First evidence for the use of polyamines as nucleophiles in a regioselective palladium-catalyzed allylic amination reaction

Article abstract of DOI:10.1016/j.tet.2014.10.019

Palladium-catalyzed reaction of unsymmetrical allylic electrophiles with polyamines gives rise to regioisomeric allylic polyamines. An original catalytic procedure providing an efficient method for the regioselective synthesis of new classes of polyamino derivatives of biological interest is reported. Based on experimental considerations, a mechanistic rationale involving a thermodynamically controlled isomerization of the initially formed branched product is proposed to account for the total regioselectivity observed.

Full text of DOI:10.1016/j.tet.2014.10.019

Tetrahedron 70 (2014) 9718e9725
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Tetrahedron
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First evidence for the use of polyamines as nucleophiles in
a regioselective palladium-catalyzed allylic amination reaction
*
ꢀ
Cyril Pieri, Sebastien Combes, Jean Michel Brunel
ꢀ
ꢀ
Centre de Recherche en Cancerologie de Marseille (CRCM), CNRS, UMR7258, Institut Paoli Calmettes, Aix-Marseille Universite, UM 105, Inserm, U1068,
F-13009 Marseille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2014
Received in revised form 26 September 2014
Accepted 7 October 2014
Available online 12 October 2014
Palladium-catalyzed reaction of unsymmetrical allylic electrophiles with polyamines gives rise to re-
gioisomeric allylic polyamines. An original catalytic procedure providing an efficient method for the
regioselective synthesis of new classes of polyamino derivatives of biological interest is reported. Based
on experimental considerations, a mechanistic rationale involving a thermodynamically controlled
isomerization of the initially formed branched product is proposed to account for the total re-
gioselectivity observed.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Palladium catalysis
Allylic amination
Polyamines
Stereoselective reaction
1. Introduction
2. Results and discussion
In the last 10 years, polyamino derivatives have attracted
a considerable interest for the searchers emphasizing the fact that
these compounds possess good to excellent antitumoral and anti-
microbial activities for a potential use in human therapeutics.1 In
this context, we previously reported the ability of squalamine,
Few years ago, the preparation of polyaminoisoprenyl de-
rivatives as a mixture of Z/E isomers has been reported by our group
involving a titanium reductive amination reaction between a poly-
amine and an isoprenyl aldehyde compound.4 Typically, our initial
experiments were performed using citral 1 (a 50:50 mixture of
neral and geranial) and tris(3-amino-propyl)amine 2 as test sub-
strates. Under these experimental conditions, the expected com-
pounds were obtained in moderate yield (around 37% yield) and as
a mixture of the two isomers in an equal amount without the
possibility to easily separate them (Scheme 1).
In this work, we have envisioned the ability to prepare selec-
tively one of these isomers. Our first approach dealt with the use of
a titanium amination reaction involving pure isomers of neral or
geranial as starting materials. Nevertheless, the needed pure al-
dehydes not being easily available, we have developed an efficient
methodology to prepare neral and geranial. This has been achieved
in a selective manner from 90% pure isomer form of nerol and
geraniol, respectively, by a MnO2 oxidation at room temperature in
toluene. In both cases, neral and geranial were obtained in 92 and
88% yields (90% pure isomer forms), respectively (Scheme 2).
Surprisingly, a subsequent titanium amination reaction in
methanol in the presence of tris(3-amino-propyl)amine led to
a mixture of the Z/E isomers in around a 50:50 ratio in a non-
optimized 35% isolated yield (Scheme 3).
a
natural marine polyaminosterol compound, and of poly-
aminogeranic derivatives to induce a significant decrease of anti-
biotic resistance in Gram-negative bacterial MDR strains.2,3 More
recently, we patented the synthesis of polyamino polyisoprenyl
derivatives and their use as original chemosensitizers to combat
antibiotic resistant Gram-negative bacteria.4 As it will be discussed
below, the major problem for the synthesis of such derivatives
consists in the regioselective outcome of the reaction involved.
Thus, controlling regioselectivity has been an important goal in
transition-metal-catalyzed allylic substitution5,6 due to the fre-
quent occurrence of branched allylic amines among natural prod-
ucts and pharmaceuticals.7
In this paper, we will report for the first time a new general
procedure for the preparation of various polyamino allylic com-
pounds involving a palladium-catalyzed reaction of unsymmetrical
allylic electrophiles with polyamines. We will probe un-
ambiguously the regioselectivity through a thermodynamically
controlled isomerization of the initially formed kinetic branched
product and we will propose a mechanistic rationale based on
detailed experiments.
Thus, whatever the experimental conditions applied (data not
shown) it was impossible to obtain the expected polyamino
* Corresponding author. E-mail address: bruneljm@yahoo.fr (J.M. Brunel).
http://dx.doi.org/10.1016/j.tet.2014.10.019
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
9719
NH2
Z-3
Citral
CHO
1 equiv.
+
N
50/50 Z/ E mixture
N
H
1) Ti(Oi-Pr)4, MeOH
Geranial Z-1
Neral E-1
20°C, 5-6h
NH2
NH2
+
2) NaBH4, 0ºC, 2 h
NH2
E-3
NH2
N
H2N
50/50 Z/ E mixture
37% overall yield
N
N
NH2
4 equiv.
2
H
Scheme 1. Titanium(IV) reductive amination of citral (50:50 mixture of geranial Z-1 and neral E-1) with tris(3-amino-propyl)amine 2.
CHO
OH
geranial Z-1
90% pure form
88% yield
92% yield
geraniol 4
90% pure form
MnO2 (12 equiv.)
or
or
Toluene, 20°C, 48 h
nerol 5
90% pure form
CHO
90% pure form
neral E-1
OH
Scheme 2. Synthesis of pure geranial Z-1 and neral E-1 by a MnO2 oxidation of geraniol 4 and nerol 5.
