
substituted 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-ones and
1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones†
Chinmay Chowdhury,* Anup Kumar Sasmal and Basudeb Achari
Received 5th June 2010, Accepted 2nd August 2010
DOI: 10.1039/c0ob00217h
We describe herein a convenient approach for the general synthesis of novel tricyclic scaffolds
incorporating a fusion of the 1,2,3-triazole ring with difficultly obtainable medium sized rings such as
[1,4]benzodiazepin-5-ones and [1,5]benzodiazocin-6-ones through Sonogashira coupling of an aryl
iodide with 2-amino-N-methyl-N-(prop-2-ynyl)benzamide or homologue followed by in situ
diazotisation, azidation and cycloaddition reactions. The strategy also allows easy accessibility of the
corresponding amide-reduced analogues. The operational simplicity and easy substrate availability
make the process cost effective and practical.
diseases. Notable amongst them are the triazolobenzodiazepines
Introduction
Alprazolam (1a) and Estazolam (1b), which have found use
as anxiolytic agents,5a-c and triazolam (1c), known as an anti-
depressant5d (Fig. 1). Besides, Flumazenil (2) belongs to the
family of cognition enhancers6 and Bretazenil (3) is popular due
to its potency against neurodegenerative diseases.7 In addition,
a tetrazole-annulated derivative G-7453 (4) has emerged as a
potential fibrinogen antagonist in recent past.8 On the other
hand 1,5-benzodiazocines, the next higher homologue of 1,4-
benzodiazepines, are comparatively less studied, despite having
various impressive activities,9 as these eight-membered rings are
relatively difficult to access. In view of the immense biological
activities of these classes of compounds coupled with our own
interest in lead evaluation studies, we became interested in
the general synthesis of 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-
ones 5 and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones 6 (Fig.
1), which could serve as potent pharmacophores in medicinal
chemistry. Careful examination of the literature indicates that
the majority of syntheses8,10 have been developed for specific
derivatives (R1 = H) of 5 through inter- or intra-molecular
cycloaddition between terminal acetylene and aryl azide, limiting
The development of novel therapeutic agents and identification
of molecular probes depend primarily on the availability of
libraries of small molecules. This in turn requires efficient synthetic
transformations that allow the synthesis of complex molecules
from relatively simple starting materials by enabling several bond
forming events to occur in the same reaction pot. Nitrogen-rich
and medium-sized heterocyclic rings are found abundantly in
many drugs, preclinical leads and bio-active natural products.
Owing to this and other reasons, there has been considerable
effort towards establishing practical and elegant syntheses of such
heterocyles over the last few years. However, seven-, eight- and
larger-membered rings are generally more difficult to prepare due
to their torsional, transannular and large-angle strain combined
with enthalpic and entropic constraints for ring closure1 and thus
pose a tremendous synthetic challenge in organic chemistry.
Among the large varieties of heterocycles, 1,4-benzodiazepines2
have been integral parts of many drugs,2a-c therapeutic leads,2d-f
and bioactive naturally occurring substances2g-h and this structural
moiety is considered a “privileged structure”2f in medicinal chem-
istry. One of the most important subclasses of 1,4-benzodiazepines
is 1,4-benzodiazepin-5-ones, which have been well recognized for
their ever evolving and broad range of biological activities, such
as antitumor,3a anti-insectan,3b fibrinogenic receptor antagonist,3c
muscarinic receptor ligands,3d human neurokinin NK1 receptors,3e
and others.3f More importantly, the spectrum of these therapeutic
activities has been enhanced significantly by developing scaf-
folds made through the fusion of 1,4-benzodiazepinone moiety
with some specific heterocycles, e.g. pyrrole,2e,4a–c imidazole,4d
triazole,4d–e and oxazole.4f Indeed, it resulted in the discovery of
many clinically and commercially successful drugs used for the
treatment of central nervous system (CNS) disorders and other
Chemistry Division, Indian Institute of Chemical Biology (CSIR), 4, Raja
S. C. Mullick Road, Kolkata, 700032, India. E-mail: chinmay@iicb.res.in;
Fax: +91 33 2473 5197; Tel: +91 33 2499 5862
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, characterization data and NMR spectra. See DOI:
10.1039/c0ob00217h
Fig. 1 Fused 1,4-benzodiazepines/1,5-benzodiazocines of interest.
Org. Biomol. Chem., 2010, 8, 4971–4977 | 4971
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
the scope for general synthetic utility. Surprisingly, synthesis of the
3-substituted derivatives (R1 = aryl/alkyl) of 5 is rarely pursued.11
Moreover, most of the aforementioned syntheses are multi-step
procedures resulting in poor overall yields, while others require
harsh reaction conditions and/or are sluggish in nature. Regarding
1,5-benzodiazocinones, although few syntheses are known,9b,12 to
the best of our knowledge there is no report on the synthesis of
3-substituted-1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones 6.
As a part of our interest in the synthesis of novel triazole
fused systems through palladium catalysed reactions,13 we recently
reported13b the synthesis of [1,2,3]triazolo[5,1-c][1,4]benzoxazines
9 through palladium-copper catalysis (Scheme 1). In continuation
of these studies, we felt that replacement of 1-azido-2-(prop-2-
ynyloxy)benzene 7a in Scheme 1 by 2-azido-N-methyl-N-(prop-2-
ynyl)benzamide 7b followed by palladium catalyzed reaction with
aryl iodide 8 would lead to the formation of 1,2,3-triazole annu-
lated 1,4-benzodiazepinone 5 (R1 = Ar, R2 = Me). Surprisingly,
repeated attempts to synthesise the requisite starting substrate
7b through diazotisation followed by in situ azidation of the
corresponding amine precursor did not lead to the expected azido
substrate 7b; instead, the intramolecular cycloadduct of 7b was
isolated each time. The propensity of such self cycloaddition is
attributable to the HOMO–LUMO energy gap (between azide
and acetylene) which is perhaps too low in the substrate 7b for
it to be stable at room temperature or even at lower ones. This
is in line with the observations of similar type by other research
groups.14
5 (or 6) (Scheme 2). Herein, we report the results obtained in this
pursuit.
