Diels-Alder reactions of 3-(1H-tetrazol-5-yl)-nitrosoalkenes: Synthesis of functionalized 5-(substituted)-1H-tetrazoles

Article abstract of DOI:10.1016/j.tet.2011.09.051

A general route to 1,2-oxazines and open chain oximes bearing a 1H-tetrazolyl substituent via Diels-Alder reaction of 3-(tetrazol-5-yl)- nitrosoalkenes is reported. It was also demonstrated that reduction of these adducts followed by deprotection of the t

Full text of DOI:10.1016/j.tet.2011.09.051

Tetrahedron 67 (2011) 8902e8909
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DielseAlder reactions of 3-(1H-tetrazol-5-yl)-nitrosoalkenes: synthesis of
functionalized 5-(substituted)-1H-tetrazoles
a
b
c
,
a,
*
*
ꢀ
Susana M.M. Lopes , Francisco Palacios , Americo Lemos , Teresa M.V.D. Pinho e Melo
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque Country, Apartado 450, 01080 Vitoria, Spain
c CIQA, FCT, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 August 2011
Received in revised form 12 September 2011
Accepted 14 September 2011
Available online 17 September 2011
A general route to 1,2-oxazines and open chain oximes bearing a 1H-tetrazolyl substituent via DielseAlder
reaction of 3-(tetrazol-5-yl)-nitrosoalkenes is reported. It was also demonstrated that reduction of these
adducts followed by deprotection of the tetrazolyl group give 5-(1-aminoalkyl)-1H-tetrazoles, a-amino
acid analogues.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
pyrroles, proline analogues, pyrrolidizine alkaloids, amongst many
other compounds of great chemical and biological interest.6k,7 The
use of 3-(tetrazol-5-yl)-nitrosoalkenes opened the way to a new
class of compounds combining the 1,2-oxazine or the open chain
oxime substructures with the tetrazol-5-yl substituent.
Over the past decades it has been well established that 5-
substituted-1H-tetrazoles are effective bioisosteres of the carbox-
ylic acid functionality. The acidity of NeH is similar to that of car-
boxylic OeH at physiological pH, both exhibit planar structures,
tetrazoles being more lipophylicdkey factor when crossing cell
membranesdthan the corresponding carboxylic analogues.1 It is
also generally accepted that tetrazole moieties exhibit stronger
metabolic stability. In fact, several literature works report the en-
hanced biological activity and metabolical stability of compounds
in which the carboxylate group has been substituted by tetrazo-
le.1c,2 Thus, the tetrazole ring has been successfully incorporated
into pharmacological drug formulations namely cardiovascular or
hypertension drugs.3 Furthermore, 1,5-disubstituted tetrazoles are
conformational mimics of a cis-blocked peptide bond, like those
found in a wide variety of biologically important peptides.
We have recently disclosed a hetero-DielseAlder approach to 5-
(substituted)-1H-tetrazoles via unprecedented reactions of 5-(1-
nitrosovinyl)-1-phenyl-1H-tetrazole with electron rich alkenes
and heterocycles, which gave new tetrahydro-3-tetrazolyl-1,2-
oxazines 1e4 and open chain oximes bearing the tetrazole func-
tionality 5.4 In fact, the DielseAlder reaction of conjugated nitro-
soalkenes has been successfully explored as an effective synthetic
strategy for a large number of 1,2-oxazines and open chain ox-
imes.5,6 These adducts and cycloadducts have proved to be invalu-
able substrates for organic chemists due to their wide and versatile
use as synthetic intermediates or useful building blocks for the
synthesis of amino-carboxylic, -phosphonic and -phosphinic acids,
O
O
O
O
N
N
N
Ph
Ph
Ph
N
N
N
O
N
n
N
N
N
N
N
N
N
N
N
3
1 n = 1 or 2
2
OH
O
OEt
N
N
Ph
Ph
5a R =
5b R =
O
N
H
R
N
N
N
N
N
N
N
R =
5c
N
4
5
N
H
We observed that 5-(1-nitrosovinyl)-1-phenyl-1H-tetrazole 7
can be generated in situ from the corresponding bromooxime 6
under very mild reaction conditions and acts as an electron-
deficient heterodiene in the presence of electron rich alkenes and
heterocycles.4 Reductive transformations of two of these adducts
gave access to 5-(1-aminoalkyl)-1-phenyl-1H-tetrazoles namely to
the tryptophan analogue 8 (Scheme 1).
The [4þ2] cycloaddition of 5-(1-nitrosovinyl)-1-phenyl-1H-tet-
razole 7 was selected as the model reaction since it was known that
generally 1-phenyl-1H-tetrazoles are very stable and frequently
crystalline compounds.8 This choice proved to be important and
precious on the course of the synthetic pathway the drawback
being the impossibility of carrying out tetrazole deprotection in
latter stages. Nevertheless, 1,5-disubstituted tetrazoles are also in-
teresting molecules and indeed pharmaceutical formulations of
this type of derivatives are known.9
* Corresponding authors. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.051

S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
8903
Ph
N
Ph
N
O
N
N
N
NOH
Ph
Ph
N
N
Red.
Na2CO3
CH2Cl2
Indole
(63%)
N
N
N
N
N
N
(66%)
N
NH2
N
H
N
N
H
N
Br
HO
N
N
5c
8
6
7
Scheme 1.
As a continuation of our work, we now describe the generation
and DielseAlder reactions of 5-(3-tetrazol-5-yl)-nitrosoalkenes,
such as II, in which the NeH tetrazole is blocked by an easily re-
movable protecting group, as a way to obtain a general route to 1,2-
oxazines, open chain oximes bearing an unprotected tetrazolyl
substituent and 5-(1-aminoalkyl)-1H-tetrazoles (Scheme 2).
ether. In the case of the benzyl derivative 11a the halogenation
reaction was carried out at room temperature for 19 h, using
1 equiv of bromine, giving the 5-bromoacetyl-1-benzyl-1H-tetra-
zole (12a) in 52% yield. However, bromination attempts of
p-nitrobenzyl derivative 11b using these reaction conditions led
only to the recovery of the starting material. Thus, 1H-tetrazole 11b
O
X
O
X
N
N
PG
H
N
N
X
N
N
N
N
N
N
N
III
IV
OH
Br
O
OH
X
OH
X
N
N
PG
PG
N
N
PG
H
N
N
N
N
N
N
N
N
N
N
X
N
N
N
N
N
V
I
VI
II
PG = protecting group
X
NH2
H
N
N
N
N
VII
Scheme 2.
2. Results and discussion
was reacted with 2 equiv of bromine at 50 ꢀC for 20 h affording the
5-bromoacetyl-1-(p-nitrobenzyl)-1H-tetrazole (12b) in 87% yield.
