Synthesis of novel macrocyclic compounds utilizing characteristic bonding properties of hypervalent sulfur

Article abstract of DOI:10.3987/COM-00-8873

The convenient method for the synthesis of 18-, 26-, and 30-membered macrocyclic compounds by utilizing the characteristic bonding properties of the hypervalent sulfur in the 10-S-3 tetraazathiapentalene derivatives and their chemical properties have been

Full text of DOI:10.3987/COM-00-8873

HETEROCYCLES, Vol. 53, No. 6, 2000, pp. 1317 - 1328, Received, 28th February, 2000
SOLUTION PARALLEL SYNTHESIS
OF CYCLIC GUANIDINES
Christelle Marmillon, Jacques Bompart, Michèle Calas#, Roger Escale,*
and Pierre-Antoine Bonnet
E.A. 2414 Pharmacochimie et Biomolécules, UFR Sciences
Pharmaceutiques et Biologiques, 15, av. C. Flahault, 34060 Montpellier
cedex 2, France ; # U.M.R. 5810, UMR-II STL, Place E. Bataillon, 34095
Montpellier cedex 5, France
Abstract- An efficient method for the solution phase synthesis of cyclic guanidines is
presented. A variety of 2-substituted monoprotected propanediamines react with a set of
5-substituted 2-methylthio-3,4,5,6-tetrahydropyrimidines under Rathke conditions for the
construction of a potential library of 81 cyclic guanidines.
The guanidine moiety is present in many active drugs with uses covering large therapeutic areas:1
cardiovascular, antihistaminic, anti-inflammatory, antidiabetic, antibacterial and fungicidal. Recent
development in combinatorial chemistry on solid phase as well as in solution2 have largely demonstrated
the parallel synthesis of numbers of compounds.3 We report here the solution phase synthesis of 6-
membered cyclic guanidines with variable lipophilicity. Many reagents have been used to prepare
protected and unprotected guanidines including carbodiimide derivatives,4 formamidinesulfinic acid,5
pyrazole-1-carboxamide derivatives6 and isothiourea derivatives.7 The latter gave access to the more
adapted method to synthesise the new cyclic guanidine (1) from propanediamines (2) and cyclic
isothioureas (3), as depicted in scheme 1.
R4
H2N
NH2
NH
R1
R2
R3
2
N
NH
NH2
R4
R1
R2
NH
1
R3
SCH3
N
R1, R2, R3, R4 alkyl or alkoxy groups
3
Scheme 1 : Retrosynthetic way for the preparation of 6-membered cyclic guanidines
a
b
c
d
e
f
g
h
i
R1, H CH3 (CH2)2C6H5 (CH2)5CH3 (CH2)9CH3 (CH2)17CH3 pOC6H4CF3 O(CH2)9CH3 O(CH2)17CH3
R3
R2, H CH3
H
H
H
H
H
H
H
R4
Table 1: Alkyl and alkoxy substitutions of propanediamines (2) and isothioureas (3).

Following this scheme, we have first synthesised8 nine propanediamines (2a-i) (Table 1) substituted in
position 2 with lipophilic alkyl- and alkoxy-groups and then the correspondent isothioureas (3a-i).
Only propanediamines (2a) and (2b) are commercially available. 2-Alkylpropanediamines (2c-f) were
obtained via malonic synthesis (Scheme 2), and 2-alkoxypropanediamines were prepared using
2-hydroxypropanediamine as starting material.
O
O
O
.2 TFA
1) BH3.S(CH3)2
H2N
H2N
H2N
H2N
C2H5O
C2H5O
C2H5O
NH3/CH3OH
rt
THF/∆
R-Br
R
R
R
C H ONa/C H OH
2 5 2 5
2) TFA/ether
C2H5O
∆
O
O
O
4c-f
5c-f
2c-f
Scheme 2: 2-Alkylpropanediamines synthesis
Alkylation9 of diethyl malonate was carried out with the corresponding alkyl halide and sodium ethoxide
under reflux. Diamides (5c-f) were finally obtained by shaking diesters (4c-f) in a saturated methanolic
solution of ammonia. Reduction10 of the amide functions with boran-methyl sulfide complex in THF gave
the diamines (2c-f) which were isolated as diammonium salt after treatment with a 50% solution of TFA
in methylene chloride. Many of these salts were found to be hygroscopic.