Results and discussion
Our synthetic approach started with the preparation of 2-amino-
N-methyl-N-(prop-2-ynyl)benzamide 10a, which was in turn syn-
thesised in a one-step reaction between commercially available
isatoic anhydride and N-methylpropargylamine as reported16
earlier. The reactions of 10a with aryl iodides 8 were carried
out under very mild conditions by stirring the mixture at room
temperature (27–32 ◦C) for 2 h in the presence of Pd(PPh3)2Cl2
(4.0 mol%), CuI (6.0 mol%), and triethylamine (7.0 equiv.) in
DMF (Scheme 2). C-arylation of the terminal alkyne of 10a took
place efficiently leading to the formation of the disubstituted
alkynes 11a–g with good to excellent yields (entries 1–7, Table
1). Bis-triphenylphosphine palladium(II) chloride and copper(I)
iodide appeared to be the catalyst and co-catalyst of choice.
After screening various solvents and bases, DMF and triethy-
lamine were found to be the best. Various aryl, hetero-aryl and
substituted aryl iodides also could be used in the C-arylation
reactions under palladium-copper catalysis, although the yields
were somewhat lower (entry 1 vs. entries 4–7; Table 1). We then
focused our attention on in situ diazotisation/azidation followed
by cycloaddition reaction in order to get access to the desired
seven-membered 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-ones 5.
Accordingly, phenyl-substituted alkyne 11a was subjected to
diazotisation reaction using sodium nitrite in dilute HCl. Sub-
sequent treatment of the generated diazonium salt with sodium
azide furnished the corresponding azido derivative as expected,
which was confirmed through isolation followed by spectroscopic
characterizations. We then decided to heat the reaction mixture
without isolating the intermediate azido compound in order
to carry out the cycloaddition in situ. Pleasingly, the reaction
was found to be complete within 15 min upon heating at 100
◦C, leading to the formation of the desired N-methyl-3-phenyl-
1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-one 5a with 85% yield
(entry 1, Table 1). The same reaction protocol was adopted
in the general synthesis of the products 5b–g, starting from
their amine precursors 11b–g (entries 2–7, Table 1) with 74–85%
yields.
Scheme 1 Synthesis of 1,2,3-triazolo-benzoxazine.13b
We then decided to change the strategy and explore the
findings noted in our general synthesis of compounds 5–6. More
specifically, we decided to employ the Sonogashira coupling
reaction15 of aryl iodides 8 with 2-amino-N-methyl-N-(prop-
2-ynyl)benzamide 10a (or higher homologue 10b) in order to
get the corresponding aryl-substituted alkyne 11 (or 12), which
upon subsequent diazotisation/azidation followed by concurrent
cycloaddition would lead to the formation of the desired product
Encouraged by the results obtained, we next turned our
attention to synthesise 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-
ones 6, the eight-membered analogues of products 5, employing
Scheme 2 Synthesis of 1,2,3-triazolo[1,5-a][1,4]benzodiazopin-6-ones and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones (5–6).
4972 | Org. Biomol. Chem., 2010, 8, 4971–4977 This journal is The Royal Society of Chemistry 2010
©

View Article Online
Table 1 Sonogashira coupling followed by in situ diazotisation, azidation, and cycloaddition reactions leading to the formation of products 5–6
Aryl Iodide
(ArI) Ar, 8
Productsa 11–12
Productsc 5–6
Overall
Yield(%)
Entry
1
(Yield%)b
(Yield%)b
Heating time
15 min
11a (85)
5a (85)
73
2
3
4
5
11b (87)
5b (85)
15 min
15 min
15 min
15 min
74
11c (85)
11d (71)
11e (82)
5c (84)
5d (83)
5e (80)
72
59
65
6
7
11f (72)
11g (72)
5f (80)
5g (74)
15 min
15 min
58
52
8
9
10
11
12
8a
8e
8f
12a (81)
12b (79)
12c (75)
12d (68)
12e (76)
6a (39)
6b (46)
6c (41)
6d (51)
6e (55)
7 h
8 h
4.5 h
5 h
5 h
32
37
31
35
42
8g
a Reaction conditions: Iodide 8 (1.0 equiv.), Acetylene 10a or 10b (1.05 equiv.), Pd(PPh3)2Cl2 (0.04 equiv.), CuI (0.06 equiv.), Et3N (7.0 equiv.) in dry
DMF (4 mL) stirred at rt for 2 h. b Chromatographically isolated pure products. c Reaction conditions: 11 or 12 (1.0 equiv.), 2 N HCl (8 mL), a solution
of NaNO2 (1.4 equiv.) in water (2.0 mL), stirred at 0–3 ◦C for 30 min. Stirring another 1 h after the addition of a solution of NaN3 (1.4 equiv.) in water
(2.0 mL) followed by heating at 100 ◦C (for entries 1–7) or 130 ◦C after addition of DMSO (8.0 mL) (for entries 8–12).
the aforesaid reaction strategy. Accordingly, 2-amino-N-methyl-
N-(but-3-ynyl)benzamide 10b, the requisite starting compound,
was prepared by the reaction of isatoic anhydride and N-
methylhomopropargylamine under the same reaction conditions
as used in the synthesis of 10a. The C-arylation reactions were
carried out efficiently using various aryl iodides 8 at room
temperature for 2 h through palladium-copper catalysis affording
(68–81%) the di-substituted alkynes 12a–e (Scheme 2 and entries
8–12, Table 1). Interestingly, when 1-bromo-4-iodobenzene 8h was
employed as substrate, the iodo group selectively participated in
the reaction as coupling partner (entry 12, Table 1). The interme-
diate amines 12a–e could easily be converted to the corresponding
azido derivatives following the diazotisation/azidation protocol
as described earlier. However, in contrast to observations in the
synthesis of seven-membered ring products 5, in situ cycloaddition
occurred (entries 8–12, Table 1) only upon addition of some
amount of DMSO (8 mL) to the reaction mixture (12 mL)
containing azide followed by immediate heating at 130 ◦C for few
hours. The yields (39–55%) of eight membered ring products 6 were
found to be somewhat lower compared to their seven-membered
analogues 5.