NH2
Z-3
NH2
N
N
H
1) Ti(Oi-Pr)4, MeOH
NH2
NH2
CHO
+
20°C, 5-6h
N
H2N
+
50/50 Z/ E mixture
2) NaBH4, 0ºC, 2 h
35% overall yield
2
NH2
4 equiv.
geranial Z-1
(90% pure form)
N
N
E-3
H
1 equiv.
NH2
Scheme 3. Titanium(IV) reductive amination of geranial Z-1 with tris(3-amino-propyl)amine 2.
derivatives in a pure stereoselective manner. We have been able to
demonstrate that this racemization occurs by mixing the pure al-
dehyde and the amine in the absence of titanium isopropoxide.
Indeed, after 2 days the corresponding imines were obtained as
a mixture of the two isomers suggesting an isomerization process
during the imine formation. The reaction mechanism of amine
addition to carbonyl compounds has been widely studied at the
experimental8 and theoretical9 levels pointing out that the isom-
erization occurs by inversion of the nitrogen atom.10 The first step
can lead to the formation of an aminoalcohol intermediate sub-
sequently followed by a water elimination step of the aminoalcohol
leading to the formation of the imine (Scheme 4).
From part these disappointing results, we have envisioned
a new and original strategy involving a palladium allylic amination
devoted to the synthesis of polyaminoisoprenyl derivatives. Thus,
palladium has become, over the last 30 years, the most versatile
transition-metal in metal-catalyzed reactions particularly those
involving carbonenitrogen and carbonecarbon bond formation.
Numerous articles reported the use of primary or secondary amines
as nucleophiles but none involving a polyamine as a nucleophile in
a palladium-catalyzed allylic amination reaction.
Geranyl acetate 8 was chosen as test substrate and the reaction
was carried out using tris(3-amino-propyl)amine 2 as polyamine
nucleophile under various experimental conditions. The formation
of four different products could be monitored, depending on the
applied reaction conditions (Scheme 5).
Thus, in all cases compound 3 appeared to be the major com-
pound formed as the thermodynamic product of the reaction and
has been encountered only in the Z isomer pure form (Table 1).
Dialkylated products 9 and 10 were also isolated as well as the
branched kinetic product 11 but in low to moderate yields
depending on the experimental conditions applied.
Although compound 3 has been determined to be formed in 82%
HPLC yield performing the reaction in EtOH (96%) (Table 1, entry 2),

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C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
NH2
using toluene or dichloromethane as solvents (Table 1, entries 5 and
CHO
6). Furthermore, we demonstrated that the amount of water in
ethanol has a dramatical effect on the outcome of the reaction (Table
1, entries 8e10) suggesting that a good compromise is obtained for
a 96:4 ratio (EtOH/H2O), the water certainly stabilizing the reactive
species as already encountered in some recent studies.11 Otherwise,
the nature of the palladium source involved has an important effect
on the ratio of the different compounds obtained. It clearly appears
that Pd(PPh3)4 is the most selective catalyst since compound 3 is
obtained in 82% in this case whereas lower yield are encountered
with Pd(OAc)2 and Pd(dba)2 in 56 and 75% yields, respectively.
Finally, phosphorus ligands involved in palladium-catalyzed
reaction often play an important role on the yield and selectivity of
such a reaction. In this context, we have investigated the impor-
tance of the nature and structure of different organophosphorus
ligands. Thus, no conversion was observed using less classical
monodentate P(n-Bu)3 and P(NMe2)3 ligands or more usual
bidentate BINAP and dppe ligands (data not shown).
N
H2N
+
geranial Z-1
(90% pure form)
2
NH2
OH
NH2
N
N
H
NH2
aminoalcohol intermediate 6
NH2
NH2
50%
NH2
N
N
N
N
Performing the reaction with tris(3-amino-propyl)amine 2 as
polyamine nucleophile under the best experimental conditions
(Table 1, entry 2) led in all cases to moderate to good chemical
yields varying from 45 to 79% for the monoalkylated derivative
depending on the nature of the considered substrate (Table 2). It is
50%
Z- 7
E-7
NH2
Scheme 4. Postulated interconversion from Z- to E-isomers of imines E-7/Z-7.
NH2
N
H
OAc
N
N
H
N
N
H
50/50 Z/ E-8
Z-3
NH2
9
NH2
Pd source
+
NH2
NH2
Solvent
NH2
10
N
N
N
H2N
N
N
H
2
NH2
NH2
11
NH2
Scheme 5. Pd(0)-catalyzed allylic amination of Z/E-8 with tris(3-amino-propyl)amine 2.
Table 1
Effect of the experimental conditions on the palladium-catalyzed amination of geranyl acetate 8 with tris(3-amino-propyl)amine 2
Entry
Experimental conditions
HPLC yieldc (%)
8
Z-3
9
10
11
1a
Pd(PPh3)4 (4 mol %), 1 h (EtOH 96%, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (EtOH 96%, reflux)
Pd(PPh3)4 (1 mol %), 1 h (EtOH 96%, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (THF, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (Toluene, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (CH2Cl2, reflux)
0
0
53
8
99
100
67
13
0
100
100
100
0
80
82
25
45
1
6
8
0
2
0
0
0
2
8
0
0
0
2
4
14
10
2
0
0
0
1
6
15
0
0
0
20
44
0
2a
3a
4a
5a
6a
0
0
7a
Pd(PPh3)4 (2.4 mol %), 1 h (CH3CN, reflux)
18
47
77
0
0
0
13
32
0
0
0
0
34
5
8a
Pd(PPh3)4 (2.4 mol %), 1 h (absolute ethanol, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h EtOH/H2O (90:10), reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (H2O, reflux)
Pd(PPh3)4 (2.4 mol %), 1 h (EtOH 96%, 25 ꢀC)
Pd(PPh3)4 (2.4 mol %), 1 h (EtOH 96%, 25e110 ꢀC)
Pd(OAc)2 (2.4 mol %), PPh3 (4 equiv/Pd) (EtOH 96%, reflux, 2 h)
Pd(dba)2 (2.4 mol %), PPh3 (4 equiv/Pd) (EtOH 96%, reflux, 2 h)
9a
10a,b
11b
12b
13
14
0
0
8
16
56
75
0
a
See Experimental section for a typical implementation.