2-Alkoxypropanediamines (2g-i) were obtained by O-alkylation of the N-protected 1,3-diaminopropan-2-
ol since the amino function protection is necessary to overcome the preferential N-alkylation. In the
literature, Ramalingam et al.9 described the synthesis of N,N’-di-tert-Boc-2-methoxy-1,3-diaminopropane
(7) with 89% yield (Scheme 3). N,N’-di-tert-Boc-diaminopropan-2-ol (6) reacts with methyl iodide in
presence of sodium hydride. Practice of this alkylation method from 6 with a longer alkyl halide like 1-
bromodecane led to the oxazolidinone (8). Such cyclisation also occurs with 1-iododecane and without
any alkyl halide. Sodium hydride pulled out first the OH hydrogen and then the formed alkoxide quickly
attacked the Boc-carbonyl function which is more electrophilic than the alkyl halide. In DMF, the tert-
butoxide anion formed in the mixture pull out the NH hydrogen of the oxazolidinone to give the N-
alkylated derivative (9).
BocNH
OCH3
NaH/THF
BocNH
CH3I
7
BocNH
BocNH
O
OH
NaH/THF
BocNH
NH
O
O
6
8
BocNH
NaH/DMF
CH3(CH2)9Br
O
N
CH3(CH2)9
9
Scheme 3: Oxazolidinone formation

At last, we put a trityl function on 2-hydroxypropanediamine in place of the Boc-protecting group
(Scheme 4). O-Alkylation of 10 with the correspondent alkyl or aryl halide in presence of NaH in DMF
led to compounds (11g-i). Diammonium salts (2g-i) were obtained after deprotection in acidic conditions.
NH
NH
(C6H5)3C
(C6H5)3C
NH
NH
(C6H5)3C
(C6H5)3C
H2N
H2N
NaH/DMF
R-X
TFA/CH2Cl2
OH
OR
OR
, 2 TFA
10
11g-i
2g-i
Scheme 4: 2-Alkoxypropanediamines synthesis
The isothiourea library was obtained in two steps from and the already described propanediamines (2b-i)
(Scheme 5) and the commercial thiourea (12a) for compound 3a.
NH
NH2
NH2
NH
.HI
R1
R2
R1
R2
R1
R2
CH3I/CH3OH
CS2/EDC
S
SCH3
∆
C H OH
2 5
NH
N
rt
3b-i
12b-i
2b-i
Scheme 5: Isothioureas synthesis
Cyclisation step11 is allowed with 1-[3-dimethylamino propyl]-3-ethylcarbodiimide hydrochloride (EDC)
and carbon disulfide in ethanol at room temperature according to the following mechanism: amine
nucleophilic attack of 2b-i on CS2 led to the thiocarbamate which is activated by reaction with EDC.
Rearrangement of this intermediate to an isothiocyanate, which then undergo a nucleophilic attack from
the other amine function, gave cyclic compounds (12b-i). The activation is carried out with methyl iodide
in methanol under reflux to afford isothiourea salts (3a-i).
The synthetic method to produce the family of guanidines (1) is depicted in Scheme 6:
NH
R3
.HI
SCH3
R4
N
.HI
R1
R2
3y
N
NH
NHBoc
CH3CN / TEA / ∆
R1
R2
Boc2O / dioxane
R1
R2
NHBoc
H2N
R3
NH2
H2N
NH
2x
13x
14xy
TFA/CH2Cl2
R1 R2
R4
N
NH
NH2
x= b,h
y= a-i
R3
.2 TFA
1xy
NH
R4
Scheme 6: Guanidine synthesis
The monoprotection12 of 2x (x and y are depicted in Table 2) was carried out with a large excess of
propanediamine and one equivalent of Boc2O in dioxane. Addition and elimination of the isothiouronium
salt (3y) on the protected propanediamine (13x), in the presence of one equivalent of triethylamine, led to

the guanidine (14xy) in acetonitrile under reflux. Desired compounds (1xy) were obtained by treatment of
5 with a solution of trifluoroacetic acid in dichloromethane.