Products 5–6 were well characterised by spectroscopic and
analytical data. Further structural confirmation came from X-ray
diffraction analysis of the products 5a and 6a (Fig. 2).17
Because of the importance of 6H-1,2,3-triazoloben-
zodiazepines18a-c and their corresponding eight-membered
variants,18d-e which serve as core structures in various
compounds having interesting pharmacological properties,18
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4971–4977 | 4973
©

View Article Online
1640 cm-1 attributable to cyclic amide was observed, while in
1H-NMR, the appearance of appropriate signals for the newly
generated benzylic protons besides the other protons provided
evidence regarding the formation of targeted products 13–14. It
was further confirmed by other spectroscopic and analytical data.
Thus, the success of our work has been extended through the
synthesis of these important classes of compounds.
Conclusions
In summary, we have described an established approach for
the general synthesis of 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-
ones/[1,5]benzodiazocin-7-ones with moderate to good overall
yields. The amides could be smoothly reduced, affording the
corresponding amine analogues. The reaction protocol requires
cheap starting materials and is carried out under mild reac-
tion conditions. It utilizes one-pot reactions involving diazotisa-
tion/azidaton followed by concurrent cycloaddition in water (or
using some amount of DMSO as co-solvent in few cases) and is
very easy to operate. Overall, this reaction approach is very simple,
convenient and cost effective.
Experimental section
General procedure for the synthesis of products 5 through in situ
diazotisation/azidation followed by concurrent cycloaddition
To a stirred and cooled (0–3 ◦C) solution of 11 (0.90 mmol) in
2 N HCl (8.0 mL) was added NaNO2 (87 mg, 1.26 mmol) in 2
mL H2O dropwise during 35 min and the mixture was allowed
to stir for another 30 min at the same temperature. A solution
of NaN3 (82 mg, 1.26 mmol) in 2 mL H2O was added dropwise
during 35 min under ice-cooled condition and the stirring was
continued for another 15 min. The reaction mixture was allowed
to come to room temperature during about 45 min. It was then
heated at 100 ◦C for 15 min. After completion of the reaction, as
checked by TLC, it was extracted with chloroform (2 ¥ 30 mL). The
combined organic extracts were washed with brine (20 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The resulting
crude residue was purified by silica gel (100–200 mesh) column
chromatography using 30–45% ethyl acetate in hexane (v/v) as
eluent to afford the product 5.
Fig. 2 Crystal structure of products 5a and 6a.
we became interested in getting easy access to 1,2,3-triazolo[1,5-
a][1,4]benzodiazepines/[1,5]benzodiazocines 13–14 as a sequel
to this work. When the products 5–6 were treated with lithium
aluminium hydride (LAH) in dry THF under reflux for 2
h, reduction of the amide functionality took place smoothly
affording the corresponding amine derivatives 13–14 with
moderate to good yields (Scheme 3 and Table 2). Structures of
all the products could easily be assigned through spectroscopic
and analytical evidences. In IR, disappearance of a peak around
5-Methyl-3-phenyl-[1,2,3]triazolo[1,5-a][1,4]benzodiazepin-6(4H)-
one (5a). Yield, 85%; solid, mp 178–180 ◦C; 1H NMR (300 MHz,
CDCl3) d 3.27 (s, 3H), 4.62 (s, 2H), 7.46–7.61 (m, 4H), 7.72–7.75
(m, 3H), 8.06 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 36.1, 41.8, 122.4, 127.0, 127.2, 128.6,
128.9, 129.0, 129.7, 130.7, 131.9, 132.6, 143.4, 166.2; IR (KBr,
cm-1) 3048, 2935, 1640, 1484, 1451, 1393; MS (ESI) (m/z) 313.13
(M+Na+). Anal. Calcd for C17H14N4O: C, 70.33; H, 4.86; N,
19.30. Found: C, 70.26; H, 4.88; N, 19.35.
Scheme 3 Reduction of products 5–6.
a
Table 2 Reduction of products 5–6 using LiAlH4
Entry
1
2
3
4
5
6
7
5-Methyl-3-(1-naphthyl)-[1,2,3]triazolo[1,5-a][1,4]benzodiaze-
pin-6(4H)-one (5b). Yield 85%, Solid, mp 200–202 ◦C; 1H NMR
(300 MHz, CDCl3) d 3.13 (s, 3H), 4.40 (s, 2H), 7.50–7.63 (m, 5H),
Substrate
Product
5a
13a
60
5b
13b
63
5e
13c
69
5f
13d
66
5g
13e
70
6a
14a
36
6b
14b
42
Yield(%)b
7.76 (t, J = 7.2 Hz, 1H), 7.95–8.01 (m, 3H), 8.13–8.16 (m, 2H); 13
C
a Reaction conditions: Product 5 or 6 (0.25 equiv.), LiAlH4 (1.0 equiv.) in
dry THF (7.0 mL) was heated under reflux for 2 h. b Chromatographically
isolated pure products.
NMR (75 MHz, CDCl3) d 36.4, 41.6, 122.4, 125.1, 125.2, 126.3,
126.5, 126.8, 127.0, 128.1, 128.3, 128.9, 129.6, 131.9, 132.2, 132.7,
132.8, 133.7, 142.6, 166.4; IR (KBr, cm-1) 3053, 1643, 1488, 1393,
4974 | Org. Biomol. Chem., 2010, 8, 4971–4977
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
1254, 1134; MS (ESI) (m/z) 341.13 (M+H+), 363.11 (M+Na+).
Anal. Calcd for C21H16N4O: C, 74.10; H, 4.74; N, 16.46; Found:
C, 74.05; H, 4.76; N, 16.49.
Calcd for C17H13FN4O: C, 66.23; H, 4.25; N, 18.17; Found: C,
66.19; H, 4.29; N, 18.12.
General procedure for the synthesis of products 6 through in situ
diazotisation/azidation followed by concurrent cycloaddition
5-Methyl-3-(3-pyridyl)-[1,2,3]triazolo[1,5-a][1,◦4]benzodiaze-
pin-6(4H)-one (5c). Yield 84%, Solid, mp 159–161 C; 1H NMR
(600 MHz, DMSO-d6) 3.06(s, 3H), 4.73 (s, 2H), 7.62 (t, J = 7.2 Hz,
1H), 7.74 (t, J = 7.2 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.89–7.91
(m, 2H), 8.57 (d, J = 7.2 Hz, 1H), 8.72 (br s, 1H), 9.03 (br s,
1H); 13C NMR (150 MHz, DMSO-d6)d 36.7, 41.9, 123.4, 127.5,
127.8, 128.8, 130.7, 132.5,132.6,134.2, 134.6, 139.0, 141.4, 143.3,
145.1, 167.0; IR (KBr, cm-1) 1640, 1482, 1385, 1263, 1134; MS
(ESI) (m/z) 292.04 (M+H+), 314.02 (M+Na+). Anal. Calcd for
C16H13N5O: C, 65.97; H, 4.50; N, 24.04; Found: C, 65.93; H, 4.47;
N, 23.98.