Catalyst degradation occurred rapidly.
Yields based on geranyl acetate.
b
c
it clearly appeared that the nature of the solvent used has a great
important influence on the outcome of the reaction. Thus, classical
solvents such as THF and acetonitrile led to the formation of the
expected product 3 in lowchemical yields (Table 1, entries 4 and 7 in
45 and 18% yields, respectively) whereas no conversion occurred
noteworthy that in some cases the dialkylated products as well as
the branched isomer were obtained in yields varying from 17 to
48%. Otherwise, by varying the nature of the polyamine used the
expected derivatives were obtained in moderate to good isolated
yields varying from 31 to 61% (Table 3).

C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
9721
Table 2
Palladium-catalyzed amination of various allylic acetate substrates with tris(3-amino-propyl)amine 2 as polyamine nucleophile
Entry
Substrate
Product (isolated yield (%))a
NH2
45%
NH2
NH2
38%
NH2
OAc
N
N
N
N
1
N
N
H
17%
NH2
H
12
14
13
NH2
NH2
NH2
48%
NH2
48%
N
N
Ph
N
H
Ph
Ph
N
OAc
Ph
2
H
16
15
N
H
NH2
Ph
Ph
N
79%
NH2
Ph
N
3
4
H
OAc
OAc
17
Ph
NH2
N
N
57%
NH2
H
18
NH2
N
N
H
71%
NH2
5
OAc
19
a
Isolated yield based on allylic acetate involved.
The best results encountered using ethanol as solvent, high
temperature under air are quite unexpected since it is generally
well admitted such reactions need to be performed under argon
and dried solvents to avoid any catalyst degradation. In this context,
although mechanistic details of the present palladium allylic
amination must await active investigation, a reasonable mecha-
nistic hypothesis is given in Scheme 6.
The mechanism of allylic substitution is generally admitted to
proceed through a h3
-p complex B, which is in equilibrium with
both
s
complexes A and C whose extent of equilibrium is highly
R 1
NHR
C
R 2
L
L
Thermodynamic product
Pd
R 1
OAc
R 2
SN2'
RNH2
RNH2
D
H
NHR
R 1
R 2
RNH2
R 1
R 2
R 1 R 2
+
-
+
RH2N
Pd
OAc
-
Pd
OAc
+
L
L
Pd
L
L
-
L
OAc
L
B
E
RNH2
SN2'
L
R 2
R 1
RHN
Kinetic product
R 1
R 2
Pd OAc
L
A
Scheme 6. Mechanistic rationale involved during the Pd allylic amination reaction.

Table 3
Palladium-catalyzed allylic amination of farnesyl and geranyl acetate 20, 8 with various polyamines
OAc
OAc
Pd(PPh3)4 (4 mol%)
NHR
NHR
R NH2
+
or
EtOH (96%), reflux, 1 h
20
8
or
Entry
Substrate
Amine
Products (isolated yield (%))a
N
NH2
N
H
NH2
H
1
20 or 8
1,3-Propanediamine
36%
34%
21
22
H
H
N
N
NH2
or
NH2
N
N
N
N
H
H
2
3
20 or 8
Spermine
H
H
54%
23
24
45%
O
NH2
or
O
NH2
N
O
N
O
H
20 or 8
1,4-Bis(3-amino-propoxy)butane
H
25
61%
26
33%
N
N
NH2
N
H
N
NH2
or
H
4
5
20 or 8
20 or 8
3,30-Diamino-N-methyldipropylamine
43%
28
31%
N
27
1,4-Bis(3-amino-propyl) piperazine
N
N
H
N
N
NH2
H
N
NH2
36%
29
36%
30
a
Isolated yield based on allylic acetate involved.

C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
9723
temperature, solvent or counter ion dependent. Thus, polyamine
attack on intermediate B is expected to yield both branched and
could activate the branched allylic amine to ionization via hydrogen
bonding. This allows the isomerization process to occur through the
formation of complex D in equilibrium with complex B, which lead,
after the attack of the amine at the less substituted carbon, to the
formation of the thermodynamic product (Scheme 7). Moreover, it
is noteworthy that performing this reaction under the same ex-
perimental conditions in dichloromethane or toluene does not lead,
as expected, to any isomerization of the kinetic product into the
thermodynamic. No activation of the branched allylic amine to
ionization via hydrogen bonding can take place in this case.
Subsequent examination of the reaction between tris(3-amino-
propyl)amine 2 and geranyl acetate 8 by HPLC analysis indicated
the initial buildup of the branched product 11 followed by its de-
crease as the linear product Z-3 began to form (Fig. 1). Thus, in
absence of DBU the amount of 11 peaked at around 3 min and then
began to decrease. By 1 h, Z-3 was the major isomer present in the
reaction mixture. The ratio of the isomers changed throughout the
reaction as the percentage of Z-3 in relation to 11 steadily increased.
This data indicates that the linear and branched isomers are able to
equilibrate. Otherwise, if 1 equiv of DBU is added to the reaction
between tris(3-amino-propyl)amine 2 and geranyl acetate 8, an
equilibrium appears between the kinetic and the thermodynamic
products remaining unchanged after 10 min.
linear products because the termini of the p-complex are not well
differentiated.12 Nevertheless, an equilibrium between the
branched and linear forms is experimentally observed. The most
likely explanation for such an isomerization seems to be by a Pd(0)
catalyzed process through an oxidative addition or a re-ionization
pathway. Thus, reaction at the h3
-p complex B should favor the
attack at the less substituted carbon, resulting in the linear product
formation. Furthermore, due to the steric hindrance around the
palladium in C compared to A, C is likely to be a very small com-
ponent in the equilibrium. Moreover, the strength of the palladium/
olefin interaction in complex D is higher than that in complex E due
to increased degree of substitution in E.13 In this context, ionization
of complex D should be more facile than complex E leading pref-
erentially to the formation of the thermodynamic linear product.
