Efficient syntheses of polyamines bearing 1H-tetrazol-5-yl units on their amino functions

Article abstract of DOI:10.1055/s-2006-942502

Linear N-benzyl-N′-trityl-α,ω-diamines and Nα,Nω-ditritylpolyamines were efficiently converted into the corresponding N-(1-benzyltetrazol-5-yl)-substituted derivatives upon treatment with benzyl isothiocyanate followed by reaction of the thus-obtained thioureas with azidotrimethylsilane under Mitsunobu reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942502

3134
SPECIAL TOPIC
Efficient Syntheses of Polyamines Bearing 1H-Tetrazol-5-yl Units on Their
Amino Functions
S
ynthese
s
of
N-1
o
-Tetrazol-5
n
-yl-Substitut
s
e
d
Polyam
t
ines antinos M. Athanassopoulos,* Thomas Garnelis, George Magoulas, Dionissios Papaioannou
University of Patras, Department of Chemistry, University Campus, 26500 Rion, Patras, Greece
Fax +30(261)0997156; E-mail: kath@chemistry.upatras.gr
Received 31 March 2006
reagent and then treating the thus-obtained thioamides
Abstract: Linear N-benzyl-N¢-trityl-a,w-diamines and Na,Nw-ditri-
tylpolyamines were efficiently converted into the corresponding N-
(1-benzyltetrazol-5-yl)-substituted derivatives upon treatment with
benzyl isothiocyanate followed by reaction of the thus-obtained
with azidotrimethylsilane under Mitsunobu reaction con-
ditions.6 We, therefore, considered it of interest to exam-
ine the possibility of obtaining, for the first time,
thioureas with azidotrimethylsilane under Mitsunobu reaction con- polyamines N-substituted with the tetrazolyl unit. For this
ditions.
purpose, we chose as a model compound the N-benzyl-N¢-
tritylpropane-1,3-diamine (3), readily available in 80%
yield by lithium aluminum hydride mediated reduction of
N-benzyl-N3-trityl-b-alaninamide (1).7 The reaction of 3
with benzyl isothiocyanate (BITC) produced unexcep-
tionally the corresponding thiourea 5 in 89% yield. We
then reacted this compound with either sodium azide or
azidotrimethylsilane (TMSA) in the presence of a variety
of reagents, expected to activate the thiourea function to-
wards reaction with azide anion, in order to obtain the cor-
Key words: polyamines, tetrazoles, Mitsunobu reaction, thiourea
derivatives, azidotrimethylsilane
N-Substituted 5-amino-1H-tetrazoles have been used as
antiallergic or hypocholesterolemic agents, as CCK-B re-
ceptor antagonists, or as the prodrug of a selective iNOS
inhibitor.1–4 Commercially available 5-amino-1H-tetra-
zole is used to introduce the required tetrazolyl moiety.
On the other hand, a variety of N-substituted 5-amino-1H-
tetrazoles have been readily obtained in very good yields
through the reaction of primary or secondary amines with
alkyl or phenyl isothiocyanates, followed by treatment of
the thus-obtained thioureas with sodium azide in the pres-
ence of mercury(II) chloride.5
responding N-tetrazolated diamine derivative
(Scheme 1).
7
The reagents used were the following: mercury(II) chlo-
ride,5 silver nitrate, iodomethane, Mukaiyama’s reagent,
and the combination of triphenylphosphine with diisopro-
pyl azodicarboxylate (DIAD). Both iodomethane and Mu-
kaiyama’s reagent failed to give compound 7 whereas in
the case of the inorganic salts incomplete reaction and
rather low yields were observed. On the other hand, the
We have recently shown that polyamines incorporating
tetrazole units in their skeleton can be readily obtained by
activating suitable polyamino-amides with Lawesson’s
H
3 or 4, BITC,
CH2Cl2, 25 °C
S
N
H
H
Bn
N
N
H
Trt
Bn
N
N
n
Trt
n
Bn
85–89%
X
1 X = O, n = 1
2 X = O, n = 2
3 X = H2, n = 1
5 n = 1
6 n = 2
LiAlH4, THF
reflux
TMSA, Ph3P, DIAD,
THF, reflux
70–76%
70–80%
4 X = H2, n = 2
TFA, CH2Cl2, CF3CH2OH
N
N
N
N
(3:6:1), 25 °C
N
93%
or
N
N
N
Bn
H
R
N
N
H2N
N
Trt
n
Bn
R
H2 (1 atm)/20% Pd(OH)2-C (50%
by weight), MeOH, 25 °C
91%
9 R = Bn
10 R = H
7 n = 1
8 n = 2
Scheme 1 Synthesis of selectively N-monotetrazolated a,w-diamines.
SYNTHESIS 2006, No. 18, pp 3134–3140
x
x.
x
x
.
