Efficient syntheses of 5-aminoalkyl-1H-tetrazoles and of polyamines incorporating tetrazole rings

Article abstract of DOI:10.1021/ol0477069

(Chemical Equation Presented) Linear N^ω-tritylated ω-amino thiobenzylamides and N^α,N^ω- ditritylated polyamino mono- or bisthioamides were efficiently converted to the corresponding tetrazole derivatives upon treatment with

Full text of DOI:10.1021/ol0477069

ORGANIC
LETTERS
2005
Vol. 7, No. 4
561-564
Efficient Syntheses of
5-Aminoalkyl-1H-tetrazoles and of
Polyamines Incorporating Tetrazole
Rings
Constantinos M. Athanassopoulos,* Thomas Garnelis, Dimitrios Vahliotis, and
Dionissios Papaioannou
Department of Chemistry, UniVersity of Patras, GR-265 00 Patras, Greece
kath@chemistry.upatras.gr
Received November 8, 2004
ABSTRACT
ω
r
ω
Linear N -tritylated
ω-amino thiobenzylamides and N ,N -ditritylated polyamino mono- or bisthioamides were efficiently converted to the
corresponding tetrazole derivatives upon treatment with azidotrimethylsilane under Mitsunobu reaction conditions.
5-Substituted 1H-tetrazoles and 1,5-disubstituted tetrazoles
are often used as metabolism-resistant isosteric replacements
for carboxylic acids and as cis amide bond surrogates,
respectively, in SAR-driven analogue synthesis in medicinal
chemistry.1-3 A variety of synthetic tetrazole-containing
biologically active substances are described in the current
literature, such as glycine-tetrazole modified S-alkyl-GSH
analogues,4 R-methylene tetrazole-based peptidomimetic
HIV protease inhibitors,5 endothelin-converting enzyme-1
(ECE-1),6 neutral endopeptidase 24.11 (NEP 24.11) non-
peptidic inhibitors,7 and urea-based inhibitors of glutamate
carboxypeptidase II (GCPII).8 5-Substituted 1H-tetrazoles are
usually prepared by the reaction of nitriles or secondary
amides under Mitsunobu reaction conditions with azides,
especially with tributyltin or trimethylsilyl azide which are
safer and soluble in organic solvents.1,9,10 On the other hand,
1,5-disubstituted tetrazoles have been obtained through
sequential treatment of secondary amides with PCl5 and
HN3.2 We have developed a general methodology for the
synthesis of polyamines based on the acylation of suitable
amines by either the isolable succinimidyl ester of N-trityl-
â-alanine (Τrt-âAla-OSu, 1)11 or the in situ activated N-trityl-
γ-aminobutyric acid (Trt-γAba, 3)12 with N,N′-dicyclohex-
ylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt),
followed by LiAlH4-mediated reduction of the resulting
(1) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379-3393 and references
therein.
(2) Yu, K. L.; Johnson, R. L. J. Org. Chem. 1987, 52, 2051-2059.
(3) Zabrocki, J.; Smith, D.; Dunbar, J. B. Jr.; Iijima, H.; Marshall, G. R.
J. Am. Chem. Soc. 1988, 110, 5875-5880.
(4) Burg, D.; Hameetman, L.; Filippov, D. V.; van der Marel, G. A.;
Mulder, G. J. Bioorg. Med. Chem. 2002, 12, 1579-1582.
(5) May, B. C. H.; Abell, A. D. J. Chem. Soc., Perkin. Trans. 1 2002,
172-178.
(6) De Lombaert, S.; Blanchard, L.; Stamford, L. B.; Tan, J., Wallace,
E. M.; Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.;
Marcopoulos, N.; Savage, P.; Chou, M.; Trapani, A. J.; Jeng, A. Y. J. Med.
Chem. 2000, 43, 488-504.
(7) De Lombaert, S.; Blanchard, L.; Tan, J.; Sakane, Y.; Berry, C.; Ghai,
R. D. Bioorg. Med. Chem. Lett. 1995, 5, 145-150.
(8) Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P. A.; Grajkowska,
E.; Wroblewski, J. T.; Yamamoto, T.; Bzdega, T.; Wroblewska, B.; Neale,
J. H. J. Med. Chem. 2004, 47, 1729-1738.
10.1021/ol0477069 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/27/2005