Otherwise, the presence of the kinetic adduct could be also ratio-
nalized though the formation of the s-palladium complex A, which
could be susceptible to a nucleophilic attack proceeding in an SN20
fashion at the more substituted terminus and leading to the
branched allylic polyamine. Moreover, the observation of an initial
branched product in the reaction followed by its disappearance,
whereas the amount of linear isomer increases, could indicate that
the allylamine isomers are able to equilibrate. Thus, pure kinetic
branched allylic amine placed in EtOH (96%) at 110 ꢀC in the pres-
ence of Pd(PPh3)4 was able to isomerize quantitatively in its ther-
modynamic linear isomer in less than 12 h. In this case, ethanol
3. Conclusion
We have described the first evidence for the use of polyamines as
nucleophiles in a regioselective palladium allylic amination reaction
in good chemical isolated yields. A mechanistic rationale involving
a kinetic branched polyamine derivative has been demonstrated and
its palladium isomerization has been proposed in agreement with
the experimentallyobserved results. Additional studies dealing with
the development of new classes of polyamino derivatives as well as
the evaluation of their potent biological activities are under current
investigations and will be reported in due course.
R 2
R 1
R 2
Thermodynamic product
R 1
NHR
Pd(PPh3)4 4 mol%
EtOH (96%), reflux
100%
RHN
Kinetic product
PdL4
EtOH
R 1 R 2
RHN
D
H
4. Experimental section
+
Pd
R 1
-
NHR
+
-
L
OEt
L
4.1. Materials and methods
R 2
Pd
OEt
L
L
R 1
R 2
All solvents were purified according to reported procedures, and
the reagents used were commercially available. Methanol, ethyl
acetate, and dichloromethane were purchased from Fisher Scien-
tific and used without further purification. Column chromatogra-
phy was performed on Merck silica gel (70e230 mesh). 1H NMR
and 13C NMR spectra were recorded in MeOD on a Bruker AC 300
E
+
RNH2
Pd
-
OEt
L
L
B
Scheme 7. Mechanistic rationale proposed for kinetic product isomerization.
Fig. 1. Conversion/time diagram for the palladium-catalyzed reaction of geranyl acetate 8 with tris(3-amino-propyl)amine 2 in the absence (A) or presence (B) of DBU.

9724
C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
and 400 spectrometer working at 300 or 400 MHz and 75 or
100 MHz, respectively (the usual abbreviations are used: s: singlet,
d: doublet, t: triplet, q: quadruplet, m: multiplet). All chemical
shifts are given in parts per million (ppm). Mass spectroscopy
analyses were performed by the Spectropole (Analytical Labora-
tory) of the Aix Marseille University (Marseille). Compounds purity
was checked by analytical HPLC (C18 column, eluant CH3CN/water/
TFA, 2.3 mL/min) with PDA detector spanning from 210 nm to
310 nm. All compounds possessed purity above 95%, as determined
by analytical HPLC-PDA at 214 and 254 nm.
123.51, 54.03, 53.59, 49.24, 48.54, 41.77, 30.93, 28.02, 26.80, 18.88.
MS (ESI) C14H32N4 m/z 257.2700 (100%, (MþHþ)).
4.2.6. {3-[Bis-(3-amino-propyl)-amino]-propyl}-bis-(3-methyl-but-
2-enyl)-amine (13). 1H NMR (MeOD, 300 MHz):
d
¼5.29 (t, J¼5.3 Hz,
2H), 3.11 (d, J¼5.3 Hz, 4H), 2.70 (t, J¼7.0 Hz, 4H), 2.44e2.56 (m, 8H),
1.78 (s, 6H),1.69 (s, 6H),1.62e1.72 (m, 6H).13C NMR (CDCl3, 75 MHz):
d
¼137.59, 122.38, 53.99, 53.58, 53.05, 53.1, 41.80, 31.11, 26.94, 25.49,
18.92. MS (ESI) C19H40N4 m/z 325.3329 (100%, (MþHþ)).
4.2.7. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(1,1-dimethyl-allyl)-
4.2. General procedure for the preparation of compounds 3e28
amine (14). 1H NMR (MeOD, 400 MHz):
d
¼5.81 (dd, J¼18.0, 10.5 Hz,
1H), 5.11 (m, 1H), 5.08 (dd, J¼5.8, 1.0 Hz, 1H), 2.70 (t, J¼7.0 Hz, 4H),
To a solution of geranyl acetate (196 mg, 1 mmol) in ethanol
(96%) (5 mL) is added tris(3-amino-propyl)amine (235 mg,
1.25 mmol). This mixture is heated under air in an oil bath at 110 ꢀC.
When the reflux is well established 46 mg of Pd(PPh3)4 (4 mol %) is
quickly added in one portion. The reflux is maintained for 1 h. After
cooling to room temperature, the solvent is removed under re-
duced pressure and the crude product is purified by column chro-
matography (silica gel; CH2Cl2/MeOH/NH4OH, 7:3:1) affording
a clear oil of Z-3 in 80% yield.
2.52 (q, J¼7.8 Hz, 8H), 1.7e1.63 (m, 14H), 1.21 (s, 6H). 13C NMR
(MeOD, 75 MHz):
d
¼145.07, 112.03, 56.91, 51.34, 41.08, 39.59, 28.79,
26.57, 25.20. MS (ESI) C14H32N4 m/z 256.2627 (100%, (MþHþ)).