2
0
0
6
Advanced online publication: 19.07.2006
DOI: 10.1055/s-2006-942502; Art ID: C03506SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Syntheses of N-1H-Tetrazol-5-yl-Substituted Polyamines
3135
best results were obtained with the system triphenylphos- amides 11 and 12 in 65 and 72% yields, respectively. At-
phine/diisopropyl azodicarboxylate, which after two tempted reduction of these amides with lithium aluminum
hours in refluxing tetrahydrofuran gave the tetrazolated hydride in refluxing tetrahydrofuran, resulted in complex
derivative 7 in 76% yield. Similarly N-benzyl-N¢-tritylbu- reaction mixtures and failed to give the corresponding tri-
tane-1,4-diamine (4), readily obtained in 70% yield by amine derivatives. We then followed an alternative route,
lithium aluminum hydride mediated reduction of amide 2, which involved the conversion of the amide to the corre-
was converted into the thiourea derivative 6 in 85% yield, sponding thioamide by treatment with Lawesson’s re-
and the latter transformed to the corresponding tetrazolat- agent, followed by reduction under mild reduction
ed derivative 8 in 70% yield. From the thus-obtained com- conditions, using the system sodium borohydride/nick-
pound 7, the detritylated derivative 9 was obtained in 93% el(II) chloride hexahydrate.8
yield by trifluoroacetic acid mediated acidolysis, whereas
complete deprotection to give 5-(3-aminopropylamino)-
Indeed, thionation of the amides 11 and 12 with Lawes-
son’s reagent in tetrahydrofuran at ambient temperature
1H-tetrazole (10) in 91% yield was performed by catalytic
produced the corresponding thioamides 13 and 14 in 60%
hydrogenolysis.
and 55% yields, respectively. These compounds were
Prompted by these results, we decided to develop a meth- then reacted with sodium borohydride/nickel(II) chloride
odology for the synthesis of selectively N1-and N8-tetra- hexahydrate in methanol–tetrahydrofuran 1:1 to give the
zolated spermidine derivatives 15 and 16, respectively expected amines 15 and 16 in 62% and 65% yields, re-
(Scheme 2, Table 1). Thus, detritylation of the 5-amino- spectively.
tetrazole derivatives 7 and 8 and coupling of the corre-
sponding products with 4-(tritylamino)butanoic acid (Trt-
gAba-OH) and N-trityl-b-alanine (Trt-bAla-OH) in the
presence of the coupling agent N-[(1H-benzotriazol-1-
yl)(dimethylamino)methylene]-N-methylmethanaminium
hexafluorophosphate N-oxide (HBTU) and N,N-diisopro-
pylethylamine (DIPEA) produced the corresponding
Finally, we turned our attention to extend this methodolo-
gy to the N-tetrazolation of Na,Nw-ditritylated tri- and tet-
raamines at their free secondary amino function. For this
purpose, we chose as model compound the readily avail-
able N1,N8-ditritylspermidine (17).9 Indeed, this com-
pound was readily converted into the corresponding
thiourea derivative 18 in 90% yield and the thus-obtained
O
1. TFA–CH2Cl2–CF3CH2OH
Bn
Bn
(3:6:1), 25 °C, 90–95%
Trt
N
N
n
Trt
N
n
N
N
m
H
H
H
2. Trt-βAla-OH or Trt-γAba-OH
HBTU, DIPEA, DMF, 25 °C,
65–72%
Bn
Bn
N
N
N
N
11 n = 1, m = 2
12 n = 2, m = 1
N
N
N
N
7 n = 1
8 n = 2
Lawesson's
reagent
55–60%
THF, 25 °C
S
Bn
Bn
Trt
N
N
H
n
N
m
NiCl2⋅6H2O, NaBH4
Trt
N
N
H
n
m
N
H
H
MeOH–THF (1:1), 25 °C
Bn
Bn
N
N
N
N
62–65%
15 n = 1, m = 2
16 n = 2, m = 1
13 n = 1, m = 2
14 n = 2, m = 1
N
N
N
N
H
S
N
Trt
Trt
BITC, CH2Cl2,
25 °C
Bn
H
N
NH
N
NH
HN
Trt
HN
Trt
90%
17
18
N
N
TMSA, Ph3P, DIAD,
THF, reflux
N
N
Trt
Bn
N
NH
77%
HN
Trt
19
Scheme 2 Synthesis of all three N-tetrazolated isomers of linear triamine spermidine.