From these building blocks (Table 1) such procedure allowed us the potential construction of a library of
81 guanidines (1). In order to study the influence of R1, R2, R3 and R4 groups on this synthetic method,
eight guanidines (1xy) were synthesised (Table 2): seven compounds from 2,2-dimethylpropanediamine
(2b) and isothiouronium salts (3a-c, 3e , 3g-i) yielding compounds (13b(a-c), 5be, 5b(g-i)) and the last
one (5hc) from 2-decyloxypropanediamine (13h) and 3c. As indicated on Table 2 the yield of these
reactions were good, at global 60-87%. Treatment of 14xy with a solution trifluoroacetic acid in
dichloromethane quantitatively yielded guanidiniums salts (1xy) after washing with ether. The purity of
these crude guanidiniums salts were good enough for their further application except for compounds
(1bg) and (1ba) which had to be purified by column chromatography. By this way and using this
procedure, with a variety of R1, R2, R3 and R4 groups in different substituted propanediamines (2) and 2-
methylthio-3,4,5,6-tetrahydropyridinium salts (3), we have demonstrated the efficacy of our approach to
built a library of 81 cyclic guanidines.
R2
R2
R1
R1
N
NH
NH2
N
NH
NHBoc
R1
R2
R3
R4
. 2TFA
R3
R3
. HI
NH
NH
R4
R4
14xy
14bg
14bh
14bc
14bi
Yield %
60
1xy
1bg
1bh
1bc
1bi
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3 OpC6H4CF3
CH3 O(CH2)9CH3
CH3 (CH2)2C6H5
CH3 O(CH2)17CH3
CH3 (CH2)5CH3
H
H
67
H
83
H
61
H
14bd
14ba
14bb
14hc
85
1be
1ba
1bb
1hc
CH3
CH3 CH3
(CH2)2C6H5
H
H
60
CH3
H
85
O(CH2)9CH3
H
87
Table 2 : Synthesised guanidines and intermediates
In summary, we have demonstrated a synthetic route to build a library of 81 cyclic guanidines from 2-
substituted propanediamines and 5-substituted 2-methylthio-3,4,5,6-tetrahydropyrimidines. MonoBoc-
protected propanediamines were converted to guanidines in good yield with reasonable purity.
EXPERIMENTAL
1
Melting points were determined in open capillary tubes with a Büchi apparatus and are uncorrected. H-
NMR were recorded at 100 MHz (Brüker AC 100) or 360 MHz (Brüker AC 360), while 13C-NMR at 25
or 90 MHz. Chemical shifts are reported relative to TMS as internal standard and the J values in Hz.
Elemental analysis were calculated with 1108.ERBA.SCIENCE apparatus. MS spectra were recorded
with JEOL JMS DX300 (FAB+) and Plaform Micromass (ESI+) apparatus by Science University of
Montpellier. Macherey Nagel precoated silica gel SIL G-25UV254 plates were employed for analytical
thin layer chromatography and silica gel Matrex 35-70µ (200-400 mesh) for column chromatography.
Diethyl 2-alkylmalonate (4c-f) were prepared according to published procedure.9

1
4c. 74%. bp 117°C (10-2 mbar); H-NMR (CDCl3): 1.25 (t, 3H, CH3, J=7.1 Hz); 2.23 (m, 2H, CH-CH2);
2.66 (m, 2H, CH2-C6H5); 3.32 (t, 1H, CH, J=7.3 Hz); 4.18 (q, 4H, CH2-O J= 7.1 Hz); 7.21 (m, 5H, C6H5.)
ppm; 13C-NMR: 14.1 (CH3); 30.4 (CH2-CH); 33.3 (CH2-C6H5); 51.2 (CH); 61.3 (CH2-O); 126.2
(p-C6H5); 128.5 (o,m-C6H5); 140.6 (C); 169.3 (C=O) ppm; Anal. Calcd for C15H20O4: C, 68.18; H, 7.58.
Found: C, 68.14; H, 7.60.
