A hetero-Diels-Alder approach to functionalized 1H-tetrazoles: Synthesis of tetrazolyl-1,2-oxazines, -oximes and 5-(1-aminoalkyl)-1H-tetrazoles

Article abstract of DOI:10.1016/j.tetlet.2010.10.095

This work describes the first and unprecedented examples of inverse electron demand Diels-Alder reactions of 5-(1-nitrosovinyl)-1-phenyl-1H- tetrazole, generated in situ from the corresponding bromooxime, with electron rich alkenes and heterocycles, provi

Full text of DOI:10.1016/j.tetlet.2010.10.095

Tetrahedron Letters 51 (2010) 6756–6759
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A hetero-Diels–Alder approach to functionalized 1H-tetrazoles: synthesis
of tetrazolyl-1,2-oxazines, -oximes and 5-(1-aminoalkyl)-1H-tetrazoles
Susana M. M. Lopes a, Américo Lemos b, , Teresa M. V. D. Pinho e Melo a,
⇑
⇑
a Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
b 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:
This work describes the first and unprecedented examples of inverse electron demand Diels–Alder
reactions of 5-(1-nitrosovinyl)-1-phenyl-1H-tetrazole, generated in situ from the corresponding
bromooxime, with electron rich alkenes and heterocycles, providing in good overall yields tetrazolyl-
1,2-oxazines and -oximes. Upon subsequent reduction these allowed the access to 5-(1-aminoalkyl)-
1H-tetrazoles, paving the way for a new entry into this important class of compounds, bioisosteres of
Received 17 September 2010
Revised 12 October 2010
Accepted 15 October 2010
Available online 26 October 2010
a
-amino acids.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
5-(1-Aminoalkyl)-1H-tetrazoles
Nitrosovinyltetrazole
Cycloaddition
Oxime
Oxazine
1. Introduction
tionality.6 The acidity of N–H is similar to that of O–H at physiolog-
ical pH, both exhibit planar structures, tetrazoles being more
lipophylic—key factor when crossing cell membranes—than the
corresponding carboxylic analogues.6d,f It is also generally accepted
that tetrazole moieties exhibit stronger metabolic stability.7 Some
studies, nevertheless, have shown that 1-substituted-1H-tetrazoles
can likewise be effective.8 Furthermore, 1,5-disubstituted tetra-
zoles are conformational mimics of a cis-blocked peptide bond, like
those found in a wide variety of biologically important peptides.9
Pharmaceutical formulations, either of 5-substituted-1H- or
1,5-disubstituted-tetrazoles, have been used as anti-inflammatory,
antiulcer, analgesic, HIV and in cephalosporin antibiotics, being the
anti-hypertensive Losartan the most successful example.10
In recent years inverse electron demand Diels–Alder reactions
of conjugated nitrosoalkenes, with electron rich heterocycles or
nucleophilic olefins, have emerged as a successful and effective
strategy to a large number of new 1,2-oxazines and open chain oxi-
mes.1 Since the efficiency of the cycloaddition is associated with
the electrophilic character of the heterodiene, nitrosoalkenes bear-
ing electron withdrawing substituents at 3- and/or 4-positions
such as aryl, trifluoromethyl, acyl, alkoxycarbonyl and phosphorus
groups have been used. These 1,2-oxazines and oximes have
proved to be useful targets, due to their wide and versatile use as
synthetic intermediates. Specifically, reduction of the 3-ethoxycar-
bonyl derivatives allows access to a great variety of nonproteino-
genic amino acids, proline analogues and pyrroles.2 Similarly, if
the heterodiene carries a phosphorus substituent at the 3- or 4-po-
sition,3 the reduction of the corresponding adducts and cycload-
For the preparation of 5-substituted tetrazoles containing the
amino functionality, the most common strategy reported in litera-
ture appears to be the [3+2] cycloaddition reaction of an azide with
the N-protected a-amino nitrile producing the corresponding pro-
ducts affords
a
- and/or b-amino-phosphinic and -phosphonic
tected amino tetrazole.11 However, this procedure cannot be re-
garded as general, due to the limited availability of the starting
acids, considered analogues or surrogates of amino acids, with
the ability of regulating various important biological functions.4
The isosteric similarities of tetrazole and carboxylate anions
have recently been provided by computational evidence,5 but over
the past decades it has as well been established that 5-substituted-
1H-tetrazoles are effective bioisosteres of the carboxylic acid func-
a-amino nitrile and/or the
a-amino acid or a-amino amide, used
as the nitrile precursor.