Synthesis 2006, No. 18, 3134–3140 © Thieme Stuttgart · New York

3136
C. M. Athanassopoulos et al.
SPECIAL TOPIC
Table 1 Conversion of Polyamine Derivatives to N-Benzylthioureas and the Latter to Polyaminotetrazolesa
Entry
Polyamine
N-Benzylthiourea Yield (%)
Polyaminotetrazole Time (h)
Yield (%)
1
2
3
4
5
6
7
8
3
4
5
6
89
85
90
90
85
87
73
80
7
8
2
2
76
70
77
82
50
47
44
48
17
20
21
22
23
24
18
25
26
27
28
29
19
30
31
32
33
34
3
16
12
17
14
14
a Conditions TMSA, Ph3P, DIAD, THF, reflux.
1
intermediate was unexceptionally converted into the N4-
tetrazolated spermidine derivative 19 in 77% yield upon
treatment with the system azidotrimethylsilane/triphenyl-
phosphine/diisopropyl azodicarboxylate in refluxing tet-
rahydrofuran for three hours (Scheme 2).
We then extended this methodology to the N1,N12-ditrityl-
spermine (N1,N12-Trt2-SPM, 20)7 and the analogous
Na,Nw-ditritylated aliphatic and aromatic tetraamine de-
rivatives 21, 22,10 23,11 and 24 (Scheme 3, Table 1) which
were obtained according to literature procedures previ-
ously described by our research group.
respectively, unless otherwise stated. The assignments of the H
spectra are based on chemical shift arguments, analysis of coupling
patterns and signal intensities whereas the 13C spectra were assigned
taking into consideration chemical shift arguments. ESI-MS were
recorded on a Micromass-Platform LC spectrometer using MeOH
as solvent. Microanalyses were performed on a Carlo Erba EA 1108
CHNS elemental analyzer in the Laboratory of Instrumental Analy-
sis of the University of Patras. Flash column chromatography was
performed on Merck silica gel 60 (230–400 mesh) and TLC on 60
Merck 60 F254 films (0.2 mm) precoated on aluminum foil. Spots
were visualized with UV light at 254 nm and the ninhydrin agent.
All solvents (Merck) were dried and/or purified according to stan-
dard procedures prior to use. Anhyd Na2SO4 was used for drying or-
ganic solvents, unless otherwise indicated. Solvents were routinely
removed at ca. 40 °C under reduced pressure (water aspirator). All
reagents employed in the present work were purchased from either
Aldrich or Fluka and were used without further purification. Tet-
raamine 24 was obtained in 65% overall yield through condensation
of Trt-bAla-OH with 4,4¢-(9-fluorenylidene)dianiline in the pres-
ence of HBTU/DIPEA, followed by LiAlH4-mediated reduction.
Compound 24 had mp 166–167 °C, Rf = 0.23 (toluene–EtOAc,
8:2). With the exception of TFA-mediated deprotections and cata-
lytic hydrogenolysis, all other reactions were routinely carried out
under an atmosphere of argon.
Indeed, treatment of the polyamine derivatives 20–24
with benzyl isothiocyanate produced the corresponding
thiourea derivatives 25–29 in 73–90% yields. These inter-
mediates were then treated with azidotrimethylsilane/
triphenylphosphine/diisopropyl azodicarboxylate in re-
fluxing tetrahydrofuran for 14–17 hours to obtain the pro-
jected, internally N-tetrazolated polyamine derivatives
30–34 in 44–82% yields. Similarly to compound 7, these
polyamine derivatives can be readily deprotected as ex-
emplified herein with the preparation of 35 and 36
through partial and complete deprotection of 30, respec-
tively.
Mono- 5, 6, 18 and Bisthiourea Derivatives 25–29; General Pro-
cedure
To a soln of N-benzyl-N¢-trityl-a,w-diamine or Na,Nw-ditrityl-
polyamine (5 mmol) in CH2Cl2 (25 mL) was added benzyl isothio-
cyanate (BITC, 1.3 equiv per free secondary amino group) and the
resulting mixture was stirred for 0.5–5 h at r.t. The solvents were
then removed under vacuum and the residue was subjected to flash
column chromatography (toluene–EtOAc, various combinations
from 8:2 to 95:5) to give the corresponding pure thioureas.
In conclusion, the present methodology provides ease ac-
cess to polyamines, bearing 1H-tetrazol-5-yl units on ei-
ther their primary or secondary amino functions, by
reacting the free amine functions with benzyl isothiocyan-
ate, followed by treatment of the thus-obtained thioureas
with azidotrimethylsilane under Mitsunobu reaction con-
ditions.
N1-Benzyl-N1-[(benzylamino)thiocarbonyl]-N3-tritylpropane-
1,3-diamine (5)
Tests to determine the biological activity of these novel,
fully deprotected, N-tetrazolated polyamines are currently
in progress.
Oil; yield: 89%; Rf = 0.22 (toluene–EtOAc, 95:5).