Scheme 1. Conversion of Nω-Tritylated Linear ω-Amino Benzylamides to Tetrazole Derivatives
mono- or polyamides.12 We therefore thought it would be
of interest to examine the suitability of these mono- or
polyamides to prepare for the first time polyamine analogues
incorporating one or more tetrazole rings.
h, without the need to add excess reagents. From the resulting
fully protected tetrazoles 6 and 7, the Trt group can be
selectively removed by trifluoroacetic acid (TFA)-mediated
acidolysis (TFA-CH2Cl2-CF3CH2OH ) 3:6:1) to give the
partially protected 5-(ω-aminoalkyl)tetrazoles 8, whereas
both protecting groups can be removed in one pot by catalytic
hydrogenolysis (the Trt group is cleaved much faster than
We initially examined the suitability of the benzylamides
Trt-âAla-NHBn (2) and Trt-γAba-NHBn (4),12 taken as
model compounds to react with either commercially available
tributyltin azide (TBTA) or trimethylsilyl azide (TMSA), in
the presence of triphenylphosphine (TPP) and diisopropyl
azodicarboxylate (DIAD). These benzylamides were readily
obtained through the acylation of benzylamine with 1 and
3, respectively, in 93% and 85% yields (Scheme 1). It was
found that both benzylamides 2 and 4 reacted at a similar
rate (e.g., reaction completed within 3 days at 25 °C) with
TMSA in the presence of TPP and DIAD and produced
similar yields (see Table 1) of the anticipated tetrazole
derivatives 6 and 7, respectively, using 2.4-2.9 equiv of
reagents. For comparison, the more sterically demanding
reagent TBTA produced a less than 10% yield of tetrazole
6 after 7 days at the same temperature. At this point, we
reasoned that the corresponding thioamides would react faster
and more efficiently under these reaction conditions.13 Thus,
treatment of benzylamide 4 with Lawesson’s reagent (LR)
produced a 62% yield of the corresponding thioamide 5. This
was then treated with the combination of reagents TMSA/
TPP/DIAD to give an 83% yield of the tetrazole 7 within 1
Table 1. Thionation of Secondary Amides with LR and
Conversion of Amides and Thioamides to Tetrazoles Using
TMSA, TPP, and DIADa
entry starting material reaction time (h) product yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2
4
4
36
0.5b
36
1
6
5
7
65
62
68
83
50
50
85
33
90
50
55
55
55
51
50
75
25
52
5
7
14
16
19
19
20
22
23
24
25
26
27
34
34
35
2
16
17
20
21
21
23
28
25
29
27
32
36
35
36
24
12
72
24
2b
24
2
16
12
6
12b
3b
5
(9) Duncia, J. V.; Pierce, M. E.; Santella, J. B. J. Org. Chem. 1991, 56,
2395-2400.
(10) Bliznets, I. V.; Vasil′ev, A. A.; Shorshnev, S. V.; Stepanov, A. E.;
Lukyanov, S. M. Tetrahedron Lett. 2004, 45, 2571-2573.
(11) Karigiannis, G.; Mamos, P.; Balayiannis, G.; Katsoulis, I.; Papaio-
annou, D. Tetrahedron Lett. 1998, 39, 5117-5120.
(12) Mamos, P.; Karigiannis, G.; Athanassopoulos, C.; Bichta, S.;
Kalpaxis, D.; Papaioannou, D. Tetrahedron Lett. 1995, 36, 5187-5190.
(13) Thioamides have been used by Blagbrough and Moya to effect mild
reduction of amide bonds in sensitive polyamine conjugates: Blagbrough,
I. S.; Moya, E. Tetrahedron Lett. 1994, 35, 2057-2060.
a The structures of new compounds described in this paper were
determined by a combination of spectroscopic techniques (ESI-MS, NMR)
and microanalysis. Fully deprotected mono- or bistetrazole polyamine
derivatives were characterized by MALDI-TOF/TOF HR-MS. b THF, reflux.
All other reactions presented in the table were perfomed at ambient
temperature.
562
Org. Lett., Vol. 7, No. 4, 2005