The desired oximes 13 were obtained as nice crystalline solids by
the reaction of 5-bromoacetyl-1H-tetrazoles 12 with hydroxyl-
amine hydrochloride in CH2Cl2/MeOH. Difference in reactivity was
again observed between the 1-benzyl-1H-tetrazole and the 1-(p-
nitrobenzyl)-1H-tetrazole derivatives. Oxime 13a could be ob-
tained in high yield carried out the reaction at room temperature,
whereas in the synthesis of oxime 13b higher temperature and the
use of a larger excess of hydroxylamine hydrochloride was required
(Table 1).
Nitrosoalkenes 14 were generated in situ, from the corre-
sponding bromooximes 13 by treatment with sodium carbonate,
whose small solubility in dichloromethane ensured a slow rate of
dehydrobromination and consequently a low concentration of the
heterodienes. Their reactivity towards dienophiles, present in the
reaction media, was then examined (Table 2).
The reaction of 13a with activated enol ether dienophiles, such
as 2,3-dihydrofuran and 3,4-dihydro-2H-pyran provided the ex-
pected 1,2-oxazines in good yields (Table 2, entries 1 and 2).
Striking and rather unexpected was the prolonged time necessary
for the complete transformation of the oxime 13a into the transient
5-(1-nitrosovinyl)-1-benzyl-1H-tetrazole 14a (TLC control) when
compared with the previous reported 5-(1-nitrosovinyl)-1-phenyl-
1H-tetrazole generation.4 The required longer reaction time may
account for the partial isomerisation of 1,2-oxazine 16 into the open
chain oxime 17 (the latter also detected by NMR of the crude
mixture, prior to column chromatography).
Two diverse pathways could be envisaged in order to obtain
the required 5-acetyl-1-protected-1H-tetrazole, precursor of the
bromooxime I. In fact, 1,5-disubstituted-1H-tetrazoles can be ob-
tained via intermolecular [3þ2] cycloaddition of organic azides
and nitriles10a or by the initial synthesis of the 5-substituted-1H-
tetrazole and subsequent N-alkylation. The latter may suffer from
the disadvantage of lack of selectivity with the formation of both
1,5-disubstituted-1H-tetrazole and 2,5-disubstituted-2H-tetrazole
derivatives.2e,11 Thus, the click chemistry approach of organic
azides was selected as the route to the target N-protected-1H-
tetrazoles 11. The neat sealed tube thermolysis of benzyl or
nitrobenzyl azides with pyruvonitrile gave after purification the
corresponding 1H-tetrazoles 11 in 73% and 54% yield, respectively.
The crude products were dissolved in a 1:1 mixture of ethyl ace-
tate/hexane and run down a short plug of silica gel. The 5-acetyl-
1-(p-nitrobenzyl)-1H-tetrazole (11b) was further purified by re-
crystallization whereas 1H-tetrazole 11a10 was dissolved in ethyl
acetate, washed with a 10% NaHCO3 aqueous solution and isolated
as an oil (Scheme 3).
The bromination was brought about by the reaction of the
acetyltetrazoles 11 with bromineedioxane complex in diethyl
O
R
°
120 C
O
N
sealed tube
24 h
N
+
RN3
CN
N
N
9a R = Bn
9b R = p-NO2C6H4 (PNB)
10
11a R = Bn 73%
11b R = PNB 54%
The DielseAlder reactions of nitrosoalkene 14a were then ex-
tended to electron rich aromatic heterocycles. With furan and 2,5-
dimethylpyrrole the 5,6-dihydro-4H-1,2-oxazines 18 and 19 were
Scheme 3.

8904
S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
Table 1
isolated in good yields (Table 2, entries 3 and 4) while with pyrrole
Oximes of 1-substituted-5-bromoacetyl-1H-tetrazoles
and indole the corresponding open chain oximes 20a and 21a were
obtained regioselectively (Table 2, entries 5 and 7). The formation
of these end products can be rationalized considering the rear-
omatisation of the primarily formed 1,2-oxazines. No evidences of
other isomers could be detected or isolated, namely either 3-
pyrrole and/or 2-indole derivatives. Similar reactivity was ob-
served when 5-bromoacetyl-1-(p-nitrobenzyl)-1H-tetrazole (13b)
was reacted with pyrrole and indole in the presence of sodium
carbonate (Table 2, entries 6 and 8).
NOH
Br
R
O
O
R
R
N
N
ii.
N
i.
N
N
N
N
N
N
Br
N
N
N
13
11
12
R
i.
Yield
ii.
Yield
At this stage we also looked at the chemical behaviour of 3-(1-
benzyl-1H-tetrazol-5-yl)-5-vinylnitroso (14a) towards cumulated
double bonds (Scheme 4). Reactions of vinylnitroso compounds
with alkoxy and/or sugar-derived allenes have been reported
before,7g,12 but described as unsuccessful with phenyl- and trime-
thylsilyl-allenes.12d To the best of our knowledge, there are no ex-
amples of reactions of nitrosoalkenes involving aryloxy or
phenyloxy allenes. However, it was observed that nitrosoalkene 14a
reacts with phenoxyallene at room temperature for 26 h to origi-
nate regioselectively cycloadduct 22, although isolated in low yield
(Scheme 4). Carrying out the reaction for a longer reaction time
compound 23 was isolated in 16% yield resulting from the tauto-
merization of the initially formed DielseAlder cycloadduct. At-
tempts to react nitrosoalkene 14a with allenoates did not lead to
isolable cycloadducts.