1H NMR: d = 7.11–7.38 (m, 25 H), 6.04 (unresolved t, 1 H), 4.89 (s,
2 H), 4.81 (d, J = 4.8 Hz, 2 H), 3.82 (t, J = 7.2 Hz, 2 H), 2.18 (t,
J = 6.0 Hz, 2 H), 1.78 (quint, J = 6.8 Hz, 3 H).
13C NMR: d = 182.4, 145.8, 138.2, 136.3, 128.9, 128.6, 127.8,
Melting points were determined with a Buchi SMP-20 apparatus
and are uncorrected. 1H NMR spectra were obtained at 400.13 MHz
and 13C NMR spectra at 100.62 MHz on a Bruker DPX spectrome-
ter. CDCl3 and TMS were used as the solvent and internal standard,
127.5, 127.4, 126.9, 126.4, 71.1, 54.4, 50.3, 49.5, 40.9, 28.7.
ESI-MS: m/z = 556.33 (M + H+), 243.11 (Trt+).
Synthesis 2006, No. 18, 3134–3140 © Thieme Stuttgart · New York

SPECIAL TOPIC
Syntheses of N-1H-Tetrazol-5-yl-Substituted Polyamines
3137
BITC, CH2Cl2,
Trt
25 °C
Trt
NH
R
HN
R
N
Y
N
N
H
N
N
Y
N
H
H
H
Bn
85–90%
Bn
N
S
N
S
H
H
SPM R = H, Y = (CH2)2
20 R = Trt, Y = (CH2)2
21 Y = (CH2)4
25 Y = (CH2)2
26 Y = (CH2)4
27 Y = (CH2OCH2)2
22 Y = (CH2OCH2)2
TMSA, Ph3P, DIAD
THF, reflux
47–82%
Trt
Trt
N
H
N
N
Y
N
TFA–CH2Cl2–CF3CH2OH
(3:6:1), 25 °C
90%
NH2
H2N
N
Y
N
H
Bn
R
Bn
R
N
N
N
N
N
N
N
N
or / and
N
N
N
N
N
N
N
N
H2 (1 atm)/20% Pd(OH)2-C
(50% by weight), MeOH, 25 °C
87%
30 Y = (CH2)2
31 Y = (CH2)4
35 Y = (CH2)2, R = Bn
36 Y = (CH2)2, R = H
32 Y = (CH2OCH2)2
Y
Y
HN
Trt
N
N
NH
Trt
BITC, CH2Cl2, 25 °C
73–80%
HN
Trt
N
N
NH
H
H
Bn
Trt
Bn
N
S
S
N
H
H
23 Y = DAM
24 Y = DAF
28 Y = DAM
29 Y = DAF
Y
HN
Trt
N
N
NH
Trt
TMSA, Ph3P, DIAD
THF, reflux
Bn
Bn
N
N
N
N
N
N
N
N
44–48%
33 Y = DAM
34 Y = DAF
DAM
DAF
Scheme 3 Synthesis of tetraamines bistetrazolated at their secondary amino function.
N1-Benzyl-N1-[(benzylamino)thiocarbonyl]-N4-tritylbutane-
1,4-diamine (6)
J = 7.3 Hz, 2 H), 1.66 (quint, J = 8.4 Hz, 2 H), 1.50 (quint, J = 7.2
Hz, 2 H).
Foam; yield: 85%; Rf = 0.18 (toluene–EtOAc, 95:5).
13C NMR: d = 181.4, 146.1, 145.7, 138.5, 128.7, 128.6, 127.9,
127.8, 127.6, 127.5, 126.4, 126.2, 71.9, 71.1, 51.3, 50.1, 48.8, 43.2,
40.9, 28.9, 28.2, 26.4.
1H NMR: d = 7.44–7.10 (m, 25 H), 5.57 (t, J = 5.2 Hz, 1 H), 4.86 (s,
2 H), 4.81 (d, J = 4.8 Hz, 2 H), 3.73 (t, J = 7.6 Hz, 2 H), 2.13 (t,
J = 6.8 Hz, 2 H), 1.74 (quint, J = 8.0 Hz, 2 H), 1.50 (quint, J = 7.6
Hz, 2 H).
ESI-MS: m/z = 780.49 (M + H+), 243.19 (Trt+).
13C NMR: d = 182.0, 146.8, 137.9, 135.9, 129.0, 128.6, 127.8,
127.6, 127.5, 126.6, 126.2, 70.8, 54.1, 52.0, 50.4, 43.1, 28.0, 25.3.
4,9-Bis[(benzylamino)thiocarbonyl]-N1,N12-ditrityl-4,9-diaza-
dodecane-1,12-diamine (25)
White solid; yield: 90%; mp 138–139 °C; Rf = 0.27 (toluene–
EtOAc, 9:1).
ESI-MS: m/z = 570.38 (M + H+), 243.20 (Trt+).