4d. 75%. bp 110°C (10-2 mbar); 1H-NMR (CDCl3): 0.75 (t, 3H, CH3, J=5.5 Hz); 1.14 (m, 14H, CH2, CH3-
CH2-O); 1.78 (m, 2H, CH-CH2); 3.19 (t, 1H, CH, J=7.4 Hz); 4.07 (q, 4H, CH2-O, J=7.1 Hz) ppm;
13C-NMR: 13.9 (CH3); 22.4 (CH3-CH2-); 27.1; 28.6; 28.7; 31.4 (CH2); 51.9 (CH); 61.0 (CH2-O); 169.4
(C=O) ppm; Anal. Calcd for C13H24O4: C, 63.93; H, 9.84. Found: C, 63.96; H, 9.82.
4e. 88%. bp 134°C (10-2 mbar); 1H-NMR (CDCl3): 0.80 (t, 3H, CH3, J=5.5 Hz); 1.18 (m, 20H, CH2, CH3-
CH2-O); 1.80 (m, 4H, CH-CH2-CH2-); 3.23 (t, 1H, CH, J=7.4 Hz); 4.11 (q, 4H, O-CH2, J=7.4 Hz) ppm;
13C-NMR: 14.1 (CH3); 22.6 (CH3-CH2); 27.3; 28.7; 29.3; 29.5; 31.9 (CH2); 52.0 (CH); 61.1 (O-CH2);
169.5 (C=O) ppm; Anal. Calcd for C17H32O4: C, 68.00; H, 10.67. Found: C, 68.04; H, 10.64.
4f. was purified over silica gel column (hexane/ ethyl acetate 95:5) 46%. bp 117°C (10-2 mbar); 1H-NMR
(CDCl3): 0.80 (t, 3H, CH3, J=5.5 Hz); 1.18 (m, 36H, CH2, CH3-CH2-O); 1.80 (m, 4H, CH-CH2-CH2-);
3.23 (t, 1H, CH, J=7.4 Hz); 4.11 (q, 4H, O-CH2, J=7.4 Hz) ppm; 13C-NMR: 14.1 (CH3); 22.6 (CH3-CH2);
27.4; 28.8; 29.4; 29.7; 32.0 (CH2); 52.1 (CH); 61.2 (O-CH2); 169.6 (C=O) ppm; Anal. Calcd for
C25H48O4: C, 72.81; H, 11.65. Found: C, 72.80; H, 11.63.
2-Alkylmalonamide (5c-f) were prepared according to published procedure.9
5c. white powder; 95%; mp 235-236°C (methanol); MS-FAB+: [M+H]+: 207; Anal. Calcd for
C11H14N2O2: C, 64.08; H, 6.80; N, 13.59. Found: C, 64.05; H, 6.82; N, 13.58.
5d. white powder; 99%; mp 201-203°C (methanol); MS-FAB+: [M+H]+: 187; Anal. Calcd for
C9H18N2O2: C, 58.06; H, 9.68; N, 15.05. Found: C, 58.11; H, 9.65; N, 15.00.
5e. white powder; 68%; mp 200-203°C (methanol); Anal. Calcd for C13H24N2O2: C, 64.69; H, 10.36; N,
11.60. Found: C, 64.63; H, 10.65; N, 11.21.
5f. white powder; 97%; mp 123-125°C (methanol); Anal. Calcd for C21H42N2O2: C, 71.19; H, 12.14; N,
7.91. Found: C, 71.36; H, 11.95; N, 7.89.
Synthesis of propanediamines (2c-f): typical procedure.10
Borane-dimethyl sulfide complex (66 mmol) was added dropwise to the suspension of malonamide (22
mmol) in THF (85 mL) under reflux. After 24 h under reflux, the reaction mixture was cooled at rt.
Methanol was added dropwise to destroy excess of borane complexe. THF was removed and the mixture
was heated 5 h in 1N HCl methanolic solution to destroy all the borane complexes. Methanol was then
removed and the mixture was poured in an aqueous 1N solution of NaOH and extract with CH2Cl2. The
organic layer was dried over Na2SO4 and evaporated under reduce pressure. The residue was then tritured
in TFA (110 mmol) ether solution affording diammonium salts (2c-f) as hygroscopic white solids. In
view of solubility problems, NMR analysis were done in CD3OD. However, in this solvent, resolution of
1H-NMR was imperfect resulting in 13C-NMR characterisation of 2c-f.