As a continuation of our work, we envisaged that a conjugated
nitrosoalkene like II, carrying a tetrazole moiety at the 3-position,
would be intercepted by a large range of electron rich olefins, het-
erocycles and nucleophiles producing a vast number of adducts
and cycloadducts (Scheme 1). The reduction of these products
would provide the
the above mentioned limitations.
a-amino tetrazole derivatives, circumventing
⇑
Corresponding authors.
E-mail address: alemos@ualg.pt (A. Lemos).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.095

S. M. M. Lopes et al. / Tetrahedron Letters 51 (2010) 6756–6759
6757
Table 1
O
O
X
N
N
Ar
X
Ar
Cycloaddition reactions of 5-(1-nitrosovinyl)-1H-tetrazole 4
N
N
O
N
N
N
NOH
Br
Ph
Ph
N
N
Na2CO3
CH2Cl2
Alkene or
Heterocycle
N
N
N
III
N
II
Products
N
N
N
N
N
N
4
3
X
OH
OH
LG
NH2
N
Ar
Ar
Alkene or heterocycles
Product
Yield (%)
N
N
OEt
O
OEt
N
N
N
N
Ph
N
N
N
N
N
IV
I
73
30
63
N
N
N
LG - Leaving group
5
OH
Scheme 1. Basis of the synthetic strategy.
Ph
O
N
O
N
(3.5)
N
N
2. Results and discussion
6
O
N
Ph
The generation of the 5-(1-nitrosovinyl)-1H-tetrazoles would
require the initial preparation of halogenated oximes such as 3.
The 5-acetyl-1-phenyl-1H-tetrazole (1) was prepared following a
known synthetic procedure12a and the subsequent bromination al-
lowed the synthesis of 5-bromoacetyl-1-phenyl-1H-tetrazole (2).
Although being described in the literature,12b the bromination step
was troublesome and satisfactory results were only obtained when
the acetyltetrazole was submitted to the action of bromine in diox-
ane/ethyl ether. The target oxime could be synthesized from the
reaction of tetrazole 2 and hydroxylamine.13 The oximation went
smoothly, but the solvent must be carefully chosen since attempts
to carry out the reaction in MeOH/H2O led to the formation of the
product of bromide displacement by methanol (Scheme 2).
By treatment with sodium carbonate in dichloromethane at
room temperature, oxime 3 was converted into the transient 5-
(1-nitrosovinyl)-1-phenyl-1H-tetrazole (4) and this was trapped
in situ by ethyl vinyl ether or heterocycles affording new tetrahy-
dro 3-(1-phenyl-1H-tetrazol-5-yl)-1,2-oxazines or 5-(1-hydroxy-
iminoethyl)-1-phenyl-1H-tetrazole derivatives14 (Table 1).
With acyclic and cyclic ethers such as ethyl vinyl ether, 2,3-
dihydrofuran and 2,3-dihydropyran, cycloadducts were isolated,
as a result of [4+2] cycloaddition reaction with inverse electron de-
mand. With heterocycles possessing higher aromatic character
such as pyrrole and indole, open chain oximes were isolated.
Although it was not unquestionably established that the products
isolated always resulted from a formal [4+2] cycloaddition reac-
tion, we assume analogously with our previous work and discus-
sions with nitrosovinyl-acrylate15 and -phosphonates3a that these
oximes are the result of rearomatization of the firstly formed cyc-
loadducts, that is, in all cases a cycloaddition is occurring and not a
conjugate addition or alkylation reaction. Indeed further support
for this assumption may come from the interesting observation
that cycloadduct 7 isolated initially as the sole product (TLC control
and IR data), underwent isomerization to a mixture 3.5/1 of ad-
duct/cycloadduct during the time elapsed between isolation and
N
N
N
N
(1)
O
7
OH
NH
N
Ph
N
N
H
N
N
N
N
8
OH
N
Ph
N
H
N
N
H
70
40
60
N
N
9
O
N
N
N
Ph
N
H
N
N
N
N
N
N
N
10
O
O
Ph
O
O
N
N
N
11
O
O
Ph
N
47
N
N
12
NMR analysis. Similar isomerization of an tetrahydro 1,2-oxazine
cycloadduct obtained with furan to open chain oxime has been
reported.16
With 2,5-dimethylpyrrole the expected imine15 was isolated as
the end result of enamine-imine tautomerism (the low yield ob-
served may reflect a slower rate of isomerization to the imine,
allowing further additions to the enamine leading to complicated
mixtures and/or degradation products). In this case a stepwise
alkylation followed by cyclization may not be unequivocally ruled
out17 but this is very unlikely since it is well established that 2,5-
disubsituted pyrroles are alkylated at 3- and/or 4-positions.18 The
other products were isolated in generally good yields, and all com-
pounds as single regioisomers, no other isomers being detected or
isolated from the reaction media.