4-[(Benzylamino)thiocarbonyl]-N1,N8-ditrityl-4-azaoctane-1,8-
diamine (18)
Foam; yield: 90%; Rf = 0.32 (toluene–EtOAc, 9:1).
1H NMR: d = 7.51–7.15 (m, 35 H), 5.59 (unresolved t, 1 H), 4.83 (d,
J = 4.8 Hz, 2 H), 3.66 (t, J = 8.7 Hz, 2 H), 3.55 (t, J = 8.7 Hz, 2 H),
2.19 (t, J = 6.4 Hz, 2 H), 2.12 (quint, J = 8.0 Hz, 2 H), 1.76 (quint,
1H NMR: d = 7.35–7.15 (m, 40 H), 6.53 (t, J = 4.8 Hz, 2 H), 4.79
(d, J = 4.8 Hz, 4 H), 3.79 (unresolved t, 4 H), 3.62 (unresolved t, 4
H), 2.20 (t, J = 6.0 Hz, 4 H), 1.75 (unresolved quint, 6 H), 1.65 (un-
resolved m, 4 H).
13C NMR: d = 181.4, 145.7, 138.8, 128.6, 127.9, 127.5, 127.3,
126.4, 71.1, 50.1, 49.7, 45.1, 40.9, 28.8, 24.3.
Synthesis 2006, No. 18, 3134–3140 © Thieme Stuttgart · New York

3138
C. M. Athanassopoulos et al.
SPECIAL TOPIC
ESI-MS: m/z = 986.88 (M + H+), 243.16 (Trt+).
1H NMR: d = 7.45–7.05 (m, 25 H), 5.33 (s, 2 H), 4.39 (s, 2 H), 3.19
(t, J = 7.6 Hz, 2 H), 2.02 (t, J = 7.2 Hz, 2 H), 1.50 (quint, J = 6.8
Hz, 2 H), 1.26 (quint, J = 7.2 Hz, 2 H).
13C NMR: d = 158.3, 145.8, 136.6, 134.4, 129.1, 128.8, 128.6,
128.5, 127.8, 127.4, 126.6, 126.3, 71.0, 68.0, 55.0, 51.5, 50.5, 43.2,
24.9.
Anal. Calcd for C64H68N6S2: C, 78.01; H, 6.96; N, 8.53; S, 6.51.
Found: C, 78.23; H, 6.71; N, 8.68; S, 6.29.
4,11-Bis[(benzylamino)thiocarbonyl]-N1,N14-ditrityl-4,11-di-
azatetradecane-1,14-diamine (26)
Foam; yield: 85%; Rf = 0.16 (toluene–EtOAc, 9:1).
ESI-MS: m/z = 1014.98 (M + H+), 243.18 (Trt+).
ESI-MS: m/z = 579.91(M + H+), 243.14 (Trt+).
4-(1-Benzyl-1H-tetrazol-5-yl)-N1,N8-ditrityl-4-azaoctane-1,8-
diamine (19)
Oil; yield: 77%; Rf = 0.25 (toluene–EtOAc, 9:1).
4,13-Bis[(benzylamino)thiocarbonyl]-N1,N16-ditrityl-7,10-di-
oxa-4,13-diazahexadecane-1,16-diamine (27)
White solid; yield: 87%; Rf = 0.45 (toluene–EtOAc, 75:25).
1H NMR: d = 7.55–7.01 (m, 35 H), 5.25 (s, 2 H), 3.23 (t, J = 7.6 Hz,
2 H), 3.05 (t, J = 6.8 Hz, 2 H), 1.98 (m, 4 H), 1.60 (quint, J = 6.8
Hz, 2 H), 1.36 (t, J = 6.8 Hz, 2 H), 1.18 (m, 2 H).
1H NMR: d = 7.49–7.15 (m, 42 H), 4.76 (d, J = 4.8 Hz, 2 H), 3.81
(t, J = 7.6 Hz, 4 H), 3.50 (unresolved t, 4 H), 3.36 (unresolved t, 4
H), 3.12 (s, 4 H), 2.17 (t, J = 6.4 Hz, 4 H), 1.83 (quint, J = 7.2 Hz,
4 H).
ESI-MS: m/z = 789.47 (M + H+), 243.16 (Trt+).
13C NMR: d = 183.6, 146.0, 138.6, 128.7, 128.6, 127.8, 127.3,
126.3, 71.0, 70.5, 70.1, 50.8, 50.0, 40.9, 28.4.
4,9-Bis(1-benzyl-1H-tetrazol-5-yl)-N1,N12-ditrityl-4,9-diaza-
dodecane-1,12-diamine (30)
Oil; yield: 82%; Rf = 0.25 (toluene–EtOAc, 9:1).
ESI-MS: m/z = 1004.51 (M + H+), 243.16 (Trt+).
ESI-MS: m/z = 1046.67 (M + H+), 243.20 (Trt+).