Dioxane/diethyl
ether Br2
(1 equiv) rt,
19 h
H2NOH$HCl
12a 52% (3 equiv) CH2Cl2/ 13a 89%
CH2
MeOH rt, 72 h
Dioxane/diethyl
ether Br2
(2 equiv)
50 ꢀC, 20 h
H2NOH$HCl
(12 equiv)
CH2Cl2/MeOH
50 ꢀC, 24 h
CH2
12b 87%
13b 89%
13b 83%
O2N
H2NOH$HCl
(6 equiv)
CH2Cl2/MeOH
50 ꢀC, 72 h
Table 2
Reactions of nitrosoalkenes 14 with cyclic enol ethers and heterocycles
X
O
NOH
Br
N
R
N
R
N
CH2Cl2
Na2CO3
Product
N
N
N
N
N
N
13a R = Bn
13b R = PNB
14a R = Bn
14b R = PNB
Entry
Oxime
Dienophile (reaction conditions)
Product
Isolated yield
O
N
O
Bn
1
13a
N
N
N
65%
O
(r.t., 50 h)
N
15
O
N
O
Bn
N
O
N
16
N
N
N
65%
9%
+
2
13a
OH
O
N
N
Bn
(r.t., 70 h)
N
N
17
N
O
Bn
N
3
4
5
13a
13a
13a
69%
51%
85%
O
O
N
(r.t., 48 h)
N
N
18
O
N
Bn
N
N
H
N
N
(r.t., 24 h)
N
N
19
OH
N
Bn
N
N
H
N
H
N
N
(r.t., 48 h)
N
20a

S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
8905
Table 2 (continued )
Entry
Oxime
Dienophile (reaction conditions)
Product
OH
Isolated yield
N
PNB
N
N
H
6
7
13b
N
H
79%
64%
N
N
N
N
(r.t., 48 h)
20b
H
N
OH
Bn
N
13a
13b
N
H
N
N
N
(r.t., 48 h)
21a
H
OH
N
N
PNB
68%
N
8
N
H
N
N
N
(r.t., 24 h)
21b
O
OPh
N
Bn
N
N
OPh
N
N
N
•
O
NOH
Br
N
Bn
Bn
N
N
22 17%
r.t., 26 h
N
CH2Cl2
Na2CO3
N
N
N
N
N
O
OPh
r.t., 67 h
OPh
Scheme 6.
N
Bn
N
14a
13a
N
•
N
23 16%
Subsequently, deprotection of the tetrazolyl substituent was
studied. Initially, general procedures reported for debenzylation of
N-benzy-1H-tetrazoles via hydrogenolysis in ethanol solution at
room temperature using Pd/C as catalyst16 or in the presence of an
acid2f were used aiming to convert oxime 21a into the corre-
sponding derivatives with unprotected tetrazolyl substituent.
However, the target compound could not be obtained. The hydro-
genolysis using a combination of Pd/C and Pd(OH)2/C in THF/iso-
propanol, described as an efficient methodology for deprotection of
aryl and alkyl ethers,17 also failed when applied to the cleavage of
the N-benzyl-1H-tetrazoles. The hydrogenolysis with Pd/C in
600 wt % for 48 h at 20 ꢀC has been described for the removal of all
four benzyl protecting group of a tetrakis(tetrazolylmethyl)-1,2-
ethanodiamine derivative.18 However, these reaction conditions
did not lead to the deprotection of oxime 21a. The target compound
26 was obtained in low yield from the hydrogenolysis of oxime 21a
using PdCl2 as catalyst in ethanol, methodology reported for
debenzylation of N-benzyl-1H-tetrazole derivatives.19 The same
reaction conditions led to the conversion of oxime 21b into de-
rivative 27 in 85% yield, instead of the desired deprotection of the
tetrazolyl group (Scheme 7).
Scheme 4.
Finally cycloaddition of nitrosoalkenes 7 and 14a with cyclo-
pentadiene was studied in order to establish the reactivity pattern as
or 2 reaction component (Scheme 5). Cycloadducts 24 were
obtained in good yield and regioselectivity confirming that the
4
p
p
heterodienes acted as the 4
p component. This is the commonly
mode of reactivity12d,13 although some exceptions are known,5f,i,14 in
which the nitrosoalkenes react with cyclopentadiene preferentially
as the 2
alkyl-nitrosoalkenes and
p counterpart, particularly with b,b-dihalo- and b-halo-b-
b
-phosphorylated nitrosoalkenes.
Scheme 5.
After the preceding disappointing results we were happy to
find that deprotection of compounds 21 could be carried out ef-
ficiently following a reported general procedure for the deben-
zylation of N-benzylamines and 1-benzyl-1H-imidazoles using
ammonium formate as catalytic hydrogen transfer agent.20 Thus,
a suspension of compound 21a or 21b and 10% Pd/C in methanol
was treated with an excess of ammonium formate and the mixture
was refluxed for 1 h giving the target compound 26 in high yield.
This methodology was also applied successfully to deprotection of
the 1H-tetrazolyl group of oximes 20. Finally, it was also demon-
strated that the optimized deprotection reaction conditions al-
lows the conversion of 5-(N-acetylaminoalkyl)-1H-tetrazole 25
into derivative 29 bearing the unprotected tetrazolyl group
(Scheme 8).
We have previously demonstrated that 5-(1-aminoalkyl)-1-
phenyl-1H-tetrazoles, bioisosteres of -amino acids, could be ob-
a
tained from the corresponding oximes by the action of aluminium
amalgam in moist THF4 (see Scheme 1). Therefore, attempts were
made to carry out the reduction of oxime 21a under these reaction
conditions, but only starting material was recovered. The same out
come was observed following a reported general procedure for the
conversion of oximes to amines under Zn/HCOOH reductive con-
ditions.15 However, the reduction of oxime 21a was achieved by
using Zn/AcOH at reflux affording 5-(N-acetylaminoalkyl)-1H-tet-
razole 25 in 58% yield (Scheme 6).

8906
S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
H2 (50 Psi),
PdCl2 (60 mol%)
EtOH, r.t., 3-24 h
spectrometer. Mass spectra were recorded under electrospray
Bn
N
N
HN
N
N
ionization (ESI). HRMS spectra were recorded on a Finnigan MAT95
S instrument. Melting points were recorded on a Reichert hot stage
and are uncorrected. Flash column chromatography was performed
with Merck 9385 silica as the stationary phase.
N
N
N
N
11-16%
HN
HN
N
HO
HO
26
21a
4.1.1. 1-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)ethanone (11b). A vial
was charged with a stir bar, azide (8.42 mmol), and pyruvonitrile
(84.2 mmol) and tightly capped. The reagents were stirred in an oil
bath set to 120 ꢀC, neat, for 24 h. The reaction mixture was then
cooled, and dissolved in ethyl acetate (25 mL). Hexane (25 mL) was
added and the mixture was run through a short plug of silica gel.
The silica plug was washed with an equal amount and composition
of solvent. The solvent was evaporated off. The compound 11b was
purified by crystallization in ethyl acetate in 54% yield (1.114 g). Mp
117.7e118.6 ꢀC (from ethyl acetate); IR (KBr) 729, 1123, 1341, 1522,
NO2
NH2
H2 (50 Psi),
PdCl2 (60 mol%)
EtOH, r.t., 3 h
N
N
N
N
N
85%
N
N
N
HN
N
HN
N
HO
HO
21b
27
1709, 3080 cmꢁ1 1H NMR 2.84 (s, 3H), 5.99 (s, 2H), 7.56 (d, 2H,
;
Scheme 7.