O
O
NOH
Br
Br
N
N
ii)
N
i)
N
N
N
N
N
N
N
N
N
Subsequently, we were happy to find that compounds 8 and 9,
by the action of aluminium amalgam in moist THF at room temper-
1
2
3
ature,19 were smoothly converted into the corresponding
a-amino-
Scheme 2. Synthesis of bromooxime 3 precursor of 5-(1-nitrosovinyl)-1-phenyl-
1H-tetrazole 4. Reagents and conditions: (i) Br2 in dioxane/ethyl ether (30:70), rt,
4 h (75%); (ii) NH2OHꢀHCl in CH2Cl2/MeOH (60:40), rt, 48 h (83%).
tetrazoles 13 and 14, respectively (Scheme 3). It should be noted
that 13 is a tryptophan analogue.

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S. M. M. Lopes et al. / Tetrahedron Letters 51 (2010) 6756–6759
Biological Activity of Phosphono- and Phosphino-Peptides; John Wiley & Sons:
N
N
N
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N
Ph
NH2
5. Matta, C. F.; Arabi, A. A.; Weaver, D. F. Eur. J. Med. Chem. 2010, 45, 1868–1872.
6. (a) Dong, L.; Marakovits, J.; Hou, X.; Guo, C.; Greasley, S.; Dagostino, E.; Ferre, R.
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Manning, D. D.; Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.; Li, Z.; Dickerson,
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N
H
i)
13 (66%)
(8, 9)
N
N
N
N
Ph
H
N
NH2
14 (66%)
Scheme 3. Reduction to 5-(1-aminoalkyl)-1H-tetrazoles. Reagents and conditions:
7. (a) Holland, G. F.; Pereira, J. N. J. Med. Chem. 1967, 10, 149–154; (b) Figdor, S. K.;
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3. Conclusions
Herein, the first examples of Diels–Alder reactions of 5-(1-nitr-
osovinyl)-1H-tetrazole 4, generated in situ from the corresponding
bromooxime 3, with electron rich alkenes and heterocycles are re-
ported. The products are obtained with high selectivity, the yields
being comparable or somewhat higher than those reported for
nitrosoalkenes bearing a 3-ethoxycarbonyl substituent and better
than those carrying a phosphonate group at the same position. Fur-
thermore, it was demonstrated that the reduction of these adducts
allows access to 5-(1-aminoalkyl)-1H-tetrazoles. Thus, the present
work may be regarded as the opening door to a novel synthetic
methodology to this important class of compounds, bioisosteres
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of a-aminoacids.
Acknowledgements
Thanks are due to Dr. T. L. Gilchrist for helpful discussions. The
authors acknowledge the Fundação para a Ciência e a Tecnologia
for the Ph.D. grant SFRH/BD/45128/2008 and the Nuclear Magnetic
Resonance Laboratory of the Coimbra Chemical Centre (www.
nmrccc.uc.pt), University of Coimbra for obtaining the NMR data.
12. (a) Clemençon, I. F.; Ganem, B. Tetrahedron 2007, 63, 8665–8669; (b) Jacobsok,
C. R.; Amstutz, E. D. J. Org. Chem. 1954, 19, 1652–1661.
Supplementary data
13. 5-Bromoacetyl-1H-1-phenyltetrazole, 2. To
a solution of 5-acetyl-1-phenyl-
tetrazole (0.188 g, 0.01 mol) in a mixture of diethyl ether/dioxane (70:30) was
added bromine (0.160 g, 0.01 mol). The reaction mixture was stirred at room
temperature for 4 h and poured onto a mixture of water/ice and extracted with
ether. The organic layer was dried over anhydrous Na2SO4 and the solvent was
evaporated off. The compound was obtained as a white solid in 79% yield. Mp
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.095.