To a well-stirred and cooled (0–3 ◦C) solution of 12 (0.90 mmol)
in 2 N HCl (8.0 mL) was added a solution of NaNO2 (87 mg,
1.26 mmol) in 2 mL H2O dropwise during 35 min and the mixture
was allowed to stir for another 30 min at the same temperature.
A solution of NaN3 (82 mg, 1.26 mmol) in 2 mL H2O was added
dropwise during 35 min under ice-cooled condition and the stirring
was continued for another 15 min at the same temperature. The
reaction mixture was then allowed to come to room temperature
during about 45 min and DMSO (8 mL) was added to the reaction
mixture. The resulting mixture was then heated at 130 ◦C until
the completion of the reaction (monitored by TLC). It was then
cooled and extracted with chloroform (2 ¥ 20 mL); the extract was
washed with brine (15 mL) and dried over Na2SO4. The solvent
was evaporated under reduced pressure and the crude product was
purified through column chromatography over silica gel (100–200
mesh) using 20–50% ethyl acetate in hexane (v/v) as eluent to
furnish the product 6.
5-Methyl-3-(2-methylphenyl)-[1,2,3]triazolo[1,5-a][1,4]benzo-
◦
diazepin-6(4H)-one (5d). Yield 83%, Solid, mp 136–138 C;1H
NMR (300 MHz, CDCl3) d 2.38 (s, 3H), 3.19 (s, 3H), 4.39 (s,
2H), 7.24–7.38 (m, 4H), 7.59 (t, J = 7.35 Hz, 1H), 7.73 (t, J =
7.5 Hz, 1H), 8.10 (t, J = 7.8 Hz, 2H), 13C NMR (75 MHz, CDCl3)
d 20.2, 36.2, 41.5, 122.3, 125.8, 127.0, 128.5, 128.8, 129.1, 130.0,
130.8, 131.8, 132.1, 132.7, 132.8, 137.9, 143.7, 166.3; IR (KBr,
cm-1) 2916, 1639, 1487, 1396, 1252, 1136; MS (ESI) (m/z) 305.06
(M+H+), 327.04 (M+Na+). Anal. Calcd for C18H16N4O: C, 71.04;
H, 5.30; N, 18.41; Found: C, 71.08; H, 5.27; N, 18.37.
6-Methyl-3-phenyl-[1,2,3]triazolo[1,5-a][1,5]benzodiazocin-7-
(4H)-one (6a). Yield 39%; Solid, mp 204–206 ◦C; 1H NMR
(600 MHz, CDCl3) d 2.97 (s, 3H), 3.05 (dd, J = 16.8, 4.2 Hz,
1H), 3.38 (ddd, J = 15.3, 6.6, 0.8 Hz, 1H), 3.68 (ddd, J = 17.1,
13.5, 6.9 Hz, 1H), 4.08 (ddd, J = 15.3, 13.5, 5.1 Hz, 1H), 7.42 (t,
5-Methyl-3-(4-methylphenyl)-[1,2,3]triazolo[1,5-a][1,4]benzo-
◦
diazepin-6(4H)-one (5e). Yield 80%, Solid, mp 221–223 C;1H
J = 7.2 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.60–7.66 (m, 6H); 13
C
NMR (300 MHz, CDCl3) d 2.44 (s, 3H), 3.26 (s, 3H), 4.60 (s,
2H), 7.33 (d, J = 7.5 Hz, 2H), 7.56–7.64 (m, 3H), 7.72 (t, J =
NMR (150 MHz, CDCl3) d 23.0, 32.6, 46.3, 127.3, 127.9, 128.2,
128.6, 128.7, 129.3, 130.5, 130.6, 131.0, 132.2, 134.4, 146.0, 167.8;
IR (KBr, cm-1) 3065, 2959, 1646, 1486, 1267, 1075; MS (EI) (m/z)
304, 276, 261, 204; Anal. Calcd. for C18H16N4O: C, 71.04; H, 5.30;
N, 18.41; Found C, 71.10; H, 5.34; N, 18.37.
7.4 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) d 21.1, 36.1, 42.0, 122.5, 127.2, 128.8,
129.7, 130.5, 132.1, 132.6, 133.0, 138.6, 143.6, 166.3; IR (KBr,
cm-1) 2916, 1639, 1486, 1393, 1255, 1136; MS (ESI) (m/z) 305.14
(M+H+), 327.11 (M+Na+). Anal. Calcd for C18H16N4O: C, 71.04;
H, 5.30; N, 18.41; Found: C, 71.08; H, 5.27; N, 18.46.
6-Methyl-3-(4-methylphenyl)-[1,2,3]triazolo[1,5-a][1,5]benzodi-
◦
1
azocin-7-(4H)-one (6b). Yield 46%; Solid, mp 203–205 C; H
NMR (300 MHz, CDCl3) d 2.42 (s, 3H), 2.97–3.06 (m, 4H), 3.37
(dd, J = 15.1, 6.7 Hz, 1H), 3.66 (ddd, J = 16.4, 13.2, 6.6 Hz, 1H),
4.08 (td, J = 14.3, 4.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.54
(d, J = 7.8 Hz, 2H), 7.63 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 21.2, 22.9, 32.5, 46.3, 127.3, 127.5, 127.8, 128.5, 129.0, 129.4,
130.5, 130.9, 132.1, 134.4, 138.0, 145.9, 167.8; IR (KBr, cm-1)
3071, 2923, 1642, 1482, 1267, 1073; MS (EI) (m/z) 318, 290, 275,
217, 204; Anal. Calcd. for C19H18N4O: C, 71.68; H, 5.70; N, 17.60;
Found C, 71.62; H, 5.74; N, 17.63.