4.2.8. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(3-phenyl-allyl)-
amine (15). 1H NMR (MeOD, 400 MHz):
d¼7.43 (d, J¼7.5 Hz, 2H),
7.33 (t, J¼7.5 Hz, 2H), 7.24 (t, J¼7.5 Hz, 1H), 6.60 (d, J¼15.8 Hz, 1H),
6.34 (td, J¼15.8, 6.5 Hz, 1H), 3.41 (d, J¼6.5 Hz, 2H), 2.69 (t, J¼7.2 Hz,
4H), 2.68 (t, J¼7.2 Hz, 2H), 2.54 (t, J¼7.2 Hz, 2H), 2.53 (t, J¼7.2 Hz,
4H), 1.73 (quint, J¼7.2 Hz, 2H), 1.66 (quint, J¼7.2 Hz, 4H). 13C NMR
4.2.1. 3-{(3-Amino-propyl)-[3-(3,7-dimethyl-octa-2,6-dienylamino)-
(MeOD, 75 MHz):
d
¼139.24, 134.35, 130.47, 129.43, 129.07, 128.19,
propyl]-amino}-propyl-amine (Z-3) (ammonium acetate salt form). 1H
54.04, 53.61, 53.29, 49.32, 41.79, 31.00, 28.20. MS (ESI) C18H32N4 m/z
NMR (MeOD, 400 MHz):
d
¼5.30 (t, J¼7.0 Hz, 1H), 5.14 (t, J¼6.9 Hz,
305.2701 (100%, (MþHþ)).
1H), 3.39 (d, J¼7.0 Hz, 2H), 2.85 (t, J¼7.2 Hz, 4H), 2.75 (t, J¼7.4 Hz,
2H), 2.58 (t, J¼6.9 Hz, 4H), 2.56 (t, J¼7.0 Hz, 2H), 2.08e2.18 (m, 4H),
1.93 (s, 3H), 1.73e1.80 (m, 6H), 1.73 (s, 3H), 1.71 (s, 3H), 1.64 (s, 3H).
4.2.9. (3-{(3-Amino-propyl)-[3-(3-phenyl-allylamino)-propyl]-
amino}-propyl)-(3-phenyl-allyl)-amine (16). 1H NMR (MeOD,
13C NMR (MeOD, 75 MHz):
d¼181.23, 143.60, 133.51, 125.79, 120.49,
400 MHz):
d
¼7.42 (d, J¼7.5 Hz, 4H), 7.32 (t, J¼7.5 Hz, 4H), 7.24 (t,
53.46, 53.25, 48.28, 47.78, 41.59, 40.88, 28.32, 28.25, 26.89, 26.78,
J¼7.5 Hz, 2H), 6.59 (d, J¼16.1 Hz, 2H), 6.32 (td, J¼16.1, 6.5 Hz, 2H),
3.39 (d, J¼6.5 Hz, 4H), 2.73 (t, J¼7.2 Hz, 2H), 2.67 (t, J¼7.2 Hz, 4H),
2.54 (t, J¼7.2 Hz, 6H), 1.73 (quint, J¼7.2 Hz, 4H), 1.66 (quint,
25.25, 18.66,17.40. MS (ESI) C19H40N4 m/z 325.3328 (100%, (MþHþ)).
4.2.2. (3-{(3-Amino-propyl)-[3-(3,7-dimethyl-octa-2,6-
dienylamino)-propyl]-amino}-propyl)-(3,7-dimethyl-octa-2,6-
J¼7.2 Hz, 2H). 13C NMR (MeOD, 75 MHz):
¼139.18, 134.42, 130.48,
d
129.45, 128.88, 128.21, 54.02, 53.56, 53.24, 49.29, 41.64, 30.50,
dienyl)-amine (9). 1H NMR (MeOD, 400 MHz):
2H), 5.14 (t, J¼6.8 Hz, 2H), 3.30 (d, J¼6.8 Hz, 4H), 2.77 (t, J¼7.2 Hz,
2H), 2.67 (t, J¼7.3 Hz, 4H), 2.50e2.56 (m, 6H), 2.04e2.18 (m, 8H),
1.71 (s, 12H), 1.68e1.78 (m, 6H), 1.64 (s, 6H). 13C NMR (MeOD,
d
¼5.29 (t, J¼6.8 Hz,
28.18. MS (ESI) C27H40
N
4 m/z 421.3323 (100%, (MþHþ)).
4.2.10. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(1,3-diphenyl-al-
lyl)-amine (ammonium acetate salt) (17). 1H NMR (MeOD,
75 MHz):
d
¼140.85, 133.31, 125.98, 123.44, 54.05, 53.56, 49.86,
400 MHz):
d
¼7.45e7.22 (m, 10H), 6.59 (d, J¼15.8 Hz, 1H), 6.38 (dd,
48.46, 41.73, 41.64, 31.77, 28.37, 26.77, 18.62, 17.27. MS (ESI)
J¼15.8, 7.8 Hz, 1H), 4.38 (d, J¼7.8 Hz, 1H), 2.84 (t, J¼7.0 Hz, 1H),
C
29H56N4 m/z 461.4575 (100%, (MþHþ)).
2.66e2.64 (m, 2H), 2.54 (q, J¼7.3 Hz, 6H), 1.91 (s, 3H), 1.76e1.69 (m,
6H). 13C NMR (MeOD, 75 MHz):
d¼ 181.21, 144.46, 139.05, 133.58,
4.2.3. {3-[Bis-(3-amino-propyl)-amino]-propyl}-bis-(3,7-dimethyl-
octa-2,6-dienyl)-amine (10). 1H NMR (MeOD, 400 MHz):
133.06,130.60,130.47,129.48,129.33,128.25,67.67 53.77, 53.29, 47.72,
d
¼5.29 (t,
40.85, 28.11, 25.28. MS (ESI) C24H36N4 m/z 380.2940 (100%, (MþHþ)).