82.5–84.3 °C (diethyl ether). IR (KBr) 769, 979, 1503, 1722, 1736 cmꢁ1 1H NMR
.
References and notes
(400 MHz) CDCl3 d 4.75 (s, 2H); 7.49–7.64 (m, 5H). 13C NMR (100 MHz) CDCl3 d
32.4, 125.2, 129.5, 131.1, 133.6, 147.7, 180.3.
5-(2-Bromo-1-hydroxyiminoethyl)-1H-1-phenyltetrazole, 3. The 5-Bromoacetyl-
1. Reviews see: (a) Lemos, A. Molecules 2009, 14, 4098–4119; (b) Rai, K. M. L. Top.
Heterocycl. Chem. 2008, 13, 1–69; (c) Reissig, H. U.; Zimmer, R. 1-Nitrosoalkenes
In Science of Synthesis; Molander, G. A., Ed.; Thieme: Stuttgard, Germany, 2006;
Vol. 33, pp 371–389; (d) Tsoungas, P. G. Heterocycles 2002, 57, 1149–1178; (e)
Lyapkalo, I. M.; Ioffe, S. Russ. Chem. Rev. 1998, 67, 467–484; (f) Gilchrist, T. L.;
Wood, J. E. In Comprehensive Heterocyclic Chemistry II; Boulton, A. J., Ed.;
Pergamon Press: Oxford, 1996; Vol. 6, pp 279–299; (g) Gilchrist, T. L. Chem. Soc.
Rev. 1983, 12, 53–73.
2. (a) Gallos, J. K.; Alexandraki, E. S.; Stathakis, C. I. Heterocycles 2007, 71, 1127; (b)
Gallos, J. K.; Sarli, V. C.; Massen, Z. S.; Varvogli, A. C.; Papadoyanni, C. Z.;
Papaspyrou, S. D.; Argyropoulos, N. G. Tetrahedron 2005, 61, 565–574; (c)
Hegazi, S.; Titouani, S. L.; Soufiaoui, M.; Tahdi, A. Tetrahedron 2004, 60, 10793–
10798; (d) Gallos, J. K.; Sarli, V. C.; Varvogli, A. C.; Papadoyanni, C. Z.;
Papaspyrou, S. D.; Argyropoulos, N. G. Tetrahedron Lett. 2003, 44, 3905–3909;
(e) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R. Synlett 1995, 1014–
1016; (f) Zimmer, R.; Arnold, T.; Homann, K.; Reissig, H.-U. Synthesis 1994,
1050–1055; (g) Gilchrist, T. L.; Lingham, D. A.; Roberts, T. G. J. Chem. Soc., Chem.
Commun. 1979, 1089–1090.
3. (a) Guimarães, E.; Lemos, A.; Lopes, M. Phosphorus, Sulfur Silicon Relat. Elem.
2007, 182, 2149–2155; (b) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios,
F. J. Org. Chem. 2007, 72, 5202–5206.
4. (a) Ordóñez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17–49;
(b) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–931;
(c) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177–6216; (d)
Kafarski, P.; Lejczak, B. In Aminophosphinic and Aminophosphonic Acids.
Chemistry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; The
1H-1-phenyltetrazole (1.88 mmol) was dissolved in
a mixture of CH2Cl2/
CH3OH (60:40) and hydroxylamine hydrochloride (0.392 g, 5.64 mmol) was
added. The reaction mixture was stirred at room temperature for 48 h. The
solvents removed and the substrate dissolved in water and ethyl acetate.
Organic layer was dried over anhydrous Na2SO4 and the solvent evaporated.
The compound was obtained as a white solid in 83% yield. Mp 143.2–144.5 °C
(from dichloromethane). IR (KBr) 687, 770, 979, 1023, 1376, 1495, 3268 cmꢁ1
.
1H NMR (400 MHz) DMSO-d6 d 4.70 (s, 2H), 7.57–7.62 (m, 5H, ArH), 13.07 (s,
1H, OH). 13C NMR (100 MHz) DMSO-d6 d 33.7, 126.3, 129.8, 130.0, 130.3, 130.9,
135.3, 142.5, 149.8
14. General procedure for Diels–Alder reactions. To a solution of oxime (0.71 mmol)
in CH2Cl2 (20 mL) and the appropriate diene (7.1 mmol), Na2CO3 (3.6 mmol)
was added at room temperature and the mixture was stirred for 16 h. The
solvent was evaporated and the product was purified by flash chromatography
[ethyl acetate/hexane (1:2)].