5-Methyl-3-(3-methoxyphenyl)-[1,2,3]triazolo[l,5-a][1,4]benzo-
◦
diazepin-6(4H)-one (5f). Yield 80%, Solid, mp 168–170 C;1H
NMR (300 MHz, CDCl3) 3.28(s, 3H), 3.90 (s, 3H), 4.63 (s, 2H),
7.00 (dd, J = 7.35, 1.5 Hz, 1H), 7.26 (m, 1H), 7.33–7.36 (m, 1H),
7.44 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.05 Hz,
1H), 8.05 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 36.0, 41.7, 55.1, 112.7, 114.2, 119.1, 122.3,
126.9, 128.9, 130.0, 130.8, 130.9, 131.9, 132.60, 132.63, 143.1,
159.9, 166.2; IR (KBr, cm-1) 3071, 2935, 1631, 1482, 1392, 1256,
1146; MS (ESI) (m/z) 321.04 (M+H+), 343.02 (M+Na+). Anal.
Calcd for C18H16N4O2: C, 67.49; H, 5.03; N, 17.49; Found: C,
67.59; H, 5.06; N, 17.54.
6-Methyl-3-(3-methoxyphenyl)-[1,2,3]triazolo[1,5-a][1,5]benzo-
diazocin-7-(4H)-one (6c). Yield 41%; Solid, mp 177–179 ◦C; 1H
NMR (600 MHz, CDCl3) d 2.97 (s, 3H), 3.03 (ddd, J = 16.6, 4.9,
0.9 Hz, 1H), 3.38 (ddd, J = 15.3, 6.9, 1.2 Hz, 1H), 3.69 (ddd, J =
17.1, 13.5, 6.9 Hz, 1H), 3.88 (s, 3H), 4.08 (ddd, J = 15.4, 13.6,
5.2 Hz, 1H), 6.96 (ddd, J = 8.2, 2.5, 0.7 Hz, 1H), 7.18 (dt, J = 7.5,
1.0 Hz, 1H), 7.25 (td, J = 2.1, 0.6 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H),
7.60–7.64 (m, 4H); 13C NMR (150 MHz, CDCl3) d 23.1, 32.6,
46.3, 55.3, 113.4, 114.0, 120.1, 127.4,128.6, 129.4, 129.7, 130.6,
131.0, 131.8, 132.2, 134.4, 145.8, 159.8, 167.8; IR (KBr, cm-1)
3059, 2925, 1644, 1488, 1252, 1078; HRMS (ESI) (m/z) Calcd.
For C19H18N4O2Na 357.1327. Found: 357.1326.
5-Methyl-3-(4-fluorophenyl)-[1,2,3]triazolo[1,5-a][1,4]benzodia-
zepin-6(4H)-one (5g). Yield 74%, Solid, mp 229–231 ◦C; 1H
NMR (300 MHz, CDCl3) d 3.26 (s, 3H), 4.59 (s, 2H), 7.20–7.26
(m, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.70–7.73 (m, 3H), 8.05 (d, J =
7.8 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 36.2, 41.8, 116.2 (d, J = 21.8 Hz), 122.5, 126.0 (d, J = 3.8 Hz),
127.1, 129.1, 129.2, 130.7, 132.1, 132.7, 132.8, 142.7, 162.9 (d, J =
247.5 Hz), 166.3; IR (KBr, cm-1) 3071, 1638, 1483, 1393, 1226,
1134; MS (ESI) (m/z) 309.09 (M+H+), 331.06 (M+Na+). Anal.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4971–4977 | 4975
©

View Article Online
6-Methyl-3-(4-fluorophenyl)-[1,2,3]triazolo[1,5-a][1,5]benzodia-
zocin-7(4H)-one (6d). Yield 51%; Solid, mp 218–220 ◦C; 1H
NMR (600 MHz, CDCl3) d 2.97 (s, 3H), 3.03 (ddd, J = 16.6,
4.9, 0.7 Hz, 1H), 3.39 (ddd, J = 15.6, 7.2, 1.2 Hz, 1H), 3.62 (ddd,
J = 16.8, 13.5, 6.9 Hz, 1H), 4.08 (ddd, J = 15.3, 13.5, 5.1 Hz,
1H), 7.18 (tt, J = 8.7, 2.3 Hz, 2H), 7.59–7.63 (m, 6H);13C NMR
(150 MHz, CDCl3) d 23.0, 32.6, 46.2, 115.8 (d, J = 21 Hz), 126.6
(d, J = 3.0 Hz), 127.3, 128.6, 129.2, 129.7 (d, J = 7.5 Hz), 130.7,
131.0, 132.1, 134.3, 145.1, 162.7 (d, J = 246 Hz), 167.7; IR (KBr,
cm-1) 3071, 2924, 1645, 1496, 1224, 1075; MS (EI) (m/z) 322, 294,
222; Anal. Calcd. For C18H15FN4O: C, 67.07; H, 4.69; N, 17.38;
Found C, 67.11; H, 4.66; N,17.34.
5-Methyl-3-(4-methylphenyl)-(4H)-[1,2,3]triazolo[1,5-a][1,4]-
benzodiazepine (13c). Yield 69%; Oil; 1H NMR (300 MHz,
CDCl3) d 2.42 (s, 3H), 2.52 (s, 3H), 3.61 (s, 2H), 3.72 (s, 2H), 7.30
(d, J = 7.8 Hz, 2H), 7.46–7.51 (m, 2H), 7.58 (td, J = 7.2, 2.4 Hz,
1H), 7.73 (d, J = 8.1 Hz, 2H), 7.95 (t, J = 7.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 21.2, 43.9, 47.1, 56.6, 122.7, 127.1, 127.7,
128.3, 128.9, 129.4, 129.5, 131.0, 136.6, 138.1, 145.4; IR (neat,
cm-1) 2949, 1484, 1455, 1253, 1132, 1005; MS (FAB+) (m/z) 291
(M + H+), 290, 262, 261; Anal. Calcd. for C18H18N4: C, 74.46; H,
6.25; N, 19.30. Found C, 74.52; H, 6.23; N, 19.35.