J¼8.8 Hz), 8.21 (d, 2H, J¼8.8 Hz); 13C NMR 28.8, 51.9, 124.2, 129.5,
140.0, 148.3, 148.8, 188.4; MS (ESI) m/z 270 (MNaþ, 100%) and 248
(MHþ, 70%); HRMS (ESI) m/z 248.07704 (C10H10N5O3 [MHþ],
248.07782).
R
N
N
N
HN
N
HCO2NH4, Pd/C 10%
MeOH, reflux, 1 h
N
N
N
N
N
N
HN
HN
4.1.2. 1-(1-Benzyl-1H-tetrazol-5-yl)-2-bromoethanone (12a). To a so-
lution of 1-benzyl-5-acetyltetrazole (0.01 mol) in a mixture of
diethyl ether/dioxane (70:30) (70 mL) was added bromine
(0.01 mol). The reaction mixture was stirred at room temperature for
19 h and then poured onto a mixture of water/ice and was extracted
with diethyl ether. The organic layer was dried over anhydrous
Na2SO4 and the solvent was evaporated off. The compound 12a was
purified by crystallization in diethyl ether, as a white solid in 52%
yield (1.462 g). Mp 66.1e67.9 ꢀC (from diethyl ether); IR (KBr) 725,
N
HO
HO
26 97% (from 21a)
92% (from 21b)
21a R = Bn
21b R = PNB
R
N
N
HN
N
HCO2NH4, Pd/C 10%
MeOH, reflux, 1 h
N
N
N
HN
HN
N
N
HO
HO
987, 1381, 1726, 2940 cmꢁ1 1H NMR 4.71 (s, 2H), 5.89 (s, 2H),
;
28 98% (from 20a)
81% (from 20b)
20a R = Bn
7.34e7.39 (m, 5H, ArH); 13C NMR 32.1, 53.1, 128.6, 129.1, 129.3, 132.9,
147.1, 181.5; MS (ESI) m/z 281 (MHþ, 100%), 277 (34), 270 (49), 255
(23), 248 (30) and 203 (21); HRMS (ESI) m/z 281.00310 (C10H10BrN4O
[MHþ], 281.00325).
20b R = PNB
Bn
HCO2NH4, Pd/C 10%
MeOH, reflux, 1 h
N
N
N
HN
N
N
N
78%
HN
HN
NHAc
NHAc
4.1.3. 2-Bromo-1-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone
(12b). To a solution of 1-benzyl-5-acetyltetrazole (0.01 mol) in
a mixture of diethyl ether/dioxane (70:30) (70 mL) was added
bromine (0.02 mol). The reaction mixture was stirred at room
temperature for 24 h. The reaction was poured onto a mixture of
water/ice and was extracted with diethyl ether. The organic layer
was dried over anhydrous Na2SO4 and the solvent was evaporated
off. The compound 12b was purified by crystallization in diethyl
ether, as a white solid in 87% yield (2.837 g). Mp 129.9e132.2 ꢀC
(from diethyl ether); IR (KBr) 675, 726, 1348, 1516, 1721,
2937 cmꢁ1; 1H NMR 4.72 (s, 2H), 6.00 (s, 2H), 7.56 (d, 2H, J¼8.4 Hz,
ArH), 8.23 (d, 2H, J¼8.4 Hz, ArH); 13C NMR 31.7, 52.1, 124.4, 129.5,
139.4, 147.2, 148.4, 181.8; MS (ESI) m/z 325 (MHþ, 8%), 259 (32)
and 203 (66); HRMS (ESI) m/z 325.98801 (C10H9BrN5O3 [MHþ],
325.98833).
25
29
Scheme 8.
3. Conclusion
Hetero-DielseAlder reaction of nitrosoalkenes bearing a N-pro-
tected-1H-tetrazole substituent at C-3 with enol ethers, phenox-
yallene, cyclopentadiene and electron rich heterocycles gave access
to a new class of compounds combining the 1,2-oxazine or open
chain oxime substructures with the tetrazol-5-yl substituent. It was
demonstrated that the tetrazolyl moiety can be efficiently
deprotected.
The reduction of an oxime derivative followed by deprotection
gave the corresponding 5-(1-aminoalkyl)-1H-tetrazole showing
that the reported methodology can be used for the synthesis of
4.1.4. 1-(1-Benzyl-1H-tetrazol-5-yl)-2-bromoethanone oxime (13a). 1-
a
-amino acid analogues.
(1-Benzyl-1H-tetrazol-5-yl)-2-bromoethanone
(12a)
(0.873 g,
3.1 mmol) was dissolved in a mixture of CH2Cl2/CH3OH (60:40)
(16.5 mL) and hydroxylamine hydrochloride (3 equiv, 0.646 g,
5.64 mmol) was added. The reaction mixture was stirred at room
temperature for 72 h. The solvent was removed and the substrate
dissolved inwater, and extractedwithethylacetate. Organiclayerwas
dried over anhydrous Na2SO4 and the solvent evaporated. The com-
pound 13a was obtained as a white solid in 89% yield (0.816 g). Mp
90.1e91.9 ꢀC (from dichloromethane); IR (KBr) 724, 991, 1461, 1534,
2836, 3030 cmꢁ1; 1H NMR 4.66 (s, 2H), 5.76 (s, 2H), 7.16e7.22 (m, 5H,
ArH), 10.21 (s, 1H, OH); 13C NMR 31.8, 52.9, 128.1, 128.8, 128.9, 133.6,
144.7,148.7; MS (ESI) m/z 296 (MHþ, 7%), 284 (25), 270 (26), 256 (67),
4. Experimental section
4.1. General
1H NMR spectra were recorded on an instrument operating at
300 or at 400 MHz 13C NMR spectra were recorded on an in-
strument operating at 100 MHz. The solvent is deuteriochloroform
except where indicated otherwise. Chemical shifts are expressed in
parts per million related to internal TMS, and coupling constants (J)
are in hertz. IR spectra were recorded on a Nicolet 6700 FTIR

S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
8907
252 (100) and 234 (66); HRMS (ESI) m/z 296.01421 (C10H11BrN5O
and J2¼1.6 Hz), 5.88 (d, 1H, J¼14.4 Hz), 5.93 (d, 1H, J¼14.4 Hz), 6.37
(d, 1H, J¼2.0 Hz), 7.27e7.31 (m, 5H, ArH); 13C NMR 25.1, 53.0, 79.8,
82.9, 100.5, 128.4, 128.7, 128.8, 133.8, 148.7, 152.8, 157.8; MS (ESI) m/
z 284 (MHþ, 100%), 240 (1) and 218 (5); HRMS (ESI) m/z 284.11545
(C14H14N5O2 [MHþ], 284.11420).
[MHþ], 296.01415).
