Synthesis of Fused Tetrazole Derivatives via a Tandem Cycloaddition and N-Allylation Reaction and Parallel Synthesis of Fused Tetrazole Amines

Article abstract of DOI:10.1021/jo035498c

A method for the synthesis of novel fused tricyclic tetrazoles from allylic bromides generated by the recently discovered DiazAll reaction has been developed. This new tandem reaction comprises a cycloaddition between a nitrile and (TMS)N₃ followed by an intramolecular N-allylation. The variation of functionalities in the benzene moiety was well-tolerated, and only a moderate difference in yield and degree of purity was noticed. An exo-methylene group in these new compounds permitted further derivatization. Structural resemblance with substances which possess important pharmacological properties motivated the synthesis of a series of ketones and a small library of amines.

Full text of DOI:10.1021/jo035498c

Syn th esis of F u sed Tetr a zole Der iva tives via a Ta n d em
Cycloa d d ition a n d N-Allyla tion Rea ction a n d P a r a llel Syn th esis of
F u sed Tetr a zole Am in es
Fredrik Ek,† Sophie Manner,† Lars-Go¨ran Wistrand,‡ and Torbjo¨rn Frejd*,†
Organic Chemistry 1, Department of Chemistry, Lund University, P.O. Box 124, S-221 00 Lund, and
Amersham Health R&D AB, Medeon-Malmo¨, S-205 12 Malmo¨, Sweden
torbjorn.frejd@orgk1.lu.se
Received October 10, 2003
A method for the synthesis of novel fused tricyclic tetrazoles from allylic bromides generated by
the recently discovered DiazAll reaction has been developed. This new tandem reaction comprises
a cycloaddition between a nitrile and (TMS)N3 followed by an intramolecular N-allylation. The
variation of functionalities in the benzene moiety was well-tolerated, and only a moderate difference
in yield and degree of purity was noticed. An exo-methylene group in these new compounds permitted
further derivatization. Structural resemblance with substances which possess important pharma-
cological properties motivated the synthesis of a series of ketones and a small library of amines.
In tr od u ction
We recently developed a method for the synthesis of
allyl aromatic compounds via generation of aryl radicals
by diazotization and a subsequent in situ allylation with
allylic bromides (the DiazAll reaction).14-16 Our interest
to develop applications of the synthesized allyl aromatic
compounds in combination with a general demand for
novel substances, which could potentially interact with
biological systems, made us attempt synthesizing tricyclic
fused tetrazoles 8a -f and 11a -f (Scheme 1 and Table
1). This type of tetrazole derivative has structural
similarities to 1,4-benzodiazepin-2,5-dione (4), represent-
ing a group of compounds which possess anxiolytic,
anticonvulsant, and antitumor properties,17 and fused
tricyclic imidazoles such as flumazenil (5), a benzodiaz-
epine antagonist (Figure 1).18,19 However, our initial
attempts to synthesize fused tetrazole derivatives using
the DiazAll reaction did not result in the expected
benzazepine 8d (Scheme 1). Instead, the allylic bromide
9 continued to react with in situ generated bromine, in
a process similar to a bromolactonization, which resulted
in 10.16 Recently, we have developed this halocyclization
methodology to access fused heterocycles, and a number
of fused tetrazole and imidazole derivatives have been
synthesized.6
The tetrazole subunit is an important structural
feature which has been used as a metabolically stable
isosteric replacement for the carboxylic acid moiety,1 as
a cis-peptide bond mimetic,2,3 as a precursor to other
heterocycles,4 in high-energy compounds,5 and as a
coordinating group in directed ortho-metalation.6-8 Sev-
eral biologically relevant substances incorporating a
tetrazole moiety have been developed (Figure 1). Losar-
tan (1), an angiotensin II antagonist, has been used to
treat hypertension,9,10 pentylenetetrazole (PTZ, 2) has
been extensively used in models for anxiety,11,12 and
tetrazole 3 has shown affinity to benzodiazepine recep-
tors.13
† Lund University.
‡ Amersham Health R&D AB.
(1) Herr, R. J . Bioorg. Med. Chem. 2002, 10, 3379-3393.
(2) Zabrocki, J .; Smith, G. D.; Dunbar, J . B., J r.; Iijima, H.; Marshall,
G. R. J . Am. Chem. Soc. 1988, 110, 5875-80.
(3) Zabrocki, J .; Marshall, G. R. Methods Mol. Med. 1999, 23, 417-
436.
(4) Moderhack, D. J . Prakt. Chem./ Chem.-Ztg. 1998, 340, 687-709.
(5) Ostrovskii, V. A.; Pevzner, M. S.; Kofman, T. P.; Shcherbinin,
M. B.; Tselinskii, I. V. Targets in Heterocycl. Syst. 1999, 3, 467-526.
(6) Ek, F.; Wistrand, L.-G.; Frejd, T. Tetrahedron 2003, 59, 6759-
6769.
(7) Flippin, L. A. Tetrahedron Lett. 1991, 32, 6857-60.