4,4¢-Methylenebis{N-[(benzylamino)thiocarbonyl]-N-[3-(trityl-
amino)propyl]aniline} (28)
Foam; yield: 73%; Rf = 0.18 (toluene–EtOAc, 95:5).
4,11-Bis(1-benzyl-1H-tetrazol-5-yl)-N1,N14-ditrityl-4,11-diaza-
tetradecane-1,14-diamine (31)
Oil; yield: 50%; Rf = 0.34 (toluene–EtOAc, 8:2).
1H NMR: d = 7.53–7.13 (m, 44 H), 7.05 (d, J = 7.6 Hz, 4 H), 5.46
(t, J = 5.2 Hz, 2 H), 4.79 (d, J = 5.6 Hz, 4 H), 4.36 (t, J = 7.2 Hz, 4
H), 3.97 (s, 2 H), 2.16 (t, J = 6.4 Hz, 4 H), 1.83 (quint, J = 7.2 Hz,
4 H).
1H NMR: d = 7.42–6.98 (m, 40 H), 5.28 (s, 4 H), 3.23 (t, J = 7.2 Hz,
4 H), 3.04 (t, J = 7.6 Hz, 4 H), 2.00 (t, J = 6.8 Hz, 4 H), 1.60 (m, 8
H), 1.29 (m, 4 H).
13C NMR: d = 182.1, 146.2, 140.7, 139.4, 138.2, 131.0, 128.7,
128.6, 128.3, 127.7, 127.3, 127.2, 126.1, 71.0, 53.1, 49.6, 40.8,
28.9.
ESI-MS: m/z = 1033.02 (M + H+), 243.19 (Trt+).
4,13-Bis(1-benzyl-1H-tetrazol-5-yl)-N1,N16-ditrityl-7,10-dioxa-
4,13-diazahexadecane-1,16-diamine (32)
Oil; yield: 47%; Rf = 0.21 (toluene–EtOAc, 8:2).
ESI-MS: m/z = 1097.46 (M + H+), 243.24 (Trt+).
4,4¢-(9-Fluorenylidene)bis{N-[(benzylamino)thiocarbonyl]-N-
[3-(tritylamino)propyl]aniline} (29)
Foam; yield: 80%; Rf = 0.36 (toluene–EtOAc, 95:5).
ESI-MS: m/z = 1246.56 (M + H+), 243.14 (Trt+).
ESI-MS: m/z = 1064.65 (M + H+), 243.21 (Trt+).
4,4¢-Methylenebis{N-(1-benzyl-1H-tetrazol-5-yl)-N-[3-(trityl-
amino)propyl]aniline} (33)
Foam; yield: 44%; Rf = 0.16 (toluene–EtOAc, 9:1).
Mono- 7, 8, 19 or Bis-tetrazolated 30–34 Polyamine Derivatives;
General Procedure
ESI-MS: m/z = 1114.52 (M + H+), 243.11 (Trt+).
To a soln of mono- or bisthiourea derivative (2.5 mmol) in THF (2.5
mL) were added DIAD and Ph3P (2.5 equiv per thiourea group) fol-
lowed by the addition 5 min later of TMSA (2.5 equiv per thiourea
group). The resulting mixture was stirred under reflux for 2–16 h
(see Table 1). Then, the solvents were removed under reduced pres-
sure and the residue was subjected to flash column chromatography
(toluene–EtOAc, various combinations from 8:2 to 95:5) to give the
corresponding pure mono- (7, 8, 19) or bis-tetrazolated (30–34)
polyamine derivatives.
4,4¢-(9-Fluorenylidene)bis{N-(1-benzyl-1H-tetrazol-5-yl)-N-[3-
(tritylamino)propyl]aniline} (34)
Foam; yield: 48%; Rf = 0.30 (toluene–EtOAc, 9:1).
1H NMR: d = 7.85 (d, J = 7.6 Hz, 2 H), 7.45–6.94 (m, 46 H), 6.56
(d, J = 8.8 Hz, 4 H), 6.47 (d, J = 7.6 Hz, 4 H), 4.76 (s, 4 H), 3.88 (t,
J = 7.2 Hz, 4 H), 2.12 (unresolved t, 4 H), 1.77 (unresolved quint, 4
H).
13C NMR: d = 155.8, 150.6, 145.7, 142.8, 142.1, 140.2, 133.3,
129.2, 128.6, 128.5, 128.1, 128.0, 127.9, 127.1, 126.4, 125.8, 123.4,
120.6, 71.2, 64.5, 53.3, 50.9, 40.9, 28.8.
N1-Benzyl-N1-(1-benzyl-1H-tetrazol-5-yl)-N3-tritylpropane-1,3-
diamine (7)
Foam; yield: 76%; Rf = 0.24 (toluene–EtOAc, 9:1).
