Synthesis of tetrazolo-fused benzodiazepines and benzodiazepinones by a two-step protocol using an Ugi-azide reaction for initial diversity generation

Article abstract of DOI:10.1016/j.tet.2012.04.068

A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the four-component Ugi-azide reaction to afford MCR (MultiComponent Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.

Full text of DOI:10.1016/j.tet.2012.04.068

Tetrahedron 68 (2012) 5606e5611
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of tetrazolo-fused benzodiazepines and benzodiazepinones by a
two-step protocol using an Ugi-azide reaction for initial diversity generation
Steven Gunawan, Muhammad Ayaz, Fabio De Moliner, Brendan Frett, Christine Kaiser, Nina Patrick,
*
Zhigang Xu, Christopher Hulme
Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2012
Received in revised form 16 April 2012
Accepted 18 April 2012
Available online 26 April 2012
A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzo-
diazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenyl-
glyoxaldehydes or ethyl glyoxylate in the four-component Ugi-azide reaction to afford MCR
(MultiComponent Reactions) derived adducts equipped with the desired diversity inputs. A subsequent
acidic treatment (TFA/DCE) allows a simultaneous deprotectionecyclization leading to the final products.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzodiazepines
Benzodiazepinones
Tetrazoles
Ugi reaction
TMSeN3
1. Introduction
activities of compounds 1 and 2. Lotrafiban6 interacts highly se-
lectively with the integrin GPIIbIIIa, whereas 2 binds highly prefer-
The benzodiazepine family represents one of the most prom-
inent classes of privileged scaffolds in medicinal chemistry.1 Other
than their well-known properties as psychoactive drugs, which
function as sedative-hypnotics, anxiolytic, muscle relaxants, and
anticonvulsants,2 they display a plethora of further activity patterns
ranging from anticancer3 and anti-HIV properties4 to cholecysto-
kinin receptors antagonism.5 Furthermore, this class possesses
several examples of diverse biological activities of closely related
structural analogs. One such example can be seen by comparing
entially to the integrin avb
3 receptor.7 This change was merely
initiated by simple modification of the ‘west-side’ amine group,
thought to recognize the RGD motif (Fig. 1).
Multicomponent reactions have recently met renewed interest
due to their capability to generate high molecular diversity through
conceptually and operationally simple chemistry, able to build
complex molecules incorporating diversity reagents in an atom
economic fashion.8 Indeed, since a widely exploited approach to
elaborate MCR adducts consists of rigidifying them into nitrogen-
Fig. 1. Structurally close benzodiazepine-based drugs showing different activities.
containing heterocycles,9 a number of MCR based benzodiazepine
syntheses have been reported.10
* Corresponding author. E-mail address: hulme@pharmacy.arizona.edu
(C. Hulme).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.068

S. Gunawan et al. / Tetrahedron 68 (2012) 5606e5611
5607
2. Results and discussion
DCE solution at elevated temperature (MW, 10 min, 120 ꢀC). Hence,
validation of the protocol was performed by preparing a small five-
member (8aee) collection with good overall yields (Fig. 2,
Scheme 2).
Whereas characterization of Ugi product 7 was skipped for the
sake of procedural simplicity, unambiguous X-ray structural as-
signment was achieved for 8a (Fig. 3).16
With a validated route in hand for five examples, we then pro-
ceeded with a parallel synthesis production campaign of 48 com-
pounds (general structure 8) on a 0.2 mM scale. To our delight, after
high-throughput purification by preparative HPLCeMS systems, all
but one reaction was found to be successful, even if recovered
amounts were extremely variable. From high-throughput perspec-
tive, extreme robustness of the strategy was demonstrated, at least
for the amine input. In fact, while no additional isocyanides other
than the two used in the validation phase were tried, 48 different
secondary amines made up the diversity-enhancing pool.
Having developed an operationally friendly fast entry into an
interesting fused heterocyclic scaffold containing a benzodiazepine
and a tetrazole,17 our next goal was to investigate replacement of
ethyl glyoxylate with arylglyoxaldehydes to pave the way toward
other chemotypes (10 and 11), and also to increase the number of
diversity reagents by one over the first methodology. Arylglyox-
aldehydes are indeed commercially available, and the additional
carbonyl group they contain is ideal for reaction with unmasked
internal amino nucleophiles. In this case, use of trifluoroethanol
proved to be unnecessary, as methanol was capable to provide
comparable yields under the same conditions, and cyclization step
turned out to be even easier to accomplish, (MW, 10 min, 80 ꢀC).