(8) Rhonnstad, P.; Wensbo, D. Tetrahedron Lett. 2002, 43, 3137-
3139.
(9) Duncia, J . V.; Carini, D. J .; Chiu, A. T.; J ohnson, A. L.; Price,
W. A.; Wong, P. C.; Wexler, R. R.; Timmermans, P. B. M. W. M. Med.
Res. Rev. 1992, 12, 149-91.
(10) Smith, R. D.; Duncia, J . V.; Lee, R. J .; Christ, D. D.; Chiu, A.
T.; Carini, D. J .; Herblin, W. F.; Timmermans, P. B. M. W. M.; Wexler,
R. R.; Wong, P. C. Methods Neurosci. 1993, 13, 258-80.
(11) Huang, R.-Q.; Bell-Horner, C. L.; Dibas, M. I.; Covey, D. F.;
Drewe, J . A.; Dillon, G. H. J . Pharmacol. Exp. Ther. 2001, 298, 986-
995.
(14) Ek, F.; Wistrand, L. G. Preparation of allylic aromatic com-
pounds by reaction of aromatic amines with a nitrite and an allylic
olefin; Eur. Patent 1013636; 2000; 11 pp.
(15) Ek, F.; Axelsson, O.; Wistrand, L.-G.; Frejd, T. J . Org. Chem.
2002, 67, 6376-6381.
(16) Ek, F.; Wistrand, L.-G.; Frejd, T. J . Org. Chem. 2003, 68, 1911-
1918.
(17) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
(Washington, D.C.) 2003, 103, 893-930.
(18) Bentue-Ferrer, D.; Bureau, M.; Patat, A.; Allain, H. CNS Drug
Rev. 1997, 2, 390-414.
(19) Haefely, W.; Hunkeler, W.; Kyburz, E.; Moehler, H.; Pieri, L.;
Polc, P.; Gerecke, M. Imidazodiazepine derivatives and intermediates
for their preparation, medicaments containing them and their thera-
peutic application; Eur. Patent 27214; 1981; 116 pp.
(12) J ung, M. E.; Lal, H.; Gatch, M. B. Neurosci. Biobehav. Rev.
2002, 26, 429-439.
(13) Daya, S.; Kaye, P. T.; Mphahlele, M. J . Med. Sci. Res. 1996,
24, 137-41.
10.1021/jo035498c CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004
1346
J . Org. Chem. 2004, 69, 1346-1352

Synthesis of Fused Tetrazole Derivatives
F IGURE 1. Examples of relevant pharmacologically active substances.
SCHEME 1. Allyla tion -Br om ocycliza tion
TABLE 1. Syn th esis of th e Tr icyclic F u sed Tetr a zole
Der iva tives via th e Dia zAll Rea ction
tert-butyl nitrite in acetonitrile at 60-70 °C gave good
yields of the allylic bromides. Additional tert-butyl nitrite
was supplied during the reaction to maintain gas evolu-
tion, which indicated conversion of the arylamine. Al-
though an excess of allylic bromide (10 equiv) was used,
5 equiv could be recovered from the reaction mixture by
distillation at reduced pressure and reused. As seen in
Table 1, a variety of substituents on the aromatic moiety
were well-tolerated and only minor changes of the yields
were observed. The purification of the crude products was
troublesome due to the reactive nature of the allylic
bromides. Silica gel chromatography resulted in ap-
proximately 20% lower yields as compared to the yields
determined by 1H NMR spectroscopy using internal
standard. Also, attempts to use reversed-phase prepara-
tive HPLC gave nonreproducible results, and byproducts
were difficult to remove. These were composed essentially
of partly polymerized allylic bromide and 1,2,3-tribromo-
2-bromomethylpropane. Thus, only allylic bromides 7b,
7c, and 7f could be obtained pure by crystallization from
the resulting viscous oil after column chromatography.
To avoid unnecessary losses of allylic bromides 7a -f, it
was crucial to find a method for the synthesis of the fused
tetrazole derivatives, which would allow the use of crude
starting material. Furthermore, such a method must be
mild enough to avoid isomerization of the exo-methylene
group.
yielda
(%)
yieldb
(%)
yieldb
(%)
R
5-Cl
72 (7a )
82c (7b)
65d (7c)
67 (7d )
72 (7e)
75e (7f)
66 (8a )
67 (8b)
63 (8c)
64 (8d )
60 (8e)
68 (8f)
63 (11a )
64 (11b)
79 (11c)
73 (11d )
81 (11e)
74 (11f)
5-Br16
4-NO2
5-NO2
4-CF3
4-Cl-5-Br
a
The yields of allylic bromides were determined by 1H NMR
b
spectroscopy using toluene as internal standard. Isolated yields
of tetrazole derivatives. c The isolated yield of 7b was 62%. The
d
isolated yield of 7c was 48%. e The isolated yield of 7f was 54%.