4.1.5. 2-Bromo-1-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone oxime
(13b). 2-Bromo-1-(1-(4-nitrobenzyl)-1H-tetrazol-5-yl)ethanone (12b)
(0.700 g, 2.15 mmol) was dissolved in a mixture of CH2Cl2/CH3OH
(60:40) (30.8 mL) and hydroxylamine hydrochloride (12 equiv,
1.792 g, 25.8 mmol) was added. The reaction mixture was stirred at
50 ꢀC for 24 h. The solvent was removed and the substrate dissolved
in water, and the extraction was made with ethyl acetate. Organic
layer was dried over anhydrous Na2SO4 and the solvent evaporated.
The compound 13b was obtained as a white solid in 89% yield
(0.651 g). Mp 150.2e152.5 ꢀC (from chloroform); IR (KBr) 731, 995,
1347, 1518, 3187 cmꢁ1; 1H NMR (DMSO-d6) 4.71 (s, 2H), 6.03 (s, 2H),
7.47 (d, 2H, J¼8.4 Hz, ArH), 8.23 (d, 2H, J¼8.4 Hz, ArH), 13.36 (s, 1H,
OH); 13C NMR (DMSO-d6) 32.4, 51.5, 123.8, 128.8, 141.9, 143.0, 147.2,
149.1; MS (ESI) m/z 340 (MHþ, 5%), 319 (50), 297 (100), 285 (13) and
263 (41); HRMS (ESI) m/z 340.99904 (C10H10BrN6O3 [MHþ],
340.99923).
4.2.5. 3-(1-Benzyl-1H-tetrazol-5-yl)-4a,6-dimethyl-4,4a,7,7a-tetra-
hydropyrrolo[2,3-e][1,2]oxazine (19). Ethyl acetate/hexane (3:1), oil,
0.108 g, 51% yield; IR (film) 723, 1115, 1411, 1647, 2968, 3421 cmꢁ1
;
1H NMR 1.22 (s, 3H), 1.97 (s, 3H), 2.78 (d, 1H, J¼18.8 Hz), 2.94 (d, 1H,
J¼16.0 Hz), 2.97e3.03 (m, 1H), 3.12 (d, 1H, J¼16.0 Hz), 4.10 (d, 1H,
J¼6.4 Hz), 5.88 (d, 1H, J¼14.8 Hz), 5.94 (d, 1H, J¼14.8 Hz), 7.27e7.33
(m, 5H, ArH); 13C NMR 19.6, 25.7, 32.3, 52.9, 76.4, 84.0, 128.3, 128.7,
128.8, 133.9, 148.7, 158.4, 172.3; MS (ESI) m/z 311 (MHþ, 100%);
HRMS (ESI) m/z 311.16118 (C16H19N6O [MHþ], 311.16149).
4.2.6. 1-(1-Benzyl-1H-tetrazol-5-yl)-2-(1H-pyrrol-2-yl)ethanone ox-
ime (20a). Ethyl acetate/hexane (1:2), grey solid, 0.164 g, 85% yield.
Mp 111.3e113.2 ꢀC (from ethyl acetate/hexane); IR (KBr) 719, 965,
1063, 1531, 3027, 3214, 3442 cmꢁ1 1H NMR 4.27 (s, 2H), 5.77 (s,
;
4.2. General procedure for the DielseAlder reaction
2H), 6.05e6.06 (m, 2H), 6.62 (d, 1H, J¼1.2 Hz), 7.06e7.29 (m, 5H,
ArH), 8.89 (br s, 1H, NH), 9.25 (s, 1H, OH); 13C NMR 24.9, 52.9, 107.9,
108.2,117.6,124.0,127.9,128.6,128.9,133.8,147.2,149.9; MS (ESI) m/
z 283 (MHþ, 100%) and 218 (6); HRMS (ESI) m/z 283.13018
(C14H15N6O [MHþ], 283.13019).
To a solution of oxime 6, 13a or 13b (0.68 mmol) in CH2Cl2
(30 mL) and the appropriate dienophile (6.8 mmol), Na2CO3
(3.4 mmol) was added and the reaction mixture stirred at room
temperature. The mixture was then filtered through Celite and the
Celite pad washed with dichloromethane. The solvent was evapo-
rated off and the product purified by flash chromatography.
4.2.7. 1-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-2-(1H-pyrrol-2-yl)
ethanone oxime (20b). Ethyl acetate/hexane (1:1), grey solid,
0.176 g, 79% yield. Mp 152.4e154.3 ꢀC (from chloroform); IR (KBr)
4.2.1. 3-(1-Benzyl-1H-tetrazol-5-yl)-4a,5,6,7a-tetrahydro-4H-furo
[3,2-e][1,2]oxazine (15). Ethyl acetate/hexane (1:2), white solid,
0.126 g, 65% yield. Mp 86.9e88.0 ꢀC (from ethyl acetate/hexane); IR
718, 981, 1064, 1348, 1524, 3228, 3430 cmꢁ1 1H NMR (DMSO-d6)
;
4.14 (s, 2H), 5.61 (s,1H), 5.82 (s,1H), 6.01 (s, 2H), 6.54 (s,1H), 7.40 (d,
2H, J¼8.0 Hz, ArH), 8.19 (d, 2H, J¼8.0 Hz, ArH), 10.51 (br s, 1H, NH),
12.62 (br s, 1H, OH); 13C NMR (DMSO-d6) 24.6, 51.3, 105.8, 107.3,
116.7, 123.8, 124.2, 128.8, 142.1, 145.0, 147.2, 150.5; MS (ESI) m/z 328
(MHþ, 100%) and 263 (15); HRMS (ESI) m/z 328.11561 (C14H14N7O3
[MHþ], 328.11526).
(KBr) 697, 718, 981, 1094, 1457, 2976 cmꢁ1 1H NMR 1.94e2.20 (m,
;
3H), 4.03 (approx. t, 2H, J¼6.8 Hz), 4.66 (approx. t, 2H, J¼11.6 Hz),
5.83e5.92 (m, 3H), 7.33 (br s, 5H, ArH); 13C NMR 23.3, 30.8, 32.7,
52.9, 68.5, 108.4, 128.4, 128.6, 128.8, 133.8, 144.6, 148.2; MS (ESI) m/
z 286 (MHþ, 6%), 252 (100), 234 (8) and 218 (14); HRMS (ESI) m/z
286.12996 (C14H16N5O2 [MHþ], 286.12985).