6-Ethoxy-3-(1-phenyl-1H-tetrazol-5-yl)-5,6-dihydro-4H-1,2-oxazine, 5. White
solid, 73% yield, mp 143.7–144.4 °C (from ethyl acetate/hexane). IR (KBr)
766, 889, 1108, 1495, 2922, 3451 cmꢁ1 1H NMR (400 MHz) CDCl3 d 1.14 (t,
.
J = 7.1 Hz, 3H), 1.91–2.06 (m, 1H, 5-H), 2.05–2.20 (m, 1H, 5-H), 2.66–2.94 (m,
2H, 4-H), 3.48–3.61 (m, 1H, CH2–ethoxy), 3.66–3.74 (m, 1H, CH2–ethoxy), 5.14
(s, 1H, 6-H), 7.34–7.59 (m, 5H, Ar-H). 13C NMR (100 MHz) CDCl3 d 14.9, 18.0,
22.9, 64.1, 95.8, 125.6, 129.2, 130.2, 135.0, 147.1, 150.0. MS (ESI) m/z 274
[M+H]+ (81%), 233 (11), 203 (35), 201 (23), 189 (15) and 171 (15). HRMS (ESI)
calcd for C13H16N5O2 [M+H]+: 274.13092; found: 274.12985.

S. M. M. Lopes et al. / Tetrahedron Letters 51 (2010) 6756–6759
6759
2-(Furan-2-yl)-1-(1-phenyl-1H-tetrazol-5-yl)ethanone oxime 6 and 3-(1-Phenyl-
1H-tetrazol-5-yl)-4a,7a-dihydro-4H-furo[2,3-e][1,2]oxazine 7. Oil, mixture of
isomers (3.5:1), 30% yield. IR (film) 738, 1045, 1266, 1421, 1499, 1731,
129.2, 130.5, 134.8, 148.4, 149.7. MS (ESI) m/z 272 [M+H]+ (100%), 200 (11).
HRMS (ESI) calcd for C13H14N5O2 [M+H]+: 272.11404; found: 272.11420.
3-(1-Phenyl-1H-tetrazol-5-yl)-4,4a,5,6,7,8a-hexahydro-pyrano[3,2-e][1,2]oxazine,
12. White solid, 47% yield. Mp 147.2–148.6 °C (from ethyl acetate/hexane). IR
3330 cmꢁ1 1H NMR (400 MHz) CDCl3 Major component d 4.38 (s, 2H), 6.15–
.
6.16 (m, 1H, 3-H of furan), 6.28–6.30 (m, 1H, 4-H of furan), 7.28–7.34 (m, 1H,
5-H of furan), 7.43–7.65 (m, 4H, Ar-H), 7.71–7.75 (m, 1H, Ar-H), 8.07 (s, 1H,
O–H). Minor component d 3.01 (dd, J1 = 15.0 Hz and J2 = 6.0 Hz, 1H, 4-H), 3.42
(dd, J1 = 15.0 Hz and J2 = 6.0 Hz, 1H, 4-H), 5.11 (t, J = 3.0 Hz, 1H, H-4a), 5.22–
5.28 (m, 1H, 7a-H), 5.31–5.36 (m, 1H, 7-H), 6.04 (d, J = 3.0 Hz, 1H, 6-H), 7.27–
7.59 (m, 5H, Ar-H). MS (ESI) m/z 270 [M+H]+ (61%), 201 (18), 181 (11), 169 (29)
and 147 (34). HRMS (ESI) calcd for C13H12N5O2 [M+H]+: 270.09800; found:
270.09855.
(KBr) 767, 901, 1032, 1158, 1494 cmꢁ1 1H NMR (400 MHz) CDCl3 d 1.59–1.81
.
(m, 4H), 2.25 (br s, 1H), 2.91–2,92 (m, 2H), 3.67–3.71 (m, 1H, 7-H), 3.92–3.97
(m, 1H, 70-H), 5.18 (d, J = 2.0 Hz, 1H, 8a-H), 7.44–7.53 (m, 5H, ArH). 13C NMR
(100 MHz) CDCl3 d 22.7, 24.5, 27.2, 27.7, 63.5, 96.7,126.0, 129.2, 130.4, 135.0,
144.0, 149.8 MS (ESI) m/z 286 [M+H]+ (100%), 281 (20), 258 (12), 209 (6). HRMS
(ESI) calcd for C14H16N5O2 [M+H]+: 286.12967; found: 286.12985.