However, our objective was still to develop a method
for the synthesis of the fused tetrazole derivatives and
to use these compounds in the synthesis of pharmacologi-
cally relevant substances. In this paper we present a
route to the synthesis of fused tetrazole derivatives. A
parallel synthetic approach toward the synthesis of an
amine library based on these novel tetrazole derivatives
is also described.
Both intra- and intermolecular synthetic strategies
were considered as indicated in Schemes 2 and 3. The
intramolecular approach was studied using allylic azide
12, which was synthesized from the corresponding bro-
mide (Scheme 2). However, when 12 was heated in
toluene or DMSO, no product could be isolated, although
Resu lts a n d Discu ssion
The DiazAll reaction was used in the initial step of the
synthesis of the fused tetrazole derivatives (Table 1).
Careful addition of the arylamine (solid) in portions to a
solution containing 3-bromo-2-bromomethylpropene and
J . Org. Chem, Vol. 69, No. 4, 2004 1347

Ek et al.
SCHEME 2. Syn th esis a n d Attem p ted In tr a m olecu la r Cycloa d d ition of 12
SCHEME 3. Tr ibu tyltin Azid e In d u ced Cycloa d d ition F ollow ed by a n In tr a m olecu la r N-Allyla tion of 7d
SCHEME 4. Mech a n ism of th e F or m a tion of
Tetr a zoles Usin g DBTO a n d (TMS)N3 Su ggested by
Witten ber ger et a l.
cases of successful intramolecular cycloaddition in the
formation of fused tetrazoles of similar compounds have
been reported.20-22 The elevated reaction temperature
(110 or 140 °C) resulted only in deterioration of 12.
Inspection of molecular models indicated that the allylic
azide and the nitrile group could not easily align properly
for ring closure, which may explain the negative result.
In support of this, Sharpless et al. reported that a seven-
membered ring system could not be obtained using an
intramolecular cycloaddition procedure.21
Therefore, we focused on the intermolecular cycload-
dition followed by an intramolecular N-allylation, which
would result in a one-pot two-step reaction. It has been
shown that a 2-tributylstannyl-substituted tetrazole
derivative is formed in the cycloaddition between a nitrile
and tributyltin azide.23 Moreover, 2-stannyl tetrazole
derivatives have been selectively N-alkylated in position
1.24 An initial experiment that involved stirring 7d with
tributyltin azide at 120 °C resulted in a fast formation
of the product as indicated by HPLC analysis. However,
considerable amounts of the isomerized byproduct 13 and
what was suspected to be the nonalkylated tetrazole
derivative 9 were also formed, indicated by NMR and
mass spectral analyses of the crude product (Scheme 3).
This experiment confirmed that the tandem tetrazole
formation-ring closure transformation was possible al-
though a milder method was necessary.
Two of the methods (NaN3/ZnCl2 and (TMS)N3/Me3Al)
resulted in deterioration of the allylic bromide or the
formed product. Fortunately, using a mixture of a cata-
lytic amount of DBTO (0.18 equiv) and (TMS)N3 (2 equiv)
gave 8d , although only 50% of 7d was consumed. In an
attempt to get complete conversion of the allylic bromide,
more azide reagent was added to the reaction mixture.
Still, the conversion did not exceed 50%. However, full
conversion was obtained using in total 0.72 mol % (four
portions added over 20 h) tin reagent and 5 equiv of
(TMS)N3, although some isomerization of the product was
noticed. Therefore, we decided to use 1 equiv of DBTO
from the start of the reaction in combination with 5 equiv
of (TMS)N3 in toluene at 105 °C under argon. As seen in
Table 1, this procedure gave the fused tetrazole deriva-
tives in good yields with typical reaction times around
10-12 h. Furthermore, the influence of the substituents
in the benzene moiety on the yield was negligible (Table
1). More importantly, no isomerization could be detected,
and the use of either pure or crude allylic bromide gave
similar results. Careful purification is essential due to
the facile isomerization of the exo-methylene group. The
crude products were not stable even when stored at 4-6
°C, but pure compounds were stable for at least 1.5 years
at -18 °C. The stoichiometric (DBTO) procedure was also
performed at elevated temperature using a sealed vessel
and oil bath or microwave-assisted heating (200 °C). This
resulted in reduced reaction times (from 10-12 h to 15-
25 min) and almost as good yields as in the ordinary
procedure. However, attempts of using crude allylic bro-
mide 7d at elevated reaction temperature resulted in a
1:1 mixture of the product 8d and the isomerized byprod-
uct 13.
A number of different methods for the synthesis of
tetrazoles from nitriles have been developed1 although
only a few of them, e.g., NaN3/ZnCl2,25 (TMS)N3/Me3Al,26
and (TMS)N3/dibutyltin oxide (DBTO),27 were considered
to be mild enough to be suitable for our application. The
DBTO method, developed by Wittenberger et al., ap-
peared to be particularly promising since this method has
been reported to be useful with sterically demanding
nitriles such as ortho-substituted benzonitriles.27
(20) Davis, B.; Brandstetter, T. W.; Smith, C.; Hackett, L.; Win-
chester, B. G.; Fleet, G. W. J . Tetrahedron Lett. 1995, 36, 7507-10.