13
2c. 58%; mp 119°C (ethanol/ether); MS-FAB+: [M+H]+: 179; C-NMR: 29.9 (CH2CH) ; 31.5 (CH2-
C6H5) ; 39.3 (CH2N) ; 125.2 (p-C6H5) ; 128.2 (o,m-C6H5) ; 141.7 (C) ppm; Anal. Calcd for
C15H20N2O4F6: C, 44.33; H, 4.93; N, 6.90; F, 28,08. Found: C, 44.28; H, 4.95; N, 6.84; F, 28.12.
2d. 82%; mp 118-120°C (ethanol/ether); MS-FAB+: [M+H]+: 159; 13C-NMR: 14.2 (CH3) ; 23.2
(CH2CH3) ; 27.7 ; 29.9 ; 32.2 (CH2) ; 36.1 (CH) ; 41.3 (CH2N) ppm; Anal. Calcd for C13H24N2O4F6: C,
40.41; H, 6.22; N, 7.25; F, 29,53. Found: C, 40.48; H, 6.23; N, 7.22; F, 29.51.
2e. 64%; mp 143-145°C (ethanol/ether); MS-FAB+: [M+H]+: 215; 13C-NMR: 14.4 (CH3) ; 23.7
(CH2CH3) ; 27.1 ; 29.9 ; 30.4 ; 30.7 ; 33.0 (CH2) ; 36.9 (CH) ; 41.4 (CH2N) ppm; Anal. Calcd for
C17H32N2O4F6: C, 46.15; H, 7.24; N, 6.34; F, 25,79. Found: C, 46.18; H, 7.18; N, 6.32; F, 25.82.

13
2f. 56%; mp 151°C (ethanol/ether); MS-FAB+: [M+H]+: 327; C-NMR: 12.6 (CH3) ; 21.7 (CH2CH3) ;
25.9 ; 27.8 ; 28.4 ; 28.7 ; 31.0 (CH2) ; 37.5 (CH) ; 42.6 (CH2N) ppm; Anal. Calcd for C25H48N2O4F6: C,
54.15; H, 8.66; N, 5.05; F, 20,58. Found: C, 54.22; H, 8.61; N, 5.02; F, 20.59.
4-(N-tert-Butyloxycarbonylaminomethyl)oxazolidin-2-one (8) :
50 mg (2 mmol) of sodium hydride (dry, 95%) was added to a stirred solution of 500 mg (1.7 mmol) of
N,N’-tert-butyloxycarbonyl-2-hydroxy-1,3-diaminopropane (6) in 10 mL of dry THF. After stirring 15 h
at rt, THF was removed and the residue poured into water, extracted with CH2Cl2 and dried (Na2SO4).
The crude product was chromatographied over silica gel (ethyl acetate). Yield: 330 mg (89%) of colorless
oil which crystallized. mp 102°C (ethyl acetate); 1H-NMR (CDCl3) : 1.32 (s, 9H, CH3); 3.31-3.53 (m, 4H,
CH2); 4.61 (m, 1H, CH); 5.37 (s, 1H, NHBoc); 6.62 (ls, 1H, NH.) ppm. 13C-NMR: 28.1 (CH3); 42.9 (CH2-
NHBoc); 43.2 (CH2); 75.6 (CH); 79.8 (C(CH3)3); 156.2 (C=O Boc); 159.9 (C=O) ppm. Anal. Calcd for
C9H16N2O4: C, 50.22; H, 7.07; N, 13.01. Found: C, 50.28; H, 7.10; N, 13.03.