Although good overall yields were obtained and the scope was ex-
tended to both primary and secondary amines, two distinct sets of
compounds were isolated (Fig. 4, Scheme 3). Indeed, while adducts 9
derived from primary amines constantly led to enamine-type
structures 10, their analogues stemming from the incorporation of
a secondary amine input furnished either adducts 10 or 11. Over and
above this issue, both 10 and 11 showed marked tendency to in-
stability and after long term storage as dried solids at room tem-
perature or short term exposure to silica gel or other acidic media,
conversion into a plethora of degradation products was observed,
probably via both hydrolysis and oxidation. Consequently, pro-
gression to parallel production of benzotetrazolodiazepines 10 and
11 was not carried out. Interconversion of structures 10 and 11 under
acidic, basic or thermal conditions was never observed.
In continuation of our studies on the generation of potentially
medicinally relevant chemotypes via the efficient post-
condensation modifications of the Ugi reaction,11 we envisioned
the possibility of fusing the multipurpose benzodiazepine core with
the similarly interesting tetrazole moiety. Lately, we have explored
the use of the Ugi-azide reaction to fruitfully embed the afore-
mentioned scaffold in multicomponent derived backbones, which
were subsequently submitted to secondary transformations
resulting in drug-like entities.12 In fact, the 1,5-disubstituted tet-
razole ring has been identified as a surrogate of the cis-amide
peptide bond,13 opening new scenarios toward the preparation of
peptidomimetics with enhanced in vivo stability.
The well-established TMSeN3 variant of the Ugi four-compo-
nent condensation also constitutes the first and key step of this
work. The process differs from the regular Ugi reaction with azi-
dotrimethylsilane being used as a replacement for the carboxylic
acid, while the other three inputs remain the same (Scheme 1).
Scheme 1. Mechanism of the four-component Ugi-azide reaction (compatible with
primary or secondary amines).
In this case, azide plays the role of the nucleophile instead of the
carboxylate ion and traps the nitrilium intermediate species 4,
resulting in the formation of the 1,5-disubstututed tetrazole 6 upon
intramolecular cyclization.14 We initially decided to employ cyclic
secondary amines and ethyl glyoxylate as the carbonyl input, along
with the azide source and ortho-N-Boc phenylisocyanides, our plan
being to endow the resulting products 7 with both an electrophilic
ester functionality and a masked amino nucleophile. According to
our experience, subsequent acidic treatment was most likely to
cleave the Boc group and trigger cyclization rendering benzodiaze-
pinones 8. The multicomponent step proceeded smoothly under
mild conditions, especially when trifluoroethanol (TFE) was used as
the solvent. Indeed, such a phenomenon is well-known and is the
outcome of the low nucleophilicity of TFE, still a polar protic solvent
suitable for the Ugi reaction, but unlike methanol unable to attack
the electrophilic Schiff base intermediate.15 In order to keep the
whole process simple and tailored forhigh-throughput applications,
crude products were only quickly passed through flash chroma-
tography and the semi-purified compounds 7 were directly sub-
mitted to the cyclization step. Predictably, the secondary
transformation was readily promoted by dissolving 7 in a 10% TFA/
3. Conclusions
In summary, we have described herein an efficient and
straightforward preparation of tetrazolo-fused benzodiazepines
and benzodiazepinones involving an Ugi-azide multicomponent
reaction for initial diversity generation followed by an acid-
promoted post-condensation cyclization step. The procedure is
perfectly amenable for high-throughput applications and library
production for the benzodiazepinones 8 and, notwithstanding the
previously discussed limitations, it represents a useful tool to gain
Scheme 2. Synthetic route toward tetrazolo-fused benzodiazepinones 8.

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S. Gunawan et al. / Tetrahedron 68 (2012) 5606e5611
Fig. 2. The pivotal collection of benzodiazepinones 8. Yields represent the combined two overall steps.
Fig. 3. Solved crystal structure of 8a showing two unique molecules in the asymmetric unit.