5-Methyl-3-(3-methoxyphenyl)-(4H)-[1,2,3]triazolo[1,5-a][1,4]-
benzodiazepine (13d). Yield 66%; Oil; 1H NMR (300 MHz,
CDCl3) d 2.53 (s, 3H), 3.60 (s, 2H), 3.74 (s, 2H), 3.89 (s, 3H),
6.95–6.97 (m, 1H), 7.39–7.54 (m, 5H), 7.58 (td, J = 6.52, 2.1 Hz,
1H), 7.95(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 44.0,
47.2, 55.3, 56.7, 112.5, 114.3, 119.5, 122.7, 128.6, 129.0, 129.5,
129.8, 130.0, 131.0, 131.9, 136.6, 145.1, 160.0; IR (neat, cm-1)
2944, 1487, 1246, 1032; MS (FAB+) (m/z) 307 (M + H+); Anal.
Calcd. for C18H18N4O: C, 70.57; H, 5.92; N, 18.29. Found C, 70.52;
H, 5.98; N, 18.27.
6-Methyl-3-(4-bromophenyl)-[1,2,3]triazolo[1,5-a][1,5]benzodi-
◦
1
azocin-7-(4H)-one (6e). Yield 55%; Solid, mp 274–276 C; H
NMR (300 MHz, CDCl3) d 2.97 (s, 3H), 3.04 (dd, J = 16.8, 4.8 Hz,
1H), 3.39 (dd, J = 15.0, 6.6 Hz, 1H), 3.62 (ddd, J = 16.7, 13.4,
6.9 Hz, 1H), 4.09 (ddd, J = 15.0, 13.6, 4.9 Hz, 1H), 7.47–7.66 (m,
8H); 13C NMR (75 MHz, DMSO-d6) d 22.3, 31.8, 45.6, 121.4,
127.2, 128.1, 129.5, 129.6, 130.86, 130.89, 131.2, 131.7, 132.3,
133.6, 143.7, 166.8; IR (KBr, cm-1) 1636, 1484, 1393; HRMS (ESI)
(m/z) Calcd. for C18H15BrN4ONa 405.0327 (M + Na+); Found:
405.0324.
5-Methyl-3-(4-fluorophenyl)-(4H)-[1,2,3]triazolo[1,5-a][1,4]ben-
zodiazepine (13e). Yield 70%; Oil; 1H NMR (300 MHz, CDCl3)
d 2.53 (s, 3H), 3.62 (s, 2H), 3.69 (s, 2H), 7.19 (t, J = 8.1 Hz, 2H),
7.45–7.52 (m, 2H), 7.59 (td, J = 7.1, 1.8 Hz, 1H), 7.79–7.84 (m,
2H), 7.94 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 43.9,
47.2, 56.6, 115.9 (d, J = 21.0 Hz), 122.7, 126.8 (d, J = 3.0 Hz),
128.4, 129.13, 129.14 (d, J = 8.3 Hz), 129.6, 129.8, 131.1, 136.5,
144.4, 162.8 (d, J = 246 Hz); IR (neat, cm-1) 2931, 1497, 1226, 1155,
1003; MS (FAB+) (m/z) 295 (M+H+), 266, 265; Anal. Calcd. for
C17H15FN4: C, 69.37; H, 5.14; N, 19.04. Found C, 69.41; H, 5.17;
N, 18.98.
General procedure for the synthesis of products 13 or 14 through
reduction using LiAlH4
To a well stirred solution of product 5 or 6 (0.25 mmol) in dry THF
(7.0 mL), lithium aluminium hydride (38 mg, 1.0 mmol) was added
and allowed to heat under reflux under argon atmosphere for 2 h.
It was cooled, diethyl ether (60 mL) was added followed by seven to
ten drops of water and the reaction mixture was kept under stirring
for five to ten min. A solid residue that appeared was filtered and
the organic layer from the filtrate was collected. The organic layer
was washed with water (15 mL) and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure and
the crude product was purified through column chromatography
over silica gel (100–200 mesh) using 30–40% ethyl acetate in hexane
(v/v) as eluent to afford the desired product 13 or 14.
6-Methyl-3-(phenyl)-(4H)-[1,2,3]triazolo[1,5-a][1,5]benzodiazo-
cine (14a). Yield 36%; Oil; 1H NMR (600 MHz, CDCl3) d 2.52
(s, 3H), 2.56 (br, 1H), 2.89 (br, 1H), 3.14 (br, 1H), 3.31(br, 2H), 3.78
(br, 1H), 7.39 (tt, J = 7.5, 1.2 Hz, 1H), 7.47–7.54 (m, 5H), 7.62–7.64
(m, 1H), 7.74–7.76 (m, 2H); 13C NMR (150 MHz, CDCl3) d 21.0,
44.1, 56.0, 56.4, 126.6, 127.2, 127.9, 128.8, 128.9, 129.9, 131.2,
132.2, 133.5, 134.6, 135.1, 144.1; IR (neat, cm-1) 3057, 2937, 1494,
1448, 1255; MS (ESI) (m/z) 291.22 (M + H+); MS (EI) (m/z) 290,
261, 218, 133; Anal. Calcd. For C18H18N4: C, 74.46; H, 6.25; N,
19.30. Found C, 74.41; H, 6.28; N, 19.36.
5-Methyl-3-phenyl-(4H)-[1,2,3]triazolo[1,5-a][1,4]benzodiaze-
pine (13a). Yield 60%; Solid, mp 124–126 ◦C; 1H NMR
(600 MHz, CDCl3) d 2.53 (s, 3H), 3.62 (s, 2H), 3.73 (s, 2H), 7.41 (tt,
J = 7.5, 1.4 Hz, 1H), 7.47 (td, J = 6.9, 1.2 Hz, 1H), 7.49–7.51 (m,
3H), 7.58 (td, J = 7.8, 1.8 Hz, 1H), 7.85 (dd, J = 7.8, 1.2 Hz, 2H),
7.95 (dd, J = 7.8, 1.2 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 44.0,
47.3, 56.7, 122.8, 127.3, 128.3, 128.5, 128.9, 129.0, 129.6, 129.9,
130.6, 131.0, 136.6, 145.3; IR (neat, cm-1) 2947, 2778, 1484, 1252,
1131; MS (FAB+) (m/z) 277 (M+H+); Anal. Calcd. for C17H16N4:
C, 73.89; H, 5.84; N, 20.27. Found C, 73.86; H, 5.81; N, 20.32.