ESI-MS: m/z = 1264.57 (M + H+), 243.08 (Trt+).
1H NMR: d = 7.39–6.98 (m, 25 H), 5.25 (s, 2 H), 4.32 (s, 2 H), 3.30
(t, J = 7.6 Hz, 2 H), 1.99 (t, J = 6.8 Hz, 2 H), 1.66 (quint, J = 6.8
Hz, 2 H).
13C NMR: d = 158.3, 145.9, 136.5, 134.3, 129.0, 128.8, 128.5,
127.8, 127.5, 126.6, 126.3, 70.9, 55.2, 50.3, 49.7, 40.9, 28.3.
Amides 11 and 12; General Procedure
To a soln of amine 7 or 8 (3 mmol) in CH2Cl2 (2 mL) cooled to 0 °C
were added 2,2,2-trifluoroethanol (0.34 mL) and TFA (1 mL). The
resulting mixture was stirred for 20–30 min at the same tempera-
ture. The solvents were then removed under vacuum and the residue
was treated with warm n-hexane to remove Ph3COH and give the
corresponding pure TFA salts in high yields (90–95%). The thus-
obtained TFA salts (2 mmol) were further treated with either Trt-
bAla-OH or Trt-gAba-OH (2 mmol) in DMF (2 mL) in the presence
of HBTU (2 mmol) and DIPEA (6 mmol), for 5 min at 0 °C and at
r.t. for 30 min. Then, the mixtures were diluted with EtOAc and
washed once with each of cold aq 1 M NaOH, H2O, cold aq 5% cit-
ESI-MS: m/z = 565.94 (M + H+), 587.96 (M + Na+), 243.15 (Trt+).
N1-Benzyl-N1-(1-benzyl-1H-tetrazol-5-yl)-N4-tritylbutane-1,4-
diamine (8)
Oil; yield: 70%; Rf = 0.32 (toluene–EtOAc, 9:1).
Synthesis 2006, No. 18, 3134–3140 © Thieme Stuttgart · New York

SPECIAL TOPIC
Syntheses of N-1H-Tetrazol-5-yl-Substituted Polyamines
3139
ric acid, and H2O. After drying (Na2SO4), filtration, evaporation of
the solvent under vacuum and flash column chromatography (tolu-
ene–EtOAc, various combinations from 1:1 to 2:8) the spermidine
derivatives 11 and 12, respectively, were obtained.
Detritylation and Complete Deprotection of Polyamino Deriva-
tives 7 and 30; General Procedure
To a soln of polyamino derivative 7 or 30 (1 mmol) in CH2Cl2 (1
mL) cooled to 0 °C were added 2,2,2-trifluoroethanol (0.17 mL)
and TFA (0.5 mL). The resulting mixture was stirred for 20–30 min
at this temperature. The solvents were then removed under vacuum
and the residue was treated with warm n-hexane to remove Ph3COH
to give the corresponding pure polyamines 9 and 35 as their TFA
salts in high yields (90–93%). For complete deprotection com-
pounds 9 and 35 (0.5 mmol) were dissolved in MeOH (10–12 mL)
and subjected to catalytic hydrogenolysis using as the catalyst 20%
Pd(OH)2-C (50% by weight) for 18–24h. The catalyst was removed
by filtration through Celite and the solvents were evaporated to dry-
ness to give 10 and 36 in 91% and 87% yields, respectively.
1-[Benzyl(1-benzyl-1H-tetrazol-5-yl)amino]-8-(tritylamino)-4-
azaoctan-5-one (11)
Oil; yield: 65%; Rf = 0.20 (toluene–EtOAc, 1:1).
ESI-MS: m/z = 650.55 (M + H+), 243.23 (Trt+).
8-[Benzyl(1-benzyl-1H-tetrazol-5-yl)amino]-1-(tritylamino)-4-
azaoctan-3-one (12)
Oil; yield: 72%; Rf = 0.26 (toluene–EtOAc, 2:8).
ESI-MS: m/z = 650.62 (M + H+), 243.18 (Trt+).
N1-Benzyl-N1-(1-benzyl-1H-tetrazol-5-yl)butane-1,4-diamine
(9)
Thioamide 13 and 14; General Procedure
To a soln of 11 or 12 (1.5 mmol) in THF (3.5 mL) was added Lawes-
son’s reagent (0.8 mmol) and the mixture stirred at r.t. until comple-
tion of the reaction (14–16 h). The solvents were removed under
vacuum and the corresponding residues were subjected to flash col-
umn chromatography (toluene–EtOAc, 8:2 and 75:25, respectively)
to give pure thioamides 13 and 14, respectively.
Oil; yield: 93%; oil.