J¼6.8 Hz, 2H), 5.13 (t, J¼6.7 Hz, 2H), 3.13 (d, J¼6.8 Hz, 4H), 2.73 (t,
J¼7.2 Hz, 4H), 2.54 (t, J¼7.3 Hz, 4H), 2.48 (t, J¼7.3 Hz, 4H), 2.08e2.17
4.2.11. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(3,7,11-trimethyl-
(m, 8H), 1.70 (s, 6H), 1.69 (s, 6H), 1.65e1.74 (m, 6H), 1.64 (s, 6H). 13
C
dodeca-2,6,10-trienyl)-amine (ammonium acetate salt) (18). 1H NMR
NMR (MeOD, 75 MHz):
d
¼140.77, 133.18, 126.09, 122.77, 54.14,
(MeOD, 400 MHz):
d
¼5.29 (t, J¼6.8 Hz, 1H), 5.16e5.11 (m, 2H), 3.27
53.63, 52.90, 41.82, 41.77, 31.97, 28.34, 27.03, 18.87, 17.56. MS (ESI)
(d, J¼6.8 Hz, 2H), 2.75 (t, J¼7.0 Hz, 4H), 2.65 (t, J¼7.3 Hz, 2H), 2.54
C
29H56N4 m/z 461.4574 (100%, (MþHþ)).
(q, J¼7.3 Hz, 6H), 2.15e1.99 (m, 8H), 1.70e1.62 (m, 14H). 13C NMR
(MeOD, 75 MHz):
d
¼139.05, 134.98, 134.87, 130.76, 124.47, 124.02,
4.2.4. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(1,5-dimethyl-1-
vinyl-hex-4-enyl)-amine (11). 1HNMR (CDCl3, 400 MHz):
123.76, 120.82, 120.77, 51.71, 51.30, 46.81, 46.11, 39.71, 39.39, 39.33,
31.56, 26.44, 26.05, 25.61, 24.60, 16.47, 15.14. MS (ESI) C24H40N4 m/z
392.3879 (100%, (MþHþ)).
d¼5.67 (dd,
J¼17.6,10.8 Hz,1H), 5.07 (t, J¼5.2 Hz,1H), 5.05 (d, J¼10.8 Hz,1H), 4.98
(d, J¼17.6 Hz,1H), 2.70 (t, J¼6.8 Hz, 4H), 2.38e2.45 (m, 8H),1.86e1.92
(m, 2H),1.64 (s, 3H),1.56 (s, 3H),1.51e1.65 (m, 6H),1.38e1.44 (m, 2H),
4.2.12. N1-(3-Amino-propyl)-N1-[3-(cyclohex-2-enylamino)-propyl]-
1.11(s, 3H).13CNMR(CDCl3, 75MHz):
d¼164.08,131.35,124.45,113.56,
propane-1,3-diamine (ammonium acetate salt) (19). 1H NMR (MeOD,
57.38, 52.36, 51.59, 39.89, 39.75, 39.63, 26.55, 25.69, 22.64,17.73,17.67,
400 MHz):
3.46 (m, 1H), 2.92e2.85 (m, 6H), 2.59e2.55 (m, 6H), 2.07 (m, 2H),
1.80e1.60 (m, 2H). 13C NMR (MeOD, 75 MHz):
d¼5.98e5.95 (d, J¼9.2 Hz,1H), 5.76e5.72 (d, J¼9.4 Hz,1H),
16.35. MS (ESI) C19H40N4 m/z 324.8245 (100%, (MþHþ)).
d¼ 181.25, 133.81,
4.2.5. {3-[Bis-(3-amino-propyl)-amino]-propyl}-(3-methyl-but-2-
127.79, 55.42, 53.51, 53.16, 46.04, 40.73, 29.21, 27.91, 27.07, 26.76,
enyl)-amine (12). 1H NMR (MeOD, 400 MHz):
d
¼5.28 (t, J¼6.8 Hz,
25.26. MS (ESI) C15H32N4 m/z 268.2627 (100%, (MþHþ)).
1H), 3.24 (d, J¼6.8 Hz, 2H), 2.72(t, J¼7.2Hz, 4H), 2.63(t, J¼7.3Hz, 2H),
2.52e2.55 (m, 6H),1.77 (s, 3H),1.72 (quint, J¼7.3 Hz, 2H),1.71 (s, 3H),
4.2.13. N1-(3,7,11-Trimethyl-dodeca-2,6,10-trienyl)-propane-1,3-
1.68 (quint, J¼7.2 Hz, 4H). 13C NMR (CDCl3, 75 MHz):
d¼137.25,
diamine (21). 1H NMR (MeOD, 400 MHz):
d¼5.28 (m, 1H), 5.14 (m,

C. Pieri et al. / Tetrahedron 70 (2014) 9718e9725
9725
2H), 3.24 (d, J¼6.3 Hz, 2H), 2.71e2.61 (m, 4H), 2.12e1.99 (m, 8H),
1.69e1.62 (s, 14H). 13C NMR (MeOD, 75 MHz):
137.03, 132.96, 126.77e126.27, 126.23e126.06, 123.85, 48.50, 48.38,
41.72, 41.64, 41.18, 34.04, 28.68, 28.32, 26.82, 18.69, 17.32, 17.03. MS
(ESI) C18H34N2 m/z 279.2794 (100%, (MþHþ)).
29.99, 28.66, 27.83, 26.76, 18.63, 17.30, 16.96. MS (ESI) C22H43N3 m/z
349.4000 (100%, (MþHþ)).