Scheme 3. Synthetic route toward tetrazolo-fused benzodiazepines 10 and 11.
access to richly substituted benzodiazepines 10 and 11, which are
relatively stable when stored at low temperature.
uncorrected. NMR spectra were recorded in CDCl3 at 400 MHz (1H
NMR) and 100 MHz (13C NMR). Low and high resolution mass
spectra were obtained using ESI methods.
4. Experimental section
4.1. General
4.2. General procedure for the preparation of
benzotetrazolodiazepinones 8
Solvents were purchased from commercial providers and used
without further purification. Other reagents were used as obtained
from commercial providers except when otherwise noted. Analyt-
ical thin layer chromatography (TLC) was performed on pre-coated
silica gel plates. Visualization was accomplished with UV light or by
staining with basic KMnO4 solution. Column chromatography was
performed using automated chromatographic systems. Melting
points were determined in an open glass capillary and are
Ethyl glyoxylate (1 mmol, 102 mg), amine (1 mmol), azido-
trimethylsilane (1 mmol, 115 mg), and isocyanide (1 mmol) were
dissolved in trifluoroethanol (0.5 mL) in a 10 mL MW vial. The re-
action was allowed to run at room temperature for 24 h. Crude
mixture was concentrated in vacuo and purified by flash chroma-
tography (hexane/EtOAc). Ugi adduct was then dissolved in a 10%
TFA/DCE solution and heated at 120 ꢀC for 10 min by means of
microwave irradiation. Reaction mixture was diluted with EtOAc

S. Gunawan et al. / Tetrahedron 68 (2012) 5606e5611
5609
Fig. 4. Synthesized benzodiazepines 10 and 11. Yields represent the combined two overall steps.
(15 mL) and washed with NaHCO3 satd solution (15 mL). The
aqueous phase was then re-extracted with EtOAc (15 mL), com-
bined organics were dried over MgSO4, and crude mixture was
purified by flash chromatography (Hexane/EtOAc) to afford
expected benzotetrazolodiazepinones.
127.0, 123.7, 123.1, 122.1, 66.5, 52.3, 25.7, 24.1, 20.1, 19.7;
[MþH]þ¼313.3; HRMS (ESI): m/z calcd for C16H21N6O [MþH]þ:
313.1771, found: 313.1766.
4.2.4. 4-(4-Benzylpiperidin-1-yl)-8,9-dimethyl-4H-benzo[b]tetrazolo
[1,5-d][1,4]diazepin-5(6H)-one (8d). White solid, 28% yield; product
purified using 5e50% EtOAc in hexane gradient; mp 207e208 ꢀC;
4.2.1. 4-(Piperidin-1-yl)-4H-benzo[b]tetrazolo[1,5-d][1,4]diazepin-
5(6H)-one (8a). White solid, 54% yield; product purified using
5e50% EtOAc in hexane gradient; mp 225e227 ꢀC; 1H NMR
1H NMR (400 MHz, CDCl3)
d ppm 9.27 (br s, 1H), 7.71 (s, 1H),
7.27e7.13 (m, 4H), 7.07e6.97 (m, 3H), 4.75 (s, 1H), 2.90 (d,
J¼10.9 Hz, 1H), 2.39 (s, 6H), 2.35 (s, 1H), 2.22e1.91 (m, 3H),
1.57e1.29 (m, 3H), 0.97e0.61 (m, 2H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d
ppm 9.23 (s,1H), 7.95 (dd, J¼8.1,1.4 Hz,1H), 7.53
(td, J¼7.8, 1.5 Hz, 1H), 7.40 (td, J¼7.8, 1.3 Hz, 1H), 7.25 (dd, J¼8.0,
1.3 Hz, 1H), 4.78 (s, 1H), 2.59e2.21 (m, 2H), 2.20e1.91 (m, 2H),
d
ppm 168.2, 150.3, 140.5, 140.0, 135.4, 129.4, 128.6, 126.9, 126.3,
1.34e1.01 (m, 6H); 13C NMR (100 MHz, CDCl3)
d
ppm 168.1, 150.8,
123.60, 123.1, 122.1, 66.1, 51.8, 51.5, 43.0, 37.8, 31.9, 31.8, 20.1, 19.7;
[MþH]þ¼403.2; HRMS (ESI): m/z calcd for C23H27N6O [MþH]þ:
403.2241, found: 403.2245.