(21) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091-4094.
(22) Smith, P. A. S.; Clegg, J . M.; Hall, J . H. J . Org. Chem. 1958,
23, 524-9.
(23) Duncia, J . V.; Pierce, M. E.; Santella, J . B., III. J . Org. Chem.
1991, 56, 2395-400.
Wittenberger and co-workers have already described
a plausible mechanism for the formation of tetrazoles
using DBTO in combination with (TMS)N3 (Scheme 4).27
In cyclization of ordinary nitriles, the tetrazole interme-
diate 14 continues to form the silylated tetrazole 15,
which is hydrolyzed upon workup to give 16.
(24) Isida, T.; Akiyama, T.; Nabika, K.; Sisido, K.; Kozima, S. Bull.
Chem. Soc. J pn. 1973, 46, 2176-80.
(25) Koguro, K.; Oga, T.; Tokunaga, N.; Mitsui, S.; Orita, R. Process
for preparation of 5-substituted tetrazoles; Eur. Patent 796852; 1997;
22 pp.
(26) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011-
14.
In our case, however, an internal allylation takes place
probably via intermediate 20 or 22. This sequence results
(27) Wittenberger, S. J .; Donner, B. G. J . Org. Chem. 1993, 58,
4139-41.
1348 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Fused Tetrazole Derivatives
F IGURE 2. Overlay of 24 and 25.
SCHEME 5. Mech a n ism of th e F or m a tion of F u sed Tetr a zole Der iva tives via a Ta n d em Rea ction
in the tricyclic fused tetrazole 23, bromotrimethylsilane,
and DBTO (Scheme 5). Although DBTO is regenerated
according to the suggested mechanism, the tandem
reaction was barely catalytic in practice.
Since our ambition was to access compounds which
might possess interesting pharmacological properties,
further derivatization of the exo-methylene compounds
8a -f was desired. Ozonolysis of exo-methylene deriva-
tives 8a -f at -78 °C followed by addition of dimethyl
sulfide gave 63-81% of the corresponding ketones (Table
1). The carbonyl group is itself a handle for further
derivatizations, and our attention was drawn to reductive
amination for the following reason.
It turned out that the marked atoms of a low-energy
conformation of 25 (Figure 2)28 coincided to a high degree
with the pharmacophore elements of epibatidine (24),29
a natural product which has shown nanomolar affinity
for the nicotinic acetylcholine receptors.30,31 The struc-
tural similarity of 25 with 24, but also the inherent
phenethylamine subunit, a common structural feature
in compounds regulating several important functions in
humans, motivated the synthesis of amine derivatives
similar to 25. Thus, we needed a method which would
allow synthesis of a larger number of amines using a
rational workup and purification procedure. Reductive
amination and purification via ion exchange chromatog-
raphy has been used for the parallel synthesis of amines
with good results.32,33 However, due to a fast reduction
of the ketones to the corresponding alcohols, the reductive
amination methodology failed, although different proce-
dures and reagents (NaCNBH334 or NaHB(OAc)335) were
tested. Instead, we decided to use a stepwise procedure
in which the enamine was formed prior to the addition
of the reducing agent. The enamines were formed in situ
using several different solvents (CH2Cl2, 1,2-dichloro-
ethane, trichloroethylene, CH3CN, and THF). In each
case, a mixture of two isomeric enamines was formed due
to the two directions in which conjugation could be
attained. Noticeably, reactions performed in methanol,
a solvent commonly used in reductive amination reac-
(28) Conformational analysis using PcSpartan Pro (AM1).
(29) The overlay was done in Chem3D using a reported low-energy
conformation of 24. See: Tønder et al. J . Med. Chem. 1999, 42, 4970-
4980.
(30) Holladay, M. W.; Dart, M. J .; Lynch, J . K. J . Med. Chem. 1997,
40, 4169-4194.
(31) Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.;
Frederiksen, K.; Sanchez, C.; Lemboel, H. L. J . Med. Chem. 1994, 37,
4085-99.
(32) Siegel, M. G.; Hahn, P. J .; Dressman, B. A.; Fritz, J . E.;
Grunwell, J . R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360.
(33) Siegel, M. G.; Shuker, A. J .; Droste, C. A.; Hahn, P. J .;
J esudason, C. D.; McDonald, J . H., III; Matthews, D. P.; Rito, C. J .;
Thorpe, A. J . Mol. Diversity 1998, 3, 113-116.
(34) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-904.
(35) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849-3862.
J . Org. Chem, Vol. 69, No. 4, 2004 1349

Ek et al.