Scheme 2. Attempted Conversion of NR-Tritylated Chiral R-Amino Benzylamides to Tetrazole Derivatives
the Bn group) within 16-20 h to give the free 5-(ω-
aminoalkyl)tetrazoles 9 in 92-96% yield.
obviously due to the low solubility of 22 in the reaction
medium (anhydrous THF or dioxane). However, even in
DMF, in which 22 was solubilized upon addition of the
reagents, only a less than 10% (as judged by TLC) conver-
sion to 28 was observed after repeated additions of reagents
and several days at 25 °C. On the other hand, treatment of
either 19 or 22 with LR in THF for 12 h at 25 °C, or 2 h
under reflux, respectively, produced the corresponding mono-
(20) and bis-thioamides (23) in 85% and 50% isolated yields,
respectively. From these thioamides the corresponding mono-
(21) and bis-tetrazole (28) derivatives were unexceptionally
obtained in 90% and 55% yields, respectively. It is worth
mentioning that transformation of 23 to its corresponding
mono-tetrazole derivative was over within 1 h, whereas its
complete conversion to the bistetrazole derivative 28 required
additional reagents and a much longer reaction time.
Similarly, the bisamides 24 and 2617 were converted first
to the corresponding bisthioamides 25 and 27 in 55% and
51% yields, respectively, and then reacted with TMSA in
the presence of TPP and DIAD to give the bistetrazole
derivatives 29 and 32 in 55% and 50% yields, respectively.
Routine detritylation of these tetrazole derivatives gave
unexceptionally the polyamines 30, 31, and 33 in 90-95%
yields, incorporating one or two tetrazole units. The former
may be considered as an analogue of spermidine (SPD)
whereas the other two are analogues of spermine (SPM).
Attempts to extend this reaction to benzylamides of NR-
tritylated L-amino acids, like Pro (10), Phe, Leu, Val, and
Ala, readily obtained through a reported procedure,14 were
unsuccessful, as were attempts to convert these benzylamides
to the corresponding thioamides using the reagent LR. It is
worth mentioning that treatment of amide 11 with TMSA/
TPP/DIAD, to obtain tetrazole 12, led instead to compound
13 in 68% yield, following flash column chromatography
(FCC) purification. Compound 13 was also obtained from
the reaction of 11 with TPP and DIAD (Scheme 2). It should
be noted that 13 was stable even at refluxing THF or toluene
for several hours.
It was suspected that steric hindrance was the cause for
these failed conversions of NR-tritylated R-amino benzyl-
amides to tetrazoles, and therefore, the corresponding meth-
ylamides were employed. Only the methylamides 14 and 15
from Ala and Leu, respectively, reacted however sluggishly
with TMSA/TPP/DIAD to provide the corresponding tetra-
zoles 17 and 18 in low yields (ca. 10%).15 Attempted
thionation of 15 gave a complex reaction mixture whereas
the less sterically demanding methylamide 14 provided the
expected thioamide 16 in 50% yield following FCC purifica-
tion. From this thioamide, the tetrazole 17 was now obtained
in 50% yield.
This methodology was easily extended to accommodate
aromatic polyamines, like the one obtained by the LiAlH4-
mediated reduction of the bisamide 34.18 Tetrazole ring
formation was effected in refluxing THF for 12 h to give
the expected bistetrazole derivative 36 in 75% yield. On the
other hand, thionation of 34 gave the corresponding bisthio-
amide 35 in low yield (25%). However, this compound was
converted to 36 in 52% yield at ambient temperature.
We then turned our attention to the application of this
methodology to the monoamide 1916 and the bisamide 22
(Scheme 3).12,17 Treatment of 19 with a total of 4.5 equiv of
each of TPP, DIAD, and TMSA within 3 days at 25 °C gave
a 33% yield of the tetrazole derivative 21, whereas bisamide
22 failed to produce the expected bistetrazole derivative 28,
(14) Mamos, P.; Dalatsis, E.; Athanassopoulos, C.; Balayiannis, G.;
Papaioannou, D.; Francis, G. W. Acta Chem. Scand. 1998, B52, 227-231.
(15) Tetrazole analogues of R-amino acids were recently prepared through
reaction of NR-Z-protected R-amino nitriles with NaN3/ZnBr2: Demko, Z.
P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525-2527.
(16) Vassis, S.; Govaris, I.; Voyagi, K.; Mamos, P.; Papaioannou, D.
Tetrahedron Lett. 2002, 43, 2597-2600.
(17) Tsiakopoulos, N.; Damianakos, C.; Karigiannis, G.; Vahliotis, D.;
Papaioannou, D.; Sindona, G. ARKIVOC 2002 (xiii), 79-104.
In conclusion, the present methodology provides easy
access to linear 5-aminoalkyl-1H-tetrazoles and polyamines
incorporating tetrazole units in their skeleton, by activating,
(18) Athanassopoulos, C. M.; Garnelis, T.; Pantazaka, E.; Papaioannou,
D. Tetrahedron Lett. 2004, 45, 8815-8818.
Org. Lett., Vol. 7, No. 4, 2005
563

Scheme 3. Synthesis of Polyamines Incorporating Tetrazole Rings
where necessary, secondary amide bonds through thionation
of Calabria (Italy) are gratefully acknowledged for providing
toward their reaction with azidotrimethylsilane under Mit-
sunobu reaction conditions. Further applications of this
methodology, as well as tests to determine the biological
activity of these novel, fully deprotected, polyamine ana-
logues, are currently in progress.
the HR-MS analysis.
Supporting Information Available: General synthetic
procedures and spectroscopic data for compounds 6 and 13
and for selected tritylated polyamine analogues incorporating
tetrazole ring(s). This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Prof. Giovanni Sindona and Dr. Anna
Napoli from the Department of Chemistry of the University
OL0477069
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Org. Lett., Vol. 7, No. 4, 2005