130.7, 129.6, 126.3, 122.8, 121.3, 66.4, 52.2, 25.8, 24.1;
[MþH]þ¼285.2; HRMS (ESI): m/z calcd for C14H17N6O [MþH]þ:
285.1459, found: 285.1459.
4.2.5. 8,9-Dimethyl-4-(pyrrolidin-1-yl)-4H-benzo[b]tetrazolo[1,5-d]
[1,4]diazepin-5(6H)-one (8e). White solid, 39% yield; product pu-
rified using 5e80% EtOAc in Hexane gradient; mp >250 ꢀC; 1H
4.2.2. 4-(4-Benzylpiperidin-1-yl)-4H-benzo[b]tetrazolo[1,5-d][1,4]di-
azepin-5(6H)-one (8b). White solid, 63% yield; product purified
using 5e40% EtOAc in hexane gradient; mp 198e199 ꢀC; 1H NMR
NMR (400 MHz, CDCl3)
1H), 4.78 (s, 1H), 2.63e2.52 (br m, 4H), 2.36 (s, 6H), 1.67e1.56 (br
m, 4H); 13C NMR (100 MHz, CDCl3)
ppm 168.5, 150.7, 140.1,
d ppm 9.39 (s, 1H), 7.74 (s, 1H), 7.01 (s,
(400 MHz, CDCl3)
d
ppm 9.49 (s, 1H), 7.97 (dd, J¼8.0, 1.2 Hz, 1H),
7.55 (td, J¼7.6, 1.2 Hz, 1H), 7.43 (td, J¼7.6, 0.9 Hz, 1H), 7.30e7.11 (m,
5H), 7.02 (d, J¼6.8 Hz, 1H), 4.79 (s, 1H), 2.89 (d, J¼10.8 Hz, 1H), 2.33
(d, J¼6.8 Hz, 2H), 2.21e1.90 (m, 3H), 1.69e1.33 (m, 3H), 0.98e0.49
d
135.4, 126.8, 123.34, 123.28, 122.4, 64.5, 52.1, 24.0, 20.1, 19.7.
[MþH]þ¼299.1; HRMS (ESI): m/z calcd for C15H19N6O: 299.1615,
found: 299.1613.
(m, 2H); 13C NMR (100 MHz, CDCl3)
d ppm 168.4, 150.7, 140.4, 130.8,
129.6, 129.3, 128.6, 126.4, 126.3, 126.2, 122.8, 121.5, 66.1, 51.7, 51.3,
43.0, 37.7, 32.0, 31.9; [MþH]þ¼375.2; HRMS (ESI): m/z calcd for
C21H23N6O [MþH]þ: 375.1928, found: 375.1924.
4.3. General procedure for the preparation of
benzotetrazolodiazepines 10 and 11
4.2.3. 8,9-Dimethyl-4-(piperidin-1-yl)-4H-benzo[b]tetrazolo[1,5-d]
[1,4]diazepin-5(6H)-one (8c). White solid, 34% yield; product puri-
fied using 5e45% EtOAc in Hexane gradient; mp >250 ꢀC; 1H NMR
Aryl glyoxaldehyde (1 mmol), amine (1 mmol), azido-
trimethylsilane (1 mmol, 115 mg), and isocyanide (1 mmol) were
dissolved in methanol (1 mL) in a 10 mL MW vial. The reaction was
allowed to run at room temperature for 24 h. Crude mixture was
concentrated in vacuo and purified by flash chromatography (hex-
ane/EtOAc). Ugi adduct was then dissolved in a 10% TFA/DCE solution
(400 MHz, CDCl3)
1H), 2.54e2.24 (m, 2H), 2.38 (s, 6H), 2.20e2.02 (m, 2H), 1.26 (m,
6H); 13C NMR (100 MHz, CDCl3)
ppm 168.3, 150.4, 140.0, 135.3,
d ppm 9.16 (s,1H), 7.72 (s,1H), 7.00 (s,1H), 4.76 (s,
d

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S. Gunawan et al. / Tetrahedron 68 (2012) 5606e5611
and heated at 80 ꢀC for 10 min by means of microwave irradiation.