TABLE 2. Syn th esis of F u sed Tetr a zole Am in es
F IGURE 3. Examples of synthesized amines.
amine. Only 1 equiv of 4-benzylpiperazine could be
applied in the synthesis of 29 (Figure 3), since the excess
amine reagent was difficult to remove from the crude
product at reduced pressure. In this case, trichlorethyl-
ene/NaHB(OAc)3 was found to be a better alternative
compared to the THF procedure. In addition, we have
demonstrated that it is possible to access a glycine
derivative of the fused tetrazoles from the corresponding
hydrochloride salt of a protected amino acid (30; Figure
3). Also, anhydrous methylamine could be employed,
although a modified procedure was applied in which the
methylamine was bubbled into the reaction mixture
containing the ketone and acetic acid. Reduction and
purification gave the methylamine derivative 31 in
moderate yield and purity (Figure 3).
a
b
Isolated yield of amine. The purity of the amines was
determined using HPLC (UV detection at 220 nm). The structural
identification was made with H NMR and mass spectroscopy.c The
1
reaction was performed on a 0.05 mmol scale in THF and using
NaCNBH3 as reducing agent. The reaction was performed on a
0.1 mmol scale in 1,2-dichloroethane and using NaBH(OAc)3 as
reducing agent.
d
tions, failed. Since the enamines are conjugated with the
benzene ring or the tetrazole moiety, the reduction was
difficult especially in those cases in which the benzene
ring was substituted with a nitro group (starting from
ketone 11c or 11d ). Thus, only two different combinations
of solvent and reducing agent gave the amines in good
yields, namely, THF/NaCNBH3 and trichloroethylene/
NaBH(OAc)3.36 Due to environmental considerations, we
preferred to use THF in combination with NaCNBH3 in
the synthesis of the small library. Using this procedure
in combination with Varian Bond Elut SCX columns for
purification gave good to excellent yields of the amines
(average yield 88%). Most often, the products were
isolated in a high degree of purity (Table 2, Figure 3,
average purity 91%), but in the case of amines synthe-
sized from the nitro-substituted ketones 11c and 11d , a
larger amount of byproducts was formed, possibly as a
result of a more problematic reduction of the enamines.
We also found that 1,2-dichloroethane (solvent) in com-
bination with benzylamine and NaHB(OAc)3 gave ter-
tiary amines in excellent yields (Table 2, row 3). The
initially formed secondary benzylamine was most likely
alkylated with 1,2-dichloroethane, and the resulting
chloroethylamine was then reduced to give the tertiary
In conclusion, we have developed a method for the
synthesis of novel fused tricyclic tetrazoles from allylic
bromides, generated by the recently discovered DiazAll
reaction. This new tandem reaction comprises a cyclo-
addition between a nitrile and (TMS)N3 induced by
DBTO followed by an intramolecular N-allylation. An exo-
methylene group in these compounds permitted further
derivatization. By ozonolysis, a series of ketones were
synthesized which were then used as starting materials
in the parallel synthesis of a small library of amines.
Overall, the variation of functionalities in the benzene
moiety was well-tolerated, and only moderate differences
in yield and degree of purity were noticed. Structural
resemblance of the synthesized ketones and amines with
substances possessing important pharmacological prop-
erties suggests possible bioactivity. This study is cur-
rently being performed, and the results will be presented
in due course.
Exp er im en ta l Section
5-Br om o-4-ch lor oa n th r a n ilon itr ile (6f). N-Bromosuc-
cinimide (2.31 g, 13.0 mmol) was added to 4-chloroanthra-
nilonitrile (1.53 g, 10.0 mmol) in CH2Cl2 (20 mL) at 0 °C. The
reaction mixture was then stirred at 25 °C until all 4-chloro-
anthranilonitrile was consumed (monitored by HPLC, usually
(36) CH2Cl2 and 1,2-dichloroethane reacted with the amines in the
reaction mixture, which resulted in other amines than the product.
1350 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Fused Tetrazole Derivatives
2-3 h).37 Saturated aqueous Na2SO3 was then added to the
reaction mixture, and the separated organic phase was washed
with brine and then dried (Na2SO4). Removal of the solvent
at reduced pressure and column chromatography (heptane-
EtOAc, 6:1) of the residue gave 1.2 g (52%) of 6f as white
removed at reduced pressure, and EtOAc was added to the
residual oil. The resulting suspension was filtered through a
pad of silica (elution with EtOAc), and the filtrate was washed
with aqueous saturated NaHCO3. A precipitate (possibly
residues from DBTO and (TMS)N3) was formed in the washing
process which could not be removed from the organic phase.
The resulting suspension was therefore dried (Na2SO4) and
then filtered through a pad of silica (elution with EtOAc), and
the filtrate was concentrated at reduced pressure. Column
chromatography (heptane-EtOAc, 2:1) of the residue followed
by recrystallization (heptane-acetone) gave 220 mg (66%) of
8a as pale yellow crystals: mp 118-119 °C; 1H NMR (CDCl3,
400 MHz) δ 8.03 (d, 1H, J ) 2.2 Hz), 7.60-7.53 (m, 2H), 5.38
(t, 2H, J ) 1.5 Hz), 5.30 (dd, 2H, J ) 7.5, 0.7 Hz), 3.74 (s, 2H);
13C NMR (CDCl3, 100 MHz) δ 154.0, 141.5, 138.6, 133.5, 132.4,
132.3, 129.6, 126.0, 115.8, 54.2, 40.1; HRMS (EI+) m/z calcd
for C11H9ClN4 (M) 232.0516, found 232.0512.