4.2.8. 1-(1-Benzyl-1H-tetrazol-5-yl)-2-(1H-indol-3-yl)ethanone ox-
ime (21a). Ethyl acetate/hexane (1:2), light brown solid, 0.145 g,
64% yield. Mp 189.6e191.3 ꢀC (from ethyl acetate/hexane); IR (KBr)
4.2.2. 3-(1-Benzyl-1H-tetrazol-5-yl)-4,4a,5,6,7,8a-hexahydropyrano
[3,2-e][1,2]oxazine (16). Ethyl acetate/hexane (1:2), white solid,
0.133 g, 65% yield. Mp 73.3e74.5 ꢀC (from ethyl acetate/hexane); IR
(KBr) 726, 899,1033,1157,1456,1604, 2950 cmꢁ1; 1H NMR 1.47e1.56
(m, 1H), 1.62e1.77 (m, 3H), 2.21e2.24 (m, 1H), 2.77e2.90 (m, 2H),
3.72e3.77 (m,1H), 3.97e4.03 (m,1H), 5.23 (d,1H, J¼2.0 Hz), 5.87 (d,
1H, J¼14.4 Hz), 5.91 (d, 1H, J¼14.4 Hz), 7.31e7.34 (m, 5H, ArH); 13C
NMR 22.7, 24.4, 26.7, 27.6, 52.9, 63.6, 96.8, 128.5, 128.6, 128.8, 134.0,
145.0, 149.1; MS (ESI) m/z 300 (MHþ, 100%), 256 (6) and 203 (5);
HRMS (ESI) m/z 300.14630 (C15H18N5O2 [MHþ], 300.14550).
698, 745, 976, 1458, 1522, 3213, 3364 cmꢁ1 1H NMR (DMSO-d6)
;
4.31 (s, 2H), 5.79 (s, 2H), 6.94e7.37 (m, 8H, ArH), 7.61 (d, 1H,
J¼8.0 Hz, ArH), 10.83 (br s, 1H, NH), 12.67 (s, 1H, OH); 13C NMR
(DMSO-d6) 22.1, 51.6, 107.7, 111.4, 118.4, 118.5, 121.0, 124.0, 126.8,
127.6, 128.0, 128.5, 134.7, 135.9, 146.4, 150.2; MS (ESI) m/z 355
(MNaþ, 100%), 333 (MHþ, 96%), 233 (10), 210 (17), 203 (29) and 171
(16); HRMS (ESI) m/z 333.14592 (C18H17N6O [MHþ], 333.14584).
4.2.9. 1-(1-(4-Nitrobenzyl)-1H-tetrazol-5-yl)-2-(1H-indol-3-yl)etha-
none oxime (21b). Ethyl acetate/hexane (1:1), light brown solid,
0.174 g, 68% yield. Mp 192.0e193.6 ꢀC (from chloroform); IR (KBr)
4.2.3. 1-(1-Benzyl-1H-tetrazol-5-yl)-2-(3,4-dihydro-2H-pyran-5-yl)
ethanone oxime (17). Ethyl acetate/hexane (1:2), white solid,
0.019 g, 9% yield. Mp 146.5e148.5 ꢀC (from ethyl acetate/hexane);
756, 975, 1056, 1348, 1523, 3223, 3400 cmꢁ1 1H NMR (DMSO-d6)
;
4.33 (s, 2H), 5.98 (s, 2H), 6.95 (t, 1H, J¼7.6 Hz, ArH), 6.97 (br s, 2H,
ArH), 7.20 (d, 2H, J¼8.4 Hz, ArH), 7.34 (d, 1H, J¼8.0 Hz, ArH), 7.56 (d,
1H, J¼8.0 Hz, ArH), 8.01 (d, 2H, J¼8.4 Hz, ArH), 10.89 (br s, 1H, NH),
12.67 (s, 1H, OH); 13C NMR (DMSO-d6) 22.0, 51.1, 107.5, 111.3, 118.3,
118.4, 120.9, 123.5, 124.1, 126.6, 128.4, 135.8, 141.8, 146.2, 146.9,
150.4; MS (ESI) m/z 378 (MHþ, 100%), 304 (8) and 263 (27); HRMS
(ESI) m/z 378.12973 (C18H16N7O3 [MHþ], 378.13091).
IR (KBr) 726, 983, 1150, 1667, 2925, 3216 cmꢁ1 1H NMR 1.62e1.68
;
(m, 2H), 1.72e1.75 (m, 2H), 3.55 (s, 2H), 3.73 (t, 2H, J¼4.8 Hz), 5.83
(s, 2H), 6.26 (s, 1H), 7.19e7.20 (m, 2H, ArH), 7.29e7.30 (m, 3H, ArH),
8.24 (s, 1H, OH); 13C NMR (DMSO-d6) 21.7, 22.9, 29.4, 51.8, 64.4,
106.5, 127.7, 128.2, 128.7, 134.8, 141.1, 145.5, 150.0; MS (ESI) m/z 300
(MHþ, 100%), 259 (6), 256 (7), 219 (9), 203 (15), 189 (7) and 171 (6);
HRMS (ESI) m/z 300.14501 (C15H18N5O2 [MHþ], 300.14550).
4.2.10. 3-(1-Benzyl-1H-tetrazol-5-yl)-5-methylene-6-phenoxy-5,6-
dihydro-4H-1,2-oxazine (22). Ethyl acetate/hexane (1:2), white
solid, 0.039 g, 17% yield. Mp 104.9e107.0 ꢀC (from ethyl acetate/
4.2.4. 3-(1-Benzyl-1H-tetrazol-5-yl)-4a,7a-dihydro-4H-furo[2,3-e]
[1,2]oxazine (18). Ethyl acetate/hexane (1:2), oil, 0.133 g, 69% yield;
IR (film) 722, 1012, 1411, 1457, 1606, 3035, 3286 cmꢁ1; 1H NMR 2.92
(dd, 1H, J1¼15.6 Hz and J2¼4.8 Hz), 3.47 (dd, 1H, J1¼15.6 Hz and
J2¼3.2 Hz), 5.13 (s, 1H), 5.19e5.23 (m, 1H), 5.40 (dd, 1H, J1¼8.0 Hz
hexane); IR (KBr) 694, 929, 1033, 1207, 1490, 1591, 3039 cmꢁ1 1H
;
NMR 3.68 (d, 1H, J¼20.8 Hz), 3.75 (d, 1H, J¼20.8 Hz), 5.30 (s, 1H),
5.39 (d, 1H, J¼1.6 Hz), 5.84 (d, 1H, J¼14.4 Hz), 5.88 (d, 1H,

8908
S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
J¼14.4 Hz), 6.02 (s, 1H), 7.06e7.34 (m, 10H, ArH); 13C NMR 27.3,
53.0, 97.7, 114.9, 117.3, 123.4, 128.6, 128.6, 128.8, 129.7, 131.5, 133.7,
147.8, 148.4, 155.9; MS (ESI) m/z 348 (MHþ, 100%), 320 (6), 292 (9)
and 254 (1); HRMS (ESI) m/z 348.14609 (C19H18N5O2 [MHþ],
348.14550).