15. Gilchrist, T. L.; Lemos, A. J. Chem. Soc., Perkin Trans. 1 1993, 1391–1395.
16. Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc., Perkin Trans. 1 1983, 1283–1292.
17. Ishibashi, H.; Mita, N.; Matsuba, N.; Kubo, T.; Nakanishi, M.; Ikeda, M. J. Chem.
Soc., Perkin Trans. 1 1992, 2821–2825.
18. (a) Davies, H. M. L.; Lian, Y. Org. Lett. 2010, 12, 924–927; (b) Herz, W.; Settine, R.
J. Org. Chem. 1959, 24, 201–204.
2-(1H-Indol-3-yl)-1-(1-phenyl-1H-tetrazol-5-yl)ethanone oxime, 8. White solid
63% yield, Mp 193.0–194.5 °C (from dichloromethane). IR (KBr) 746, 972, 1421,
1496, 3428 cmꢁ1
.
1H NMR (400 MHz) CDCl3/DMSO d 4.40 (s, 2H), 6.94–7.05 (m,
4H, Ar-H), 7.10–7.14 (m, 1H, Ar-H), 7.24–7.28 (m, 2H, Ar-H), 7.33–7.39 (m, 2H,
ArH), 7.56–7.61 (m, 1H, Ar-H), 10.09 (br s, 1H, O–H), 11.99 (s, 1H, N–H). 13C
NMR (100 MHz) CDCl3/DMSO d 23.0, 107.9, 111.5, 118.9, 121.6, 124.3, 125.0,
127.0, 129.1, 129.6, 134.8, 136.3, 145.6, 150.9. MS (ESI) m/z 319 [M+H]+ (100%),
226 (51), 204 (31), 169 (77) and 147 (84). HRMS (ESI) calcd for C17H15N6O
[M+H]+: 319.12944; found: 319.13019.
19. General procedure for reduction of oximes. The aluminium amalgam used in
these reductions was freshly prepared as follows. Aluminium foil was cut into
small pieces. The pieces were then washed successively with: diethyl ether,
ethanol, 2% mercuric chloride solution, ethanol and finally with ether. Each
washing lasted for ten seconds. The strips were added immediately to a
solution of the oxime (0.31 mmol) in moist tetrahydrofuran (7 mL, 10% H2O),
and the mixture was stirred at room temperature with TLC control. The
mixture was then filtered through celite, the celite pad was washed well with
THF and diethyl ether and the combined filtrates were reduced in volume.
Dichloromethane was added, the solution was dried over Na2CO3, solvent was
evaporated off and the product was purified by flash chromatography.
2-(1H-Indol-3-yl)-1-(1-phenyl-1H-tetrazol-5-yl)ethanamine, 13. Eluent [CH2Cl2/
MeOH (9:1)], white solid 66% yield. Mp 151.9–153.7 °C (from diethyl ether). IR
1-(1-Phenyl-1H-tetrazol-5-yl)-2-(1H-pyrrol-2-yl)ethanone oxime, 9. White solid
70% yield. Mp 108.6–109.9 °C (from dichloro-metane). IR (film) 708, 963, 1413,
1495, 3425 cmꢁ1 1H NMR (400 MHz) CDCl3 d 4.23 (s, 2H), 6.03 (s, 1H, 3-H of
.
pyrrole), 6.08 (d, J = 2.8 Hz, 1H, 4-H of pyrrole), 6.67 (br s, 1H, 5-H of pyrrole),
7.19 (d, 2H, J = 7.2 Hz, Ar-H), 7.42–7.52 (m, 3H, Ar-H), 8.62 (s, 1H, N–H), 8.84
(br s, 1H, O–H). 13C (100 MHz) CDCl3 d 25.6, 108.1, 108.4, 117.8, 123.8, 125.6,
130.3, 134.8, 146.3, 150.2. MS (ESI) m/z 269 [M+H]+ (88%), 201 (19), 169 (6) and
147 (6). HRMS (ESI) calcd for
269.11454.
C
13H13N6O [M+H]+: 269.11373; found:
(KBr) 694, 742, 1070, 1495, 3302 cmꢁ1 1H NMR (400 MHz) CDCl3 d 1.80 (br s,
.