1
crystals: mp 176-178 °C; H NMR (CDCl3, 400 MHz) δ 7.60
(s, 1H), 6.89 (s, 1H), 4.49 (br s, 2H); 13C NMR (CDCl3, 100 MHz)
δ 149.2, 140.8, 136.4, 116.6, 115.7, 109.6, 96.5; HRMS (EI+)
m/z calcd for C11H9Br2ClN (M) 229.9246, found 229.9244.
Typ ica l P r oced u r e for th e Syn th esis of Allyl Ar om a tic
Br om id es 7a -7f. 2-(2-Br om om eth yl-2-p r op en yl)-5-ch lo-
r oben zon itr ile (7a ). Arylamine 6a (0.30 g, 2.0 mmol) was
added in small portions to a mixture of acetonitrile (4 mL),
3-bromo-2-bromomethylpropene (4.28 g, 20.0 mmol), and tert-
butyl nitrite (0.48 mL, 4.0 mmol), keeping the temperature
between 60 and 70 °C. During the 20 min of addition, more
tert-butyl nitrite (0.24 mL, 2.0 mmol) was added in portions
to maintain the evolution of gas. After complete addition of
6a , the temperature was kept at 60 °C, and stirring was
continued for 1 h before removal of the solvent at reduced
pressure. The remaining 3-bromo-2-bromomethylpropene (2.15
g, 10.0 mmol) was then recovered by distillation (30 °C, 0.7
mmHg). Ether was added to the remaining oil, and the formed
precipitate was filtered off and discarded. The filtrate was
concentrated at reduced pressure, and the yield was deter-
mined to be 72% by 1H NMR analysis using toluene as internal
standard. The toluene was then removed by distillation at
reduced pressure. Column chromatography (heptane-EtOAc,
23:2) of the residue gave 0.29 g (53%, 85-90% purity) of 7a
as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, 1H, J )
2.2 Hz), 7.53 (dd, 1H, J ) 8.3, 2.2 Hz), 7.36 (d, 1H, J ) 8.4
Hz), 5.35 (d, 1H, J ) 0.7 Hz), 4.91 (d, 1H, J ) 0.5 Hz), 4.01 (s,
2H), 3.80 (d, 2H, J ) 0.5 Hz); 13C NMR (CDCl3, 100 MHz) δ
142.7, 141.1, 134.6, 133.6, 133.0, 132.2, 118.8, 116.8, 115.1,
38.3, 36.0; HRMS (CI+) m/z calcd for C11H10NClBr (M + H)
269.9687, found 269.9716.
Typ ica l P r oced u r e for th e Syn th esis of Keton es 11a -
f. 9-Ch lor o-5,6-d ih yd r o-4H-1,2,3,3a -tetr a a za ben zo[e]a zu -
len e-5-on e (11a ). Ozone was bubbled through a solution of
8a (220 mg, 0.95 mmol) in dichloromethane (5 mL) and
methanol (5 mL) at -78 °C until a blue color of the reaction
mixture persisted (10-12 min).39 The solution was flushed
with argon to remove excess ozone, and dimethyl sulfide (4
mL) was then added. The reaction mixture was slowly warmed
to room temperature (3 h). EtOAc was added, the aqueous
phase was extracted twice with EtOAc, and the combined
organic phase was washed with H2O and brine and then dried
(Na2SO4). Removal of the solvent at reduced pressure followed
by column chromatography (heptane-EtOAc, 1:1) and recrys-
tallization (heptane-EtOAc) gave 140 mg (63%) of 11a as pale
yellow crystals: mp 193-195 °C dec; 1H NMR (acetone-d6, 400
MHz) δ 7.96 (d, 1H, J ) 2.2 Hz), 7.69 (dd, 1H, J ) 8.3, 2.3
Hz), 7.59 (d, 1H, J ) 8.3 Hz), 5.40 (s, 2H), 4.04 (s, 2H); 13C
NMR (acetone-d6, 100 MHz) δ 199.7, 153.9, 134.0, 132.8, 132.6,
131.0, 129.0, 125.5, 56.6, 48.2. Anal. Calcd for C10H7ClN4O:
C, 51.19; H, 3.01; N, 23.88. Found: C, 51.08; H, 3.11; N, 23.81.