tetrazol-5-yl)-2-(1H-indol-3-yl)ethanone oxime (21b) (0.082 g,
0.22 mmol) in absolute ethanol (15 mL) was shaken at room tem-
perature with PdCl2 (60 mol %, 0.040 g, 0.13 mmol) at an initial
hydrogen pressure of 50 psi for 3 h. The catalyst was removed by
filtration through a Celite pad, which was then washed with eth-
anol. The combined filtrates were concentrated under reduce
pressure. The compound 27 was purified by crystallization in
diethyl ether in 85% yield (0.065 g). Mp 148.6e149.8 ꢀC (from
4.2.11. 3-(1-Benzyl-1H-tetrazol-5-yl)-5-methyl-6-phenoxy-6H-1,2-
oxazine (23). Ethyl acetate/hexane (1:3), white solid, 0.038 g, 16%
yield. Mp 129.3e130.8 ꢀC (from ethyl acetate/hexane); IR (KBr) 726,
755, 947, 1218, 1489, 1663, 3078 cmꢁ1; 1H NMR 2.17 (s, 3H), 5.93 (s,
2H), 6.14 (s, 1H), 6.91 (d, 1H, J¼0.8 Hz), 7.11e7.16 (m, 3H, ArH),
7.21e7.38 (m, 7H, ArH); 13C NMR 19.1, 53.0, 95.3, 111.9, 117.7, 123.6,
128.6, 128.7, 128.8, 129.8, 133.7, 136.8, 145.5, 147.9, 156.6; MS (ESI)
m/z 370 (MNaþ, 53%), 348 (MHþ, 100%), 322 (31), 254 (65) and 252
(12); HRMS (ESI) m/z 348.14569 (C19H18N5O2 [MHþ], 348.14550).
diethyl ether); IR (KBr) 755, 973, 1521, 1617, 3204, 3377, 3466 cmꢁ1
;
1H NMR (DMSO-d6) 4.29 (s, 2H), 5.12 (br s, 2H, NH2), 5.56 (s, 2H),
6.37 (d, 2H, J¼8.0 Hz, ArH), 6.81 (d, 2H, J¼8.0 Hz, ArH), 6.97e7.06
(m, 3H, ArH), 7.32 (d, 2H, J¼8.0 Hz, ArH), 7.62 (d, 2H, J¼7.6 Hz, ArH),
10.84 (s, 1H, NH), 12.66 (s, 1H, OH); 13C NMR (DMSO-d6) 22.1, 51.6,
107.8, 111.4, 113.5, 118.4, 118.5, 121.0, 121.3, 124.0, 126.8, 129.2, 135.9,
146.5, 148.7, 149.7; MS (ESI) m/z 348 (MHþ, 100%) and 333 (3);
HRMS (ESI) m/z 348.15653 (C18H18N7O [MHþ], 348.15673).
4.2.12. 3-(1-Phenyl-1H-tetrazol-5-yl)-4,4a,5,7a-tetrahy-
drocyclopenta[e][1,2]oxazine (24a). Ethyl acetate/hexane (1:2),
white solid, 0.116 g, 64% yield. Mp 110.1e112.5 ꢀC (from ethyl ace-
4.3. General procedure for N-deprotection of compounds 20a,
20b, 21a, 21b and 25
tate/hexane); IR (KBr) 697, 760, 1362, 1495, 1593, 2947, 3071 cmꢁ1
;
1H NMR 2.28e2.33 (m, 1H), 2.61e2.66 (m, 1H), 2.70e2.77 (m, 1H),
2.94e3.02 (m, 1H), 3.07e3.13 (m, 1H), 4.95 (d, 1H, J¼7.6 Hz),
5.76e5.77 (m, 1H), 6.09e6.11 (m, 1H), 7.43e7.53 (m, 5H, ArH); 13C
NMR 26.5, 35.3, 39.4, 85.2, 125.9, 129.0, 129.2, 129.3, 130.5, 134.8,
137.6, 149.7, 156.5; MS (ESI) m/z 268 (MHþ, 100%); HRMS (ESI) m/z
268.12018 (C14H14N5O [MHþ], 268.11929).
To a stirred suspension of compounds 20a, 20b, 21a, 21b or 25
(0.35 mmol) and an equal weight of 10% Pd/C in methanol (10 mL),
anhydrous ammonium formate (3.5 mmol) was added in a single
portion under nitrogen. The resulting mixture was stirred under
reflux for 1 h. The reaction mixture was cooled at room tempera-
ture and the catalyst was removed by filtration through a Celite
pad, which was then washed with methanol. The combined filtrates
were concentrated under reduced pressure and the residue dis-
solved in ethyl acetate and washed with aqueous HCl (1 M). The
organic layer was dried over anhydrous Na2SO4 and the solvent
evaporated.
4.2.13. 3-(1-Benzyl-1H-tetrazol-5-yl)-4,4a,5,7a-tetrahy-
drocyclopenta[e][1,2]oxazine (24b). Ethyl acetate/hexane (1:2),
white solid, 0.095 g, 50% yield. Mp 63.8e65.6 ꢀC (from ethyl ace-
tate/hexane); IR (KBr) 695, 720, 905, 1111, 1437, 2905 cmꢁ1; 1H NMR
2.16e2.22 (m, 1H), 2.61e2.72 (m, 2H), 2.93e2.99 (m, 1H), 3.01e3.07
(m, 1H), 5.01 (d, 1H, J¼7.2 Hz), 5.82e5.84 (m, 1H), 5.89 (d, 1H,
J¼14.4 Hz), 5.94 (d,1H, J¼14.4 Hz), 6.05e6.06 (m,1H), 7.24e7.31 (m,
5H, ArH); 13C NMR 25.8, 35.2, 39.3, 52.9, 85.4, 128.5, 128.7, 128.8,
128.9, 133.9, 137.9, 149.1, 157.6; MS (ESI) m/z 304 (MNaþ, 100%), 282
(MHþ, 80%), 247 (7) and 203 (14); HRMS (ESI) m/z 282.13422
(C15H16N5O [MHþ], 282.13494).
4.3.1. 2-(1H-Indol-3-yl)-1-(1H-tetrazol-5-yl)ethanone oxime (26).