Reaction mixture was diluted with EtOAc (15 mL) and washed with
NaHCO3 satd solution (15 mL). The aqueous phase was then re-
extracted with EtOAc (15 mL), combined organics were dried over
MgSO4, and crude mixture was purified by flash chromatography
(hexane/EtOAc or EtOAc/MeOH) to afford title compounds.
yield; product purified using 10e40% EtOAc in hexane gradient; mp
195e197 ꢀC; 1H NMR (400 MHz, CDCl3)
ppm 7.80 (s, 1H), 7.58 (dd,
d
J¼8.3, 1.9 Hz, 1H), 7.52 (d, J¼1.8 Hz, 1H), 7.33 (s, 1H), 6.86 (d,
J¼8.2 Hz, 1H), 6.03 (dd, J¼3.6, 1.3 Hz, 2H), 5.58 (s, 1H), 2.40 (s, 3H),
2.39 (s, 3H), 2.40e2.33 (m, 2H), 2.05e1.96 (m, 2H), 1.29e1.20 (m,
3H), 1.17e1.09 (m, 3H); 13C NMR (100 MHz, CDCl3)
d ppm 159.7,
150.6, 150.1, 148.4, 138.1, 136.9, 135.1, 132.4, 127.6, 123.4, 121.4, 121.2,
108.2, 108.00, 101.8, 60.1, 51.9, 25.5, 24.00, 19.6, 19.5;
[MþH]þ¼417.2; HRMS (ESI): m/z calcd for C23H25N6O2 [MþH]þ:
417.2034, found: 417.2034.
4.3.1. 5-(Benzo[d][1,3]dioxol-5-yl)-4-(piperidin-1-yl)-6H-benzo[b]
tetrazolo[1,5-d][1,4]diazepine (10a). Yellow solid, 44% yield; prod-
uct purified using 5e40% EtOAc in hexane gradient; mp
203e204 ꢀC; 1H NMR (400 MHz, CDCl3)
d
ppm 7.76 (d, J¼8.0 Hz,
1H), 7.30e7.25 (m, 1H), 7.17e7.12 (m, 1H), 6.97 (d, J¼1.2 Hz, 1H),
6.93 (dt, J¼8.0, 1.5 Hz, 1H), 6.86 (dd, J¼8.0, 1.2 Hz, 1H), 6.78 (d,
J¼8.0 Hz, 1H), 6.03 (s, 1H), 4.77 (s, 1H), 2.90 (s, 4H), 1.40 (s, 6H); 13C
4.3.7. 4-(8,9-Dimethyl-5-phenyl-4H-benzo[b]tetrazolo[1,5-d][1,4]di-
azepin-4-yl)morpholine (11b). Yellow solid, 51% yield; product pu-
rified using 10e100% EtOAc in hexane gradient; mp 154e156 ꢀC; 1H
NMR (100 MHz, CDCl3)
d
ppm 153.1, 149.4, 148.0, 147.3, 140.6, 131.9,
NMR (400 MHz, CDCl3) d ppm 8.05e7.94 (m, 2H), 7.84 (s, 1H),
130.3, 127.3, 124.6, 123.5, 121.5, 120.7, 120.1, 108.8, 108.0, 101.4, 52.6,
26.1, 23.80; [MþH]þ¼389.1; HRMS (ESI): m/z calcd for C21H21N6O2
[MþH]þ: 389.1721, found: 389.1724.
7.56e7.43 (m, 3H), 7.38 (s, 1H), 5.72 (s, 1H), 3.26 (t, J¼4.5 Hz, 4H),
2.50e2.43 (m, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.15e2.07 (m, 2H); 13C
NMR (100 MHz, CDCl3) d ppm 159.8, 149.4, 138.4, 137.7, 136.6, 136.0,
131.6, 128.9, 128.0, 127.9, 121.52, 121.50, 121.3, 66.3, 59.7, 50.9, 19.6,
19.5; [MþH]þ¼375.3; HRMS (ESI): m/z calcd for C21H23N6O
[MþH]þ: 375.1928, found: 375.1935.