Typical Exam ples of th e Syn th esis of Tetr azole Am in es
26-28 via Step w ise Red u ctive Am in a tion . 5-(N-Ben zyl-
am in o)-9-br om o-5,6-dih ydr o-4H-1,2,3,3a-tetr aazaben zo[e]-
a zu len e (26b). Benzylamine (1.0 mL, 0.045 mM in THF) and
acetic acid (1.0 mL, 0.05 mM in THF) were added to ketone
11b (14 mg, 0.05 mmol). The reaction mixture was stirred at
reflux until complete consumption of the amine (monitored by
HPLC). The reaction mixture was cooled, NaCNBH3 (13 mg,
0.20 mmol) and acetic acid (1.0 mL, 0.1 mM in THF) were
added, and stirring was continued for 48 h at 24 °C. After
complete reduction of the enamines, NaOH (1 M, 1 mL), brine
(1 mL), and ether (1 mL) were added to the reaction mixture,
and stirring was continued for 30 min. The organic phase was
then applied to a Varian Bond Elut SCX column, which had
been prewashed twice with MeOH (10 mL) and once with THF
(10 mL). The column was then washed twice with MeOH (10
mL) to remove neutral impurities. The product was then eluted
from the column using ammonia in MeOH (3 × 2 mL).
Removal of the volatile material in the eluate by passing a
gentle stream of argon over the solution, maintaining the
temperature at 50 °C, gave 16 mg (98%) of 26b: 1H NMR
(CDCl3, 300 MHz) δ 8.23 (d, 1H, J ) 2.1 Hz), 7.60 (dd, 1H, J
) 8.1, 2.1 Hz), 7.38-7.25 (m, 5H), 7.21(d, 1H, J ) 8.2 Hz),
4.50 (dd, 1H, J ) 15.5, 5.2 Hz), 4.45 (dd, 1H, J ) 15.3, 5.3
Hz), 3.92 (d, 1H, J ) 13.4 Hz), 3.88 (d, 1H, J ) 13.4 Hz), 3.71
(m, 1H), 2.98 (dd, 1H, J ) 15.0, 4.8 Hz), 2.79 (dd, 1H, J )
14.9, 7.1 Hz); MS (ESP+) (M + H) m/z 370.2.
2-(2-Azid om eth yl-2-p r op en yl)-5-n itr oben zon itr ile (12).
7d (61 mg, 0.22 mmol) was added to a mixture of NaN3 (74
mg, 1.14 mmol) in acetone (1.4 mL) under argon atmosphere.
The resulting mixture was stirred for 15 min at 22 °C and
then at reflux for 2 h. The mixture was cooled to ambient
temperature, and water and ether were added. The aqueous
phase was extracted with ether, and the combined organic
phases were dried (Na2SO4) before removal of the solvent at
reduced pressure. Column chromatography (heptane-EtOAc,
8:2) of the residue gave 31 mg (58%) of 12 as a pale yellow oil:
1H NMR (CDCl3, 400 MHz) δ 8.53 (d, 1H, J ) 2.4 Hz), 8.40
(dd, 1H, J ) 8.6, 2.4 Hz), 7.59 (d, 1H, J ) 8.6 Hz), 5.30 (s,
1H), 4.97 (s, 1H), 3.80 (s, 2H), 3.76 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 149.6, 147.1, 140.2, 132.0, 128.5, 127.9, 118.5,
116.0, 115.1, 56.1, 39.1; HRMS (CI+) m/z calcd for C11H10O2N5
(M + H) 244.0836, found 244.0844.
Typ ica l P r oced u r e for th e Syn th esis of Com p ou n d s
8a -f. 9-Ch lor o-5-m eth ylen e-5,6-d ih yd r o-4H-1,2,3,3a -tet-
r a a za ben zo[e]a zu len e (8a ). Dibutyltin oxide (0.50 g, 2.0
mmol) was added to a mixture of crude or purified 7a (2.0
mmol)38 and (TMS)N3 (1.3 mL, 10.0 mmol) in dry toluene (10
mL). The mixture was stirred at 105 °C under argon for 10-
12 h (the reactions were monitored by HPLC). The volatile
material of the reaction mixture was then removed at reduced
pressure, and the residue was dissolved in methanol to
methanolyze the remaining reagents. The methanol was
(37) The starting material and product had the same Rf value in
straight-phase chromatography (heptane-EtOAc). The dibrominated
byproduct differed in Rf value from the other substances. To obtain a
pure product, it was therefore important to consume all starting
material.
9-Ch lor o-5-m or ph olin o-5,6-dih ydr o-4H-1,2,3,3a-tetr aaza-
ben zo[e]a zu len e (27a ). Morpholine (1 mL, 0.2 mM in THF)
(38) The allylation reactions gave approximately 2.0 mmol of nitrile-
containing products and byproducts. Therefore, the amounts of DBTO
and (TMS)N3 used in the tandem reaction were based on the fact that
the reaction mixture contained 2 mmol of crude allylic bromide.
However, the final yields of the fused tetrazoles were calculated using
the yields (internal standard) from the allylation reactions.
(39) Some of the starting materials, i.e., 8c and 8f, were difficult to
dissolve in MeOH/CH2Cl2, which complicated these reactions. However,
additional solvent and a change in the solvent composition remedied
this problem. Also, the corresponding products 11c and 11f had poor
solubility in common solvents, but recrystallization without prior
chromatography gave the pure compounds.