Crystallization in diethyl ether, white solid, 0.082 g, 97% yield; de-
composes >160 ꢀC (from diethyl ether); IR (KBr) 745, 978, 1063,
1458, 1570, 2469, 2857, 3220, 3397 cmꢁ1; 1H NMR (DMSO-d6) 4.30
(s, 2H), 7.02 (t, 1H, J¼7.6 Hz, ArH), 7.10 (t, 1H, J¼7.2 Hz, ArH), 7.18 (s,
1H), 7.36 (d, 1H, J¼8.4 Hz, ArH), 7.70 (d, 1H, J¼8.0 Hz, ArH), 10.91 (s,
1H, NH), 12.42 (s, 1H, OH); 13C NMR (DMSO-d6) 21.4, 108.0, 111.3,
118.4, 118.5, 120.9, 124.1, 126.8, 135.8, 145.9; MS (ESI) m/z 243 (MHþ,
77%), 203 (100), 189 (46), 171 (32) and 152 (19); HRMS (ESI) m/z
243.09860 (C11H11N6O [MHþ], 243.09889).
4.2.14. N-(1-(1-Benzyl-1H-tetrazol-5-yl)-2-(1H-indol-3-yl)ethyl)
acetamide (25). Zinc (0.235 g, 3.6 mmol) was added to a solution of
1-(1-Benzyl-1H-tetrazol-5-yl)-2-(1H-indol-3-yl)ethanone oxime
(21a) (0.1 g, 0.30 mmol) in acetic acid (5 mL). The resulting mixture
was stirred under reflux for 27 h. The reaction mixture was cooled
at room temperature and the zinc salts was removed by filtration
through a Celite pad, which was then washed with ethyl acetate.
The combined filtrates were concentrated under reduced pressure
and the residue dissolved in ethyl acetate and neutralized with
aqueous NaOH (1 M). The organic layer was dried over Na2SO4 and
the solvent evaporated. The compound 25 was purified by flash
chromatography [ethyl acetate (100%)] and obtained as a white
solid in 58% yield (0.063 g). Mp 135.0e136.1 ꢀC (from ethyl acetate/
hexane); IR (KBr) 725, 746, 1457, 1532, 1674, 3033, 3292, 3395,
4.3.2. 2-(1H-Pyrrol-2-yl)-1-(1H-tetrazol-5-yl)ethanone oxime (28).
Crystallization in diethyl ether, white solid, 0.055 g, 81% yield; de-
composes >150 ꢀC (from diethyl ether); IR (KBr) 744, 1047, 1418,
1560, 2882, 3179, 3407 cmꢁ1; 1H NMR (DMSO-d6) 4.16 (s, 2H), 5.73
(s, 1H), 5.89 (d, 1H, J¼2.0 Hz), 6.61 (s, 1H), 10.57 (br s, 1H, NH), 12.40
(s, 1H, OH); 13C NMR (DMSO-d6) 24.0, 105.7, 107.3, 116.6, 124.6,
144.6; MS (ESI) m/z 193 (MHþ, 77%) and 192 (50); HRMS (ESI) m/z
193.08320 (C7H9N6O [MHþ], 193.08324).
4.3.3. N-(2-(1H-Indol-3-yl)-1-(1H-tetrazol-5-yl)ethyl)acetamide
(29). Crystallization in diethyl ether, white solid, 0.074 g, 78% yield;
decomposes >210 ꢀC (from diethyl ether); IR (KBr) 744, 1053, 1545,
1641, 2682, 3068, 3325 cmꢁ1; 1H NMR (CDCl3/DMSO-d6) 1.95 (s, 3H),
3.38e3.49 (m, 2H), 5.65 (approx. q, 1H, J¼7.2 Hz), 6.86 (s, 1H), 7.01 (t,
1H, J¼7.6 Hz, ArH), 7.10 (t, 1H, J¼7.2 Hz, ArH), 7.33 (d, 1H, J¼8.0 Hz,
ArH), 7.46 (d, 1H, J¼8.0 Hz, ArH), 7.84 (br d, 1H, J¼4.8 Hz, NH), 10.11
(s, 1H, NH), 15.61 (s, 1H, NH); 13C NMR (CDCl3/DMSO-d6) 27.7, 34.8,
50.0, 114.0, 116.3, 123.0, 123.8, 126.2, 128.4, 132.2, 141.1, 174.9.
3415 cmꢁ1
;
1H NMR 1.93 (s, 3H), 3.31 (dd, 1H, J1¼14.0 Hz and
J2¼9.2 Hz), 3.36 (dd, 1H, J1¼14.0 Hz and J2¼6.0 Hz), 5.16 (d, 1H,
J¼15.2 Hz), 5.39 (d, 1H, J¼15.2 Hz), 5.55 (approx. q, 1H, J¼6.8 Hz),
6.74 (br d, 1H, J¼1.2 Hz, NH) 6.90 (d, 2H, J¼7.2 Hz, ArH), 7.00 (d, 1H,
J¼8.0 Hz, ArH), 7.07 (t, 1H, J¼7.6 Hz, ArH), 7.13e7.20 (m, 4H, ArH),
7.29e7.33 (m, 2H, ArH), 8.13 (s, 1H, NH); 13C NMR 22.8, 30.1, 44.2,
50.7, 109.4, 111.4, 118.2, 120.0, 122.4, 123.3, 126.9, 127.5, 128.6, 128.9,
133.3, 136.0, 156.0, 170.2; MS (ESI) m/z 383 (MNaþ, 100%), 361
(MHþ, 95%), 258 (21), 203 (20) and 171 (12); HRMS (ESI) m/z
361.17643 (C20H21N6O [MHþ], 361.17714).
Acknowledgements
4.2.15. 1-(1-(4-Aminobenzyl)-1H-tetrazol-5-yl)-2-(1H-indol-3-yl)
Thanks are due to FCT (Grant SFRH/BD/45128/2008; Project PEst-
ethanone oxime (27). A solution of 1-(1-(4-nitrobenzyl)-1H-
C/QUI/UI0313/2011), FEDER, COMPETE and QREN for financial

S.M.M. Lopes et al. / Tetrahedron 67 (2011) 8902e8909
8909
Org. Biomol. Chem. 2004, 2, 828e834; (k) Hegazi, S.; Titouani, S. L.; Soufiaoui, M.;
Tahdi, A. Tetrahedron 2004, 60, 10793e10798.
support. The authors acknowledge the Nuclear Magnetic Resonance
Laboratory of the Coimbra Chemical Centre (www.nmrccc.uc.pt),
University of Coimbra for obtaining the NMR data.
7. Recent examples: (a) Yioti, E. G.; Mati, I. K.; Arvanitidis, A. G.; Massen, Z. S.;
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Supplementary data
Copies of 1H and 13C NMR spectra for all new compounds.
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2011.09.051.
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