4.3.2. 5-Phenyl-4-(piperidin-1-yl)-6H-benzo[b]tetrazolo[1,5-d][1,4]
diazepine (10b). Yellow solid, 51% yield; product purified using
10e40% EtOAc in hexane gradient; mp 195e197 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
ppm 7.76 (dd, J¼8.0, 1.5 Hz, 1H), 7.47e7.38 (m,
4.3.8. 5-(Benzo[d][1,3]dioxol-5-yl)-4-(3,4-dihydroisoquinolin-2(1H)-
yl)-8,9-dimethyl-4H-benzo[b]tetrazolo[1,5-d][1,4]diazepine
(11c). Yellow viscous oil, 23% yield; product purified using
10e100% EtOAc in Hexane gradient; 1H NMR (400 MHz, CDCl3)
5H), 7.29e7.24 (m, 1H), 7.16e7.11 (m, 1H), 6.76 (dd, J¼7.9, 1.3 Hz,
1H), 4.82 (s, 1H), 3.02e2.79 (m, 4H), 1.40e1.22 (m, 6H); 13C NMR
(100 MHz, CDCl3)
d ppm 153.2, 150.3, 140.5, 138.2, 130.4, 128.9,
128.3, 127.7, 127.2, 124.6, 123.6, 120.8, 120.2, 52.6, 26.1, 23.8;
[MþH]þ¼345.3; HRMS (ESI): m/z calcd for C20H21N6 [MþH]þ:
345.1822, found: 345.1819.
d ppm 7.80 (s, 1H), 7.58e7.53 (m, 2H), 7.34 (s, 1H), 7.12e7.00 (m,
2H), 6.99e6.91 (m, 1H), 6.91e6.80 (m, 2H), 6.04 (dd, J¼4.2, 1.3 Hz,
2H), 5.82 (s, 1H), 3.62 (d, J¼14.9 Hz, 1H), 3.32 (d, J¼14.9 Hz, 1H),
2.59e2.41 (m, 4H), 2.34 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz,
4.3.3. 5-Phenyl-N-(4-(trifluoromethoxy)phenyl)-6H-benzo[b]tetra-
zolo[1,5-d][1,4]diazepin-4-amine (10c). Yellow solid, 48% yield;
product purified using 0e30% MeOH in EtOAc gradient; mp
CDCl3) d ppm 158.6, 150.8, 149.6, 148.6, 138.4, 136.3, 135.7, 133.7,
133.0, 132.3, 128.4, 128.2, 126.6, 126.3, 125.9, 123.5, 121.5, 121.1,
108.3,108.0,101.9, 58.9, 53.3, 48.0, 28.1,19.6,19.5; [MþH]þ¼465.3; ;
HRMS (ESI): m/z calcd for C27H25N6O2 [MþH]þ: 465.2034, found:
465.2027.
193e195 ꢀC; 1H NMR (400 MHz, CDCl3)
d
ppm 7.79 (dd, J¼8.0,
1.4 Hz, 1H), 7.70e7.36 (m, 5H), 7.32 (td, J¼7.7, 1.5 Hz, 1H), 7.19 (td,
J¼7.9, 1.3 Hz, 1H), 6.89 (d, J¼8.9 Hz, 2H), 6.83 (dd, J¼8.0, 1.2 Hz, 1H),
6.58 (d, J¼9.0 Hz, 2H), 5.30 (s, 1H), 5.19 (s, 1H); 13C NMR (400 MHz,
4.3.9. 5-(Benzo[d][1,3]dioxol-5-yl)-8,9-dimethyl-4-(4-(pyridin-2-yl)
CDCl3)
d
ppm 151.5, 152.9, 144.6, 138.4, 136.1, 133.8e131.2 (m),
piperazin-1-yl)-4H-benzo[b]tetrazolo[1,5-d][1,4]diazepine
(11d).
130.8, 130.1, 129.0, 128.8, 127.6, 127.2, 127.0, 126.6, 125.3, 123.6,
122.1, 121.9, 121.6, 121.2, 114.5, 105.5; [MþH]þ¼437.1; HRMS (ESI):
m/z calcd for C22H16F3N6O [MþH]þ: 437.1332, found: 437.1331.