4a,6-Dimethyl-3-(1-phenyl-1H-tetrazol-5-yl)-4,4a,7,7a-tetrahydropyrrolo[2,3-e]-
2H, NH2), 3.32 (dd, 1H, J1 = 14.0 Hz and J2 = 7.2 Hz), 3.37 (dd, 1H, J1 = 14.0 Hz
and J2 = 7.2 Hz), 4.43 (approx. t, 1H, J = 7.2 Hz), 6.82 (d, 1H, J = 1.6 Hz), 6.97–
7.021 (m, 3H, ArH), 7.15–7.21 (m, 2H, ArH), 7.29–7.41 (m, 3H, ArH), 7.43–7.45
(m, 1H, ArH), 8.11 (br s, 1H, NH). 13C NMR (100 MHz) CDCl3 d 34.3, 47.4, 110.7,
111.3, 118.1, 119.8, 122.3, 123.1, 125.2, 127.0, 129.5, 130.3, 133.3, 136.2, 158.6.
MS (ESI) m/z 305 [M+H]+ (15%), 281 (28), 260 (100), 207 (13). HRMS (ESI):
Calcd for C17H16N6 [M+H]+: 305.15082, found 305.15092.
[1,2]oxazine, 10. Eluent [ethyl acetate/dichloromethane (1:1)], oil 40% yield. IR
(film) 690, 764, 1017, 1414, 1496, 1646 cmꢁ1 1H NMR (400 MHz) CDCl3 d 1.30
.
(s, 3H, 4a-Me), 2.00 (s, 3H, 6-Me), 2.71 (d, J = 18.8 Hz, 1H, 4-H), 2.92–2.99 (m,
2H, 40-H and 7-H), 3.13 (d, J = 16.0 Hz, 1H, 70-H), 4.12 (d, J = 6.4 Hz, 1H, 7a-H),
7.43–7.55 (m, 5H, ArH). 13C NMR (100 MHz) CDCl3 d 19.6, 25.7, 33.0, 45.3, 76.4,
83.8, 125.9, 129.3, 130.6, 134.7, 149.5, 157.4, 172.7. MS (ESI) m/z 297 [M+H]+
(100%), 201 (7) and 162 (6). HRMS (ESI) calcd. for C15H17N6O [M+H]+
297.14588; found: 297.14584.
:
1-(1-phenyl-1H-tetrazol-5-yl)-2-(1H-pyrrol-2-yl)ethanamine, 14. Eluent [CH2Cl2/
MeOH (9:1))], oil, 50% yield. IR (film) 692, 764, 1653, 3418 cmꢁ1 1H NMR
.
3-(1-Phenyl-1H-tetrazol-5-yl)-4a,5,6,7a-tetrahydro-4H-furo[3,2-e][1,2]oxazine,
11. White solid, 60% yield. Mp 160.2–161.9 °C (from ethyl acetate/hexane). IR
(400 MHz) CDCl3 d 3.20 (dd, J1 = 14.4 Hz, J2 = 8.4 Hz, 1H, 2-H), 3.28 (dd,
J1 = 14.4 Hz, J2 = 5.6 Hz, 1H, 20-H), 3.56 (bt, J = 4.4 Hz, 2H, N–H2), 4.05 (dd,
J1 = 8.4 Hz, J2 = 5.6 Hz, 1H, 1-H), 5.77 (s, 1H, 3-H of pyrrole), 6.06 (d, J = 0.8 Hz,
1H, 4-H of pyrrole), 6.62 (d, J = 0.8 Hz, 1H, 5-H of pyrrole), 7.02 (d, J = 7.6 Hz, ,
2H, Ar-H), 7.47–7.57 (m, 3H, Ar-H), 8.75 (br s, 1H, N–H).
(KBr) 770, 888, 1008, 1123, 1494 cmꢁ1 1H NMR (400 MHz) CDCl3 d 1.72–1.82
.
(m, 1H), 2.21–2.29 (m, 1H), 2.79–2.87 (m, 1H), 2.99–3.14 (m, 2H), 3.95–3.97
(m, 1H, 6-H), 4.01–4.12 (m, 1H, 60-H), 5.46 (d, J = 4.8 Hz, 1H, 7a-H), 7.44–7.54
(m, 5H, ArH). 13C NMR (100 MHz) CDCl3 d 24.9, 29.0, 34.7, 68.7, 101.2, 126.0,