d¼140.47e140.40,
4.2.20. {3-[(3-Amino-propyl)-methyl-amino]-propyl}-(3,7-dimethyl-
octa-2,6-dienyl)-amine (28). 1H NMR (MeOD, 400 MHz):
d
¼5.29 (t,
J¼6.8 Hz, 1H), 5.14 (t, J¼6.8 Hz, 1H), 3.33 (d, J¼6.8 Hz, 2H), 2.81 (t,
J¼7.0 Hz, 2H), 2.71 (t, J¼7.3 Hz, 2H), 2.50 (t, J¼7.3 Hz, 2H), 2.48 (t,
J¼7.3 Hz, 2H), 2.28 (s, 3H), 2.19e2.07 (m, 4H), 1.79e1.74 (m, 4H),
1.72 (s, 3H), 1.70 (s, 3H), 1.64 (s, 3H). 13C NMR (MeOD, 75 MHz):
4.2.14. N1-(3,7-Dimethyl-octa-2,6-dienyl)-propane-1,3-diamine
(ammonium acetate salt) (22). 1H NMR (MeOD, 300 MHz):
(t, J¼6.9 Hz, 1H), 5.13 (t, J¼7.0 Hz, 1H), 3.31 (d, J¼6.9 Hz, 2H), 2.80 (t,
J¼7.1 Hz, 2H), 2.72 (t, J¼7.3 Hz, 2H), 2.06e2.17 (m, 4H), 1.73e1.78
(m, 2H), 1.70 (s, 3H), 1.69 (s, 3H), 1.63 (s, 3H). 13C NMR (MeOD, 75
d¼5.28
d
¼142.09, 133.40, 125.90, 122.15, 57.53, 57.16, 48.69, 48.04, 42.98,
41.58, 41.39, 29.66, 28.28, 27.58, 26.79, 25.20, 18.66. MS (ESI)
C
MHz):
d
¼ 179.00, 139.48, 131.12, 123.73, 120.30, 45.90, 45.79, 39.39,
17H35N
3 m/z 282.2903 (100%, (MþHþ)).
38.84, 29.72, 26.11, 24.60, 16.46, 15.11. MS (ESI) C13H26N2 m/z
210.2169 (100%, (MþHþ)).
4.2.21. {3-[4-(3-Amino-propyl)-piperazin-1-yl]-propyl}-(3,7,11-
trimethyl-dodeca-2,6,10-trienyl)-amine (ammonium acetate salt
4.2.15. {3-[4-(3-Amino-propylamino)-butylamino]-propyl}-(3,7,11-
trimethyl-dodeca-2,6,10-trienyl)-amine (ammonium salt form)
form) (29). 1H NMR (MeOD, 400 MHz):
d
¼5.28 (m, 1H), 5.14 (m,
2H), 3.23 (d, J¼5.8 Hz, 2H), 2.70e2.43 (m, 16H), 2.12e2.0 (m, 8H),
(23). 1H NMR (MeOD, 400 MHz):
d
¼5.28 (t, J¼7.1 Hz, 1H), 5.14e5.11
1.92 (s, 3H), 1.69e1.62 (s, 16H). 13C NMR (MeOD, 75 MHz):
(m, 2H), 3.36 (m, 2H), 3.15 (d, J ¼ 6.5 Hz, 2H), 2.76e2.50 (m, 10H),
d
¼ 181.23, 140.25, 140.22, 136.99, 133.21e132.94, 126.80e126.29,
2.19e1.96 (m, 8H), 1.91 (s, 3H), 1.76e1.55 (m, 20H). 13C NMR (MeOD,
126.07, 124.09, 59.10, 58.20, 49.29, 48.49, 41.89, 41.76e41.64, 33.84,
75 MHz):
d
¼
181.17, 141.20, 137.17e137.05, 133.26e133.00,
31.18, 28.54, 26.92, 24.69, 19.40, 18.80, 17.40, 17.14. MS (ESI)
C
126.77e126.24, 126.05, 122.47e122.39, 55.36, 53.38, 52.99, 51.16,
49.01, 48.92, 41.77, 41.17, 32.48, 28.98, 28.69, 28.49, 28.30, 26.86,
26.25, 25.26, 18.74, 17.48, 17.09. MS (ESI) C25H50N4 m/z 406.4035
(100%, (MþHþ)).
25H48N4 m/z 404.3879 (100%, (MþHþ)).
4.2.22. {3-[4-(3-Amino-propyl)-piperazin-1-yl]-propyl}-(3,7-
dimethyl-octa-2,6-dienyl)-amine (ammonium acetate salt form)
(30). 1H NMR (MeOD, 400 MHz):
d
¼5.26 (t, J¼7.0 Hz, 1H), 5.11 (t,
4.2.16. 3-{4-[3-(3,7-Dimethyl-octa-2,6-dienylamino)-propylamino]-
J¼7.0 Hz, 1H), 3.26 (d, J¼7.0 Hz, 2H), 2.74 (t, J¼7.0 Hz, 2H), 2.66 (t,
butylamino}-propyl-ammonium acetate (24). 1H NMR (MeOD,
J¼7.0 Hz, 2H), 2.60e2.46 (br m, 8H), 2.43 (t, J¼7.4 Hz, 4H), 2.14e2.03
400 MHz):
d
¼5.28 (t, J¼6.6 Hz, 1H), 5.13 (t, J¼7.0 Hz, 1H), 3.16 (d,
(m, 4H), 1.91 (s, 3H), 1.76e1.70 (m, 4H), 1.68 (s, 6H), 1.61 (s, 3H). 13
C
J¼6.8 Hz, 2H), 2.82 (t, J¼7.1 Hz, 2H), 2.80 (t, J¼7.0 Hz, 2H), 2.75 (t,
J¼7.3 Hz, 2H), 2.69 (t, J¼6.8 Hz, 2H), 2.58 (t, J¼7.3 Hz, 2H), 2.52 (t,
J¼7.0 Hz, 2H), 2.08e2.17 (m, 4H),1.92 (s, 3H),1.73e1.80 (m, 6H),1.70
(s, 6H), 1.64 (s, 3H), 1.59e1.54 (m, 4H). 13C NMR (MeOD, 75 MHz):
NMR (MeOD, 75 MHz):
d
¼ 181.42, 141.33, 133.32, 125.96, 122.92,
58.47, 58.02, 54.66, 49.01, 48.15, 41.60, 29.85, 28.35, 27.41, 26.87,
18.74, 17.37. MS (ESI) C20H40N4 m/z 337.3324 (100%, (MþHþ)).
d
¼181.25, 141.42, 133.33, 126.02, 122.24, 55.31, 53.39, 52.95, 51.06,
Supplementary data
48.87, 41.78, 41.71, 41.09, 31.95, 29.23, 28.85, 28.33, 26.82, 26.19,
25.20, 18.66, 17.37. MS (ESI)
C20H42N4 m/z 338.3479 (100%,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.019.