Yellow solid, 41% yield; product purified using 10e100% EtOAc in
hexane gradient; mp 228e230 ꢀC; 1H NMR (400 MHz, CDCl3)
d
ppm 8.10 (dd, J¼4.9, 1.1 Hz, 1H), 7.82 (s, 1H), 7.59 (dd, J¼8.3, 1.8 Hz,
1H), 7.54 (d, J¼1.8 Hz, 1H), 7.43e7.38 (m, 1H), 7.35 (s, 1H), 6.88 (d,
J¼8.2 Hz, 1H), 6.58 (dd, J¼6.9, 5.0 Hz, 1H), 6.49 (d, J¼8.6 Hz, 1H),
6.03 (dd, J¼8.6, 7.6 Hz, 3H), 5.68 (s, 1H), 3.16e3.02 (m, 4H),
2.62e2.48 (m, 2H), 2.38 (s, 3H), 2.37 (s, 2H), 2.26e2.14 (m, 2H); 13C
4.3.4. N,5-Bis(4-methoxyphenyl)-6H-benzo[b]tetrazolo[1,5-d][1,4]di-
azepin-4-amine (10d). Yellow solid, 62% yield; product purified
using 0e30% MeOH in EtOAc gradient; mp 195e197 ꢀC; 1H NMR
(400 MHz, CDCl3)
7.06e6.86 (m, 6H), 6.76 (d, J¼11.7 Hz, 2H), 6.64e6.48 (m, 4H), 3.82
(s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
ppm 158.5, 155.0,
149.6, 141.3, 132.2, 131.31, 131.1, 130.0, 127.7, 126.1, 125.4, 121.3,
120.0, 118.6, 117.4, 116.2, 116.1, 114.3, 114.2, 112.8, 101.0, 55.8, 55.4;
[MþH]þ¼413.3; HRMS (ESI): m/z calcd for C23H21N6O2: 413.1721,
found: 413.1723.
d
ppm 9.65 (s, 1H), 7.40 (d, J¼8.9 Hz, 1H),
NMR (100 MHz, CDCl3) d ppm 159.2, 158.8, 150.9, 149.7, 148.6, 147.9,
138.4, 137.4, 136.8, 135.6, 132.1, 127.7, 123.5, 121.4, 121.3, 113.7, 108.2,
108.0, 107.2, 101.9, 59.3, 50.3, 44.9, 19.7, 19.5; [MþH]þ¼495.3;
HRMS (ESI): m/z calcd for C27H27N8O2 [MþH]þ: 495.2252, found:
495.2251.
d
Acknowledgements
4.3.5. N-(3,4-Dimethoxyphenyl)-5-phenyl-6H-benzo[b]tetrazolo[1,5-
d][1,4]diazepin-4-amine (10e). Yellow solid, 59% yield; product
purified using 0e30% MeOH in EtOAc gradient; mp 126e128 ꢀC; 1H
The authors thank Kristen Keck for compound purification, Alex
Laetsch for compound management, Gary Nichol for X-ray crys-
tallographic work, and Nicole Schechter for proof-reading. National
Institute of Health (NIH) is gratefully acknowledged for funding
(P41GM086190).
NMR (400 MHz, CDCl3)
(s, 1H), 7.03e6.96 (m, 3H), 6.93 (s, 1H), 6.61e6.35 (m, 3H), 3.93 (s,
3H), 3.82 (s, 3H), 3.30 (br s, 1H); 13C NMR (100 MHz, CDCl3)
ppm
d ppm 10.17 (s, 1H), 7.28e7.14 (m, 4H), 7.04
d
149.8, 149.5, 146.3, 141.34, 141.27, 133.4, 132.1, 130.9, 128.8, 128.71,
128.67, 126.7, 126.1, 121.9, 120.1, 119.9, 118.5, 117.4, 113.9, 100.7, 94.4,
56.2, 56.1; [MþH]þ¼413.3; HRMS (ESI): m/z calcd for C23H21N6O2
[MþH]þ: 413.1721, found: 413.1717.
Supplementary data
4.3.6. 5-(Benzo[d][1,3]dioxol-5-yl)-8,9-dimethyl-4-(piperidin-1-yl)-
4H-benzo[b]tetrazolo[1,5-d][1,4]diazepine (11a). Yellow solid, 59%
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.068.

S. Gunawan et al. / Tetrahedron 68 (2012) 5606e5611
5611
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heim, Germany, 2005; (b) Doemling, A. Chem. Rev. 2006, 106, 17; (c) Sunder-
haus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300.
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