6-Methyl-3-(4-methylphenyl)-(4H)-[1,2,3]triazolo[1,5-a][1,5]-
benzodiazocine (14b). Yield 42%; Oil; 1H NMR (600 MHz,
CDCl3) d 2.41 (s, 3H), 2.54 (s, 3H), 2.57 (br, 1H), 2.92 (br, 1H),
3.16 (br, 1H), 3.35 (br, 2H), 3.83 (br, 1H), 7.29 (d, J = 8.4 Hz,
2H), 7.50–7.53 (m, 3H), 7.61–7.64 (m, 3H); 13C NMR (150 MHz,
CDCl3) d 20.7, 21.2, 43.8, 55.7, 56.1, 126.6, 127.1, 128.1, 129.2,
129.5, 129.9, 132.4, 134.5, 134.8, 137.9, 144.3; IR (neat, cm-1) 3029,
2926, 1498, 1461, 1255; HRMS (ESI) (m/z) Calcd. For C19H21N4
305.1766 (M + H+). Found 305.1762.
5-Methyl-3-(1-naphthyl)-(4H)-[1,2,3]triazolo[1,5-a][1,4]benzo-
diazepine (13b). Yield 63%; Oil; 1H NMR (300 MHz, CDCl3) d
2.40 (s, 3H), 3.59 (s, 2H), 3.69 (s, 2H), 7.49–7.67 (m, 7H), 7.91–7.96
(m, 2H), 8.03 (d, J = 7.5 Hz, 1H), 8.18 (t, J = 4.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 43.9, 46.9, 56.7, 122.8, 125.2, 125.8,
126.1, 126.6, 127.4, 128.1, 128.2, 128.6, 129.0, 129.2, 129.5, 131.0,
131.9, 132.0, 133.8, 136.7, 144.7; IR (neat, cm-1) 3051, 2933, 2788,
1491, 1251; MS (ESI) (m/z) 327.25 (M + H+). Anal. Calcd. for
C21H18N4: C, 77.28; H, 5.56; N, 17.17. Found C, 77.34; H, 5.59; N,
17.19.
Acknowledgements
A.S. thanks CSIR, India for a fellowship. B.A. thanks CSIR, India
for an EMS grant. Partial financial support from CSIR net-work
project (IAP-0001) and DST (project no SR/S1/OC-42/2009) is
also gratefully acknowledged.
4976 | Org. Biomol. Chem., 2010, 8, 4971–4977
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
8 A. W. Thomas, Bioorg. Med. Chem. Lett., 2002, 12, 1881.
Notes and references
9 (a) T. Howard, in Comprehensive Heterocyclic Chemistry II, vol. 7., ed.
A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, New York,
1996, p. 151; (b) P. Herold, J. W. Herzig, P. Wenk, T. Leutert, P. Zbinden,
W. Fuhrer, S. Stutz, K. Schenker, M. Meier and G. Rihs, J. Med. Chem.,
1995, 38, 2946; (c) W. Heitmann, H. Liepmann, U. Matzel, H. Zeugner,
A. M. Fuchs, H. Krahling, M. Ruhland, F. Mol and M. T. M. Tulp,
Eur. J. Med. Chem., 1988, 23, 249.
1 (a) E. L. Eliel and S. H. Wilen, in Stereochemistry of Organic
Compounds, Wiley, New York, NY, 1994; (b) P. Appukkuttan, W.
Dehaen and E. Van Der Eycken, Org. Lett., 2005, 7, 2723; (c) D. R.
Spring, S. Krishna, H. E. Blackwell and S. L. Schreiber, J. Am. Chem.
Soc., 2002, 124, 1354; (d) K. C. Majumder, I. Ansary, B. Sinha and B.
Chattopadhyay, Synthesis, 2009, 3593.
2 (a) D. J. Greenblatt and R. I. Shader, in Benzodiazepines in Clinical
Practice, Raven Press, New York, 1974; (b) L. H. Sternbach, in The
Benzodiazepine Story, ed. F. Hoffmann-La Roche, Roche Scientific Ser-
vices, Basel, 2nd edn, 1983, P. 5; (c) J. K. Landquist, in Comprehensive
Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon,
Oxford, 1984, Vol. 1, p. 170; (d) G. Mohiuddin, P. S. Reddy, K. Ahmed
and C. V. Ratnam, Heterocycles, 1986, 24, 3489; (e) D. E. Thurston
and D. S. Bose, Chem. Rev., 1994, 94, 433; (f) A. A. Patchet and R.
P. Nargund, Annu. Rep. Med. Chem., 2000, 35, 289; (g) A. Witt and J.
Bergman, J. Org. Chem., 2001, 66, 2784; (h) S. Eguchi, Arkivoc, 2005,
(part ii), 98.
3 (a) T. Kaneko, H. Wong, T. W. Doyle, W. C. Rose and W. T. Bradner,
J. Med. Chem., 1985, 28, 388; (b) W. Zhang, J. P. William, Y. Lu,
T. Nagashima and Q. Chu, Tetrahedron Lett., 2007, 48, 563; (c) R.
M. Keenam, J. F. Callaham, J. M. Samanen, W. E. Bondinell, R. R.
Calvo, I. Chen, C. DeBrosse, D. S. Eggleston, R. C. Haltiwanger, S.
M. Hwang, D. R. Jakes, T. W. Ku, W. H. Miller, K. A. Newlander, A.
Nichols, M. F. Parker, L. S. Southhall, I. Uzinskas, J. A. Vasko-Moser,
J. W. Venslavsky, A. S. Wong and W. F. Huffmann, J. Med. Chem.,
1999, 42, 545; (d) F. Novelli, A. Sparatore, B. Tass and F. Sparatore,
Bioorg. Med. Chem. Lett., 1999, 9, 3031; (e) T. Sugimori, T. Okawa, S.
Eguchi, A. Kakehi, E. Yashima and Y. Okamoto, Tetrahedron, 1998,
54, 7997; (f) A. Walser and R. I. Fryer, in Chemistry of Heterocyclic
Compounds, Bicyclic Diazepines, ed. E. C. Taylor and A. Weissberger,
Wiley, Chichester, UK, 1991, Vol. 50, P. 431, Chapters V-VIII.