(MþHþ)).
4.2.17. {3-[4-(3-Amino-propoxy)-butoxy]-propyl}-(3,7,11-trimethyl-
dodeca-2,6,10-trienyl)-amine (25). 1H NMR (MeOD, 300 MHz):
References and notes
d
¼5.27 (t, J¼6.3 Hz, 1H), 5.14 (m, 2H), 3.54e3.46 (m, 8H), 3.23 (d,
J¼6.4 Hz, 2H), 2.77 (t, J¼6.7 Hz, 2H), 2.69 (t, J¼7.0 Hz, 2H), 2.12e1.99
(m, 8H), 1.69e1.62 (s, 20H). 13C NMR (MeOD, 75 MHz):
1. Ralton, L.; Bestwick, C. S.; Thoo Lin, P. K. Curr. Bioact. Compd. 2007, 3, 179.
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3. Brunel, J. M.; Lieutaud, A.; Lome, V.; Pages, J. M.; Bolla, J. M. Bioorg. Med. Chem.
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d
¼140.38,
ꢁ
137.15e137.03, 132.96, 126.78e126.29, 126.06, 123.98, 72.63, 71.37,
70.87, 48.48, 41.74, 40.99, 34.39, 34.36, 31.28, 28.46, 28.30, 26.84,
24.61, 18.72, 17.32, 17.06. MS (ESI) C25H48N2O2 m/z 409.4325 (100%,
(MþHþ)).
4. Bolla, J. M.; Brunel, J. M.; Casanova, J. P. F.; Lorenzi, V.; Berti, L. Preparation of
polyaminoisoprenyl derivatives for use in medical and nonmedical antibiotic or
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Org. Lett. 2014, 16, 2442; (f) Krishnan, D.; Wu, M.; Chiang, M.; Li, Y.; Leung, P. H.;
Pullarkat, S. A. Organometallics 2013, 32, 2389.
6. Ricci, A. Modern Amination Methods; Wiley-VCH: Weinheim, Germany, 2000.
7. Alhanout, K.; Rolain, J. M.; Brunel, J. M. Curr. Med. Chem. 2010, 17, 3909.
8. (a) Sayer, J. M.; Peskin, M.; Jencks, W. P. J. Am. Chem. Soc. 1973, 95, 4277; (b)
Rosenberg, S.; Silver, S. M.; Sayer, J. M.; Jencks, W. P. J. Am. Chem. Soc. 1974, 96,
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(e) Brighente, I. M. C.; Yunes, R. A. J. Braz. Chem. Soc. 1997, 8, 549.
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601; (b) Williams, I. H. J. Am. Chem. Soc. 1987, 109, 6299.
4.2.18. {3-[4-(3-Amino-propoxy)-butoxy]-propyl}-(3,7-dimethyl-
octa-2,6-dienyl)-amine (26). 1H NMR (MeOD, 300 MHz):
d
¼5.29 (t,
J¼6.8 Hz, 1H), 5.14 (t, J¼6.8 Hz, 1H), 3.44 (t, J¼5.8 Hz, 2H), 3.53 (t,
J¼6.0 Hz, 2H), 3.50e3.46 (m, 4H), 3.30 (d, J¼6.8 Hz, 2H), 2.83 (t,
J¼6.9 Hz, 2H), 2.74 (t, J¼7.2 Hz, 2H), 2.17e2.06 (m, 4H), 1.85e1.77
(m, 4H), 1.71 (s, 6H), 1.67e1.63 (m, 4H), 1.64 (s, 3H). 13C NMR
(MeOD, 75 MHz):
d¼141.49, 133.36, 125.95, 122.83, 72.71, 72.65,
71.20, 70.87, 48.27, 41.63, 40.78, 33.22, 30.88, 28.43, 28.33, 26.76,
24.61, 18.61, 17.25. MS (ESI) C20H40N2O2 m/z 340.1245 (100%,
(MþHþ)).
10. (a) Jennings, W. B.; Boyd, D. R. J. Am. Chem. Soc. 1972, 94, 7187; (b) Lin, J. F.; Wu,
C. C.; Lien, M. H. J. Phys. Chem. 1995, 99, 16903; (c) Guerra, A.; Lunazzi, L. J. Org.
Chem. 1995, 60, 7959.
4.2.19. {3-[(3-Amino-propyl)-methyl-amino]-propyl}-(3,7,11-
trimethyl-dodeca-2,6,10-trienyl)-amine (27). 1H NMR (MeOD,
ꢀ
ꢀ
11. Leyva-Perez, A.; Oliver-Meseguer, J.; Rubio-Marques, P.; Corma, A. Angew. Chem.,
Int. Ed. 2013, 52, 11554.
400 MHz):
d
¼5.28 (t, J¼6.5 Hz, 1H), 5.14e5.10 (m, 2H), 3.29 (m, 2H),
12. (a)Zimmer-DeIuliis, M.;GWatson,I.D.;Yudin,A. K.;Morris, R.H.Can.J.Chem.2008,
87, 1; (b) Bao, H.; Qi, X.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133, 1206; (c) Zhao, X.;
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Chen, Y.; Li, M. B.; Zhou, M. G.; Tian, S. K. J. Am. Chem. Soc. 2012, 134, 14694.
13. Nelson, D. J.; Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564.
2.78 (t, J¼6.9 Hz, 2H), 2.68 (t, J¼7.1 Hz, 2H), 2.50e2.47 (m, 4H), 2.26
(s, 3H), 2.14e2.01 (m, 8H), 1.76e1.74 (m, 4H), 1.70e1.68 (s, 6H), 1.62
(s, 6H). 13C NMR (MeOD, 75 MHz):
d¼141.76, 137.16, 133.01, 126.98,
126.24, 122.60, 57.66, 57.26, 48.89, 48.21, 43.00, 41.72, 41.52, 36.24,