J . Org. Chem, Vol. 69, No. 4, 2004 1351

Ek et al.
and acetic acid (1 mL, 0.05 mM in THF) were added to ketone
11a (12 mg, 0.05 mmol). The reaction mixture was stirred at
reflux until complete consumption of the ketone (monitored
by HPLC). The reaction mixture was cooled, NaCNBH3 (13
mg, 0.20 mmol) and acetic acid (1 mL, 0.2 mM in THF) were
added, and stirring was continued for 48 h at 24 °C. After
complete reduction of the enamines, NaOH (1 M, 1 mL), brine
(1 mL), and ether (1 mL) were added to the reaction mixture,
and stirring was continued for 30 min. The organic phase,
separated from the alkaline aqueous phase, was concentrated
by passing a gentle stream of argon over the solution. The
remaining oil was kept at reduced pressure until the excess
morpholine had evaporated. The residue was dissolved in
MeOH and then applied to a Varian Bond Elut SCX column
which had been prewashed twice with MeOH (10 mL) and once
with THF (10 mL). The column was then washed twice with
MeOH (10 mL) to remove neutral impurities. The product was
then eluted from the column using ammonia in MeOH (3 × 2
mL). Removal of the volatile material in the eluate by passing
a gentle stream of argon over the solution, maintaining the
temperature at 50 °C, gave 13 mg (84%) of 27a : 1H NMR
(CDCl3, 300 MHz) δ 8.03 (d, 1H, J ) 2.3 Hz), 7.47 (dd, 1H, J
) 8.2, 2.3 Hz), 7.34 (d, 1H, J ) 8.2 Hz), 4.86 (dd, 1H, J )
14.8, 4.8 Hz), 4.33 (dd, 1H, J ) 14.8, 6.1 Hz), 3.67 (t, 4H, J )
4.7 Hz), 3.50 (m, 1H), 2.96 (dd, 1H, J ) 14.8, 5.2 Hz), 2.87
(dd, 1H, J ) 14.7, 8.7 Hz), 2.64 (m, 4H); MS (ESP+) (M + H)
m/z 306.3.
mL) was added to the reaction mixture, and stirring was
continued for 30 min. The organic phase was then applied to
a Varian Bond Elut SCX column which had been prewashed
twice with MeOH (10 mL) and once with THF (10 mL). The
column was then washed twice with MeOH (10 mL) to remove
neutral impurities. The product was then eluted from the
column using ammonia in MeOH (3 × 2 mL). Removal of the
volatile material in the eluate by passing a gentle stream of
argon over the solution, maintaining the temperature at 50
°C, gave 32 mg (93%) of 28e: 1H NMR (CDCl3, 300 MHz) δ
8.12 (d, 1H, J ) 8.0 Hz), 7.69 (br d, 1H, J ) 8.1 Hz), 7.63 (s,
1H), 7.40-7.20 (m, 5H), 4.80 (dd, 1H, J ) 14.7, 5.8 Hz), 4.38
(dd, 1H, J ) 14.7, 6.7 Hz), 3.81 (d, 1H, J ) 14.3 Hz), 3.78 (m,
1H), 3.70 (d, 1H, J ) 14.3 Hz), 3.04 (dd, 1H, J ) 14.6, 5.2 Hz),
2.95 (dd, 1H, J ) 14.5, 8.9 Hz), 2.64 (m, 2H), 1.12 (t, 1H, 7.1
Hz); MS (ESP+) (M + H) m/z 388.4.
Ack n ow led gm en t. We thank Amersham Health
R&D AB, the Swedish Research Council, and The Royal
Physiographic Society in Lund for financial support and
Einar Nilsson and Susanna Henriksson for obtaining
mass spectral data. Acadia Pharmaceutical (Roger Ols-
son and Ian Sarvary) is gratefully acknowledged for the
kind gift of Varian Bond Elut SCX columns and for help
regarding reactions using microwave heating.
5-(N-Ben zyleth ylam in o)-8-tr iflu or om eth yl-5,6-dih ydr o-
4H-1,2,3,3a -tetr a a za ben zo[e]a zu len e (28e). Benzylamine
(1.0 mL, 0.09 mM in 1,2-dichloroethane) and acetic acid (1.0
mL, 0.1 mM in 1,2-dichloroethane) were added to ketone 11e
(27 mg, 0.10 mmol). The reaction mixture was stirred at reflux
until complete consumption of the amine (monitored by
HPLC). The reaction mixture was cooled, NaBH(OAc)3 (63 mg,
0.30 mmol) was added, and stirring was continued for 48 h at
reflux. After complete reduction of the enamines and N-
alkylation of the resulting secondary amine, NaOH (1 M, 1
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal paragraph, experimental procedure and characterization
data for 7b-7f, 8b-8f, and 11b-11f, 1H NMR and mass
spectral data for 26a , 26c-f, 27b-f, 28a -d , 28f, and 29-31,
1
and H NMR and mass spectra and HPLC chromatograms for
6f, 7b, 7d , 7f, 8a -f, and 26-31 (divided into four PDF files).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035498C
1352 J . Org. Chem., Vol. 69, No. 4, 2004