4 (a) K. M. Rahman, A. S. Thomson, C. H. James, M. Narayanaswamy
and D. E. Thurston, J. Am. Chem. Soc., 2009, 131, 13756; (b) T. Wang,
A. S. Lui and I. S. Cloudsdale, Org. Lett., 1999, 1, 1835; (c) A. Kamal,
V. Devaiah, K. L. Reddy and N. Shankaraiah, Adv. Synth. Catal., 2006,
348, 249; (d) For a review article on azole-fused benzodiazepines, see:
M. Gerecke, E. Kyburz, R. Borer and W. Gassner, Heterocycles, 1994,
39, 693; (e) D. K. Mohapatra, P. K. Maity, M. Shabab and M. I. Khan,
Bioorg. Med. Chem. Lett., 2009, 19, 5241; (f) S. Kobayashi, Bull. Chem.
Soc. Jpn., 1975, 48, 302.
10 (a) M. Alajarin, J. Cabrera, A. Pastor and J. M. Villalgordo, Tetrahedron
Lett., 2007, 48, 3495; (b) I. Akritopoulou-Zanze, V. Gracias and S. W.
Djuric, Tetrahedron Lett., 2004, 45, 8439; (c) D. L. Coffen, R. I. Fryer,
D. A. Katonak and F. Wong, J. Org. Chem., 1975, 40, 894; (d) G.
Broggini, G. Molteni, A. Terraneo and G. Zecchi, Tetrahedron, 1999,
55, 14803; (e) G. Broggini, I. De Marchi, M. Martinelli, G. Paladino and
A. Penoni, Lett. Org. Chem., 2004, 1, 221; (f) G. Broggini, I. De Marchi,
M. Martinelli, G. Paladino, T. Pilati and A. Terraneo, Synthesis, 2005,
2246.
11 Zecchi and coworkers synthesised few specific derivatives (R1
=
Ph/Me/H, R2 = Ph) of [1,2,3]triazolo[1,5-a][1,4]benzodiazepines 5
through multi-step approach using alkynyl bromide, which is not easily
accessible. For details see: G. Broggini, G. Molteni and G. Zecchi,
Synthesis, 1995, 647.
12 (a) H. Yoshida, E. Shirakawa, Y. Honda and T. Hiyama, Angew.
Chem., Int. Ed., 2002, 41, 3247; (b) J. B. Bremner and W. Sengpracha,
Tetrahedron, 2005, 61, 941; (c) I. O’Neil, C. L. Murray, A. J. Potter and
S. B. Kalindjian, Tetrahedron Lett., 1997, 38, 3609.
13 (a) C. Chowdhury, S. Mukherjee, B. Das and B. Achari, J. Org. Chem.,
2009, 74, 3612; (b) C. Chowdhury, A. K. Sasmal and P. K. Dutta,
Tetrahedron Lett., 2009, 50, 2678; (c) C. Chowdhury, S. B. Mandal and
B. Achari, Tetrahedron Lett., 2005, 46, 8531.
14 L. Garanti, G. Molteni and G. Broggini, J. Chem. Soc., Perkin Trans.
1, 2001, 1816; See also ref. 4e and 10d.
15 (a) K. Sonogashira, Y. Tohda and N. Haghihara, Tetrahedron Lett.,
1975, 16, 4467; (b) K. Sonogashira, in Comprehensive Organic Synthesis,
ed. B. M. Trost, Pergamon, Oxford, 1991, vol 3, p. 521.
16 M. C. Venuti, Synthesis, 1982, 266.
17 The crystal data has been deposited at Cambridge Crystallographic
Data Centre [CCDC No: 774490 for product 5a and 775332 for
product 6a]. Copies of the data can be obtained free of charge
via www.ccdc.ac.uk/conts/retrieving.html or CCDC, 12 union Road,
Cambridge CB2 1EZ, UK.
18 For preclinical antitumor activities, see: (a) J. T. Hunt, C. Z. Ding, R.
Batorsky, M. Bednarz, R. Bhide, Y. Cho, S. Chong, S. Chao, J. Gullo-
Brown, P. Guo, S. H. Kim, F. Y. F. Lee, K. Leftheris, A. Miller, T.
Mitt, M. Patel, B. A. Penhallow, C. Ricca, W. C. Rose, R. Schmidt, W.
A. Slusarchyk, G. Vite and V. Manne, J. Med. Chem., 2000, 43, 3587;
For anti-HIV activities, see: (b) K. A. Perker and C. A. Coburn, J.
Org. Chem., 1992, 57, 97; For antifungal agents, see: (c) L. Meerpoel,
J. V. Gestel, F. V. Gerven, F. Woestenborghs, P. Marichal, V. Sipido, G.
Terence, R. Nash, D. Corens and R. D. Richards, Bioorg. Med. Chem.
Lett., 2005, 15, 3453; For inhibitors of hepatitis C virus, see: (d) I.
Stansfield, C. Ercolani, A. Mackay, I. Conte, M. Pompei, U. Koch, N.
Gennari, C. Giuliano, M. Rowley and F. Narjes, Bioorg. Med. Chem.
Lett., 2009, 19, 627; For other activities, see: (e) J. Rujirawanich and T.
Gallagher, Org. Lett., 2009, 11, 5494.
5 (a) P. J. Snyder, J. Werth, B. Giordani, A. F. Caveney, D. Feltner and
P. Maruff, Hum. Psychopharmacol. Clin. Exp., 2005, 20, 263; (b) J.
Levine, D. P. Cole, K. N. Roy Chengappa and S. Gerson, Depress.
Anxiety, 2001, 14, 94; (c) G. L. Post, R. O. Patrick, J. E. Crowder, J.
Houston, J. M. Ferguson, R. J. Bielski, L. Bailey, H. G. Pearlman, V. S.
Shu and M. W. Pierce, J. Clin. Psychopharmacol., 1991, 11, 249; (d) D.
J. Greenblatt, J. S. Harmatz, L. Shapiro, N. Engelhardt, T. A. Gouthro
and T. A. Shader, N. Engl. J. Med., 1991, 324, 1691.
6 (a) W. Frostl and L. Maitre, Pharmacopsychiatry, 1989, 22, 54;
(b) S. R. Donohue and R. F. Dannals, Tetrahedron Lett., 2009, 50,
7271.
7 A. G. Katsifis, M. E. McPhee, F. Mattner and D. D. Ridley, Aust. J.
Chem., 1999, 52, 1061 and see also reference 4e.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4971–4977 | 4977
©