1H NMR: d = 8.32 (br s, 3 H), 7.4–6.95 (m, 10 H), 5.30 (s, 2 H), 4.35
(s, 2 H), 3.52 (t, J = 6.4 Hz, 2 H), 2.95 (unresolved m, 2 H), 2.00
(quint, J = 6.4 Hz, 2 H).
ESI-MS: m/z = 323.24 (M + H+).
1-[Benzyl(1-benzyl-1H-tetrazol-5-yl)amino]-8-(tritylamino)-4-
azaoctane-5-thione (13)
N1-(1H-Tetrazol-5-yl)butane-1,4-diamine (10)
Oil; yield: 91%.
Oil; yield: 60%; Rf = 0.36 (toluene–EtOAc, 1:1).
ESI-MS: m/z = 665.98 (M + H+), 243.14 (Trt+).
ESI-MS: m/z = 142.99 (M + H+).
4,9-Bis(1-benzyl-1H-tetrazol-5-yl)-4,9-diazadodecane-1,12-di-
amine (35)
Oil; yield: 90%; Rf = 0.36 (CHCl3–MeOH–NH3, 6:4:0.4).
8-[Benzyl(1-benzyl-1H-tetrazol-5-yl)amino]-1-(tritylamino)-4-
azaoctane-3-thione (14)
Oil; yield: 55%; Rf = 0.64 (toluene–EtOAc, 2:8).
ESI-MS: m/z = 666.05 (M + H+), 243.27 (Trt+).
1H NMR (DMSO-d6): d = 7.72 (br s, 6 H), 7.36–7.10 (m, 10 H), 5.48
(s, 4 H), 3.20 (t, J = 7.2 Hz, 4 H), 2.97 (unresolved t, 4 H), 2.62 (m,
4 H), 1.66 (quint, J = 7.2 Hz, 4 H), 0.98 (unresolved m, 4 H).
Reduction of Thioamides 13 and 14; General Procedure
To a soln of 13 or 14 (1 mmol) and NiCl2·6H2O (8.5 mmol) in
MeOH–THF (1:1, 24 mL) precooled to 0 °C was added NaBH4 (50
mmol) in 5 portions over 15 min and the resulting mixture was
stirred at r.t. for 30 min. The mixture was then filtered through
Celite and the solvents were removed under vacuum. The resulting
residue was diluted with CHCl3 and washed once with each of 5%
aq NaHCO3, H2O, sat. aq EDTA, and H2O. After drying (Na2SO4),
filtration, evaporation of the solvent under vacuum and flash col-
umn chromatography (CHCl3–MeOH–NH3, 95:5:0.5) the corre-
sponding spermidine derivatives 15 and 16, respectively, were
obtained.
13C NMR (DMSO-d6): d = 157.7, 135.3, 129.3, 128.5, 127.2, 51.1,
50.4, 48.2, 36.9, 25.5, 24.2.
ESI-MS: m/z = 519.51 (M + H+).
4,9-Bis(1H-tetrazol-5-yl)-4,9-diazadodecane-1,12-diamine (36)
Oil; yield: 87%.
1H NMR (DMSO-d6): d = 3.39 (t, J = 5.7 Hz, 4 H), 3.34 (unresolved
m, 4 H), 2.79 (t, J = 5.7 Hz, 4 H), 1.82 (unresolved m, 4 H), 1.50
(unresolved m, 4 H).
13C NMR (DMSO-d6): d = 158.8, 49.7, 46.9, 36.9, 25.8, 24.6.
ESI-MS: m/z = 339.26 (M + H+).
N1-Benzyl-N1-(1-benzyl-1H-tetrazol-5-yl)-N8-trityl-4-aza-
octane-1,8-diamine (15)
Oil; yield: 62%; Rf = 0.28 (CHCl3–MeOH–NH3, 95:5:0.5).
Acknowledgment
1H NMR: d = 7.48–7.05 (m, 25 H), 5.37 (s, 2 H), 4.40 (s, 2 H), 3.34
(t, J = 7.2 Hz, 2 H), 2.48 (t, J = 6.0 Hz, 2 H), 2.45 (t, J = 6.8 Hz, 2
H), 2.13 (t, J = 6.3 Hz, 2 H), 1.71 (quint, J = 7.2 Hz, 2 H), 1.49 (m,
4 H).
We thank the European Social Fund (ESF), Operational Program
for Educational and Vocational Training II (EPEAEK II) and parti-
cularly the program PYTHAGORAS II, for funding this work.
13C NMR: d = 158.3, 146.2, 136.5, 134.4, 129.1, 128.8, 128.6,
128.5, 127.7, 127.2, 126.6, 126.2, 70.1, 54.75, 50.5, 49.7, 49.3,
46.5, 43.4, 28.6, 27.5, 27.2.
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Synthesis 2006, No. 18, 3134–3140 © Thieme Stuttgart · New York

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