4-(N-tert-Butyloxycarbonylaminomethyl)-N-decyl-oxazolidin-2-one (9) :
23 mg (0.96 mmol) of sodium hydride (dry, 95%) and 174 mg (0.79 mmol) of 1-bromodecane were
added to a stirred solution of 230 mg (0.79 mmol) of N,N’-tert-butyloxycarbonyl-2-hydroxy-1,3-
diaminopropane (6) in 8 mL of dry DMF. After stirring 15 h at rt, DMF was removed and the residue
poured into water, extracted with CH2Cl2. The organic layer was washed with a aqueous saturated
NaHCO3 solution (2x), dried over Na2SO4 and removed under vacuum. The crude product was
chromatographied over silica gel (ethyl acetate:hexane 90:10) affording 420 mg (67%) of 9 as a colorless
oil. 1H-NMR (CDCl3) : 0.81 (t, 3H, CH3, J=5.7 Hz) ; 1.20 (m, 16H, CH2) ; 1.37 (s, 9H, CH3 Boc) ; 3.09-
3.51 (m, 6H, CH2-N) ; 4.54 (m, 1H, CH) ; 5.00 (s, 1H, NH) ppm. 13C-NMR: 14.1 (CH3) ; 22.6 (CH2-
CH3) ; 26.6 ; 27 .2 ; 29.2 ; 29.5 ; 31.8 (CH2) ; 28.3 (CH3 Boc) ; 43.4 ; 44.1 ; 46.6 (CH2-N) ; 72.2 (CH) ;
79.9 (C(CH3)3) ; 156.2 (C=O Boc); 159.9 (C=O) ppm; Anal. Calcd for C19H36N2O4: C, 64.04; H, 10.11;
N, 7.87. Found: C, 64.08; H, 10.10; N, 7.84.
N,N’-Di(triphenylmethyl)-2-hydroxy-1,3-diaminopropane (10) :
To a solution of 2-hydroxy-1,3-diaminopropane (20.0 g, 0.22 mol) in dry DMF (355 mL) was added
triethylamine (61.9 mL, 0.44 mol) and stepwise trityl chloride (136.0 g, 0.484 mol). After stirring
overnight at rt, DMF was removed and the residue poured into water, extracted with CH2Cl2. The organic
layer was washed with an aqueous saturated NaHCO3 solution (2x), dried over Na2SO4 and evaporated
under reduce pressure. The residue was then tritured in methanol affording a precipitate which was
filtered and washed with methanol and ether to give 87.9 g (69%) of 10 as a beige powder. mp 186-
187°C (methanol); 1H-NMR (CDCl3) : 2.40 (d, 4H, CH2-N, J=4.5 Hz); 3.87 (t, 1H, CH, J=4.5 Hz); 7.30-
13
7.48 (m, 30H, C6H5) ppm ; C-NMR: 47.9 (CH2); 70.3 (C(C6H5)3); 70.5 (CH-O); 125.4; 126.7; 128.2
(C6H5); 140.6 (C) ppm; Anal. Calcd for C41H38N2O: C, 85.71; H, 6.62; N, 4.88. Found: C, 85.75; H, 6.63;
N, 4.83.
N,N’-Di(triphenylmethyl)-2-(4-benzotrifluorure)-1,3-diaminopropane (11g ) :
Sodium hydride (dry, 95%) (334 mg, 13.9 mmol) was added in small portions to a solution of N,N’-
di(triphenylmethyl)-2-hydroxy-1,3-diaminopropane (10) (2.0 g, 3.5 mmol) in dry DMF (35 mL). After 1
h stirring, 4-chlorobenzotrifluoride (0.7 ml, 5.22 mmol) was added and the reaction mixture was heated in
an oil bath at 120-130°C for 15 h. DMF was removed under vacuum, the residue poured into water and
extracted with CH2Cl2. The organic layer was washed with an aqueous saturated NaHCO3 solution (2x),
dried over Na2SO4 and evaporated under reduce pressure. The crude product was chromatographied over
1
silica gel (petroleum ether:ethyl acetate 95:5) to yield 1.97 g (78%) of 11g as a colorless oil. H-NMR
CDCl3) : 2.66 (d, 4H, CH2, J=2.5 Hz); 4.80 (m, 1H, CH); 6.88 (d, 2H, o-OC6H4CF3, A2B2, J=8.8 Hz);
13
7.28-7.71 (m, 32H, m-OC6H4CF3, C6H5) ppm ; C-NMR: 45.5 (CH2); 70.8 (C(C6H5)); 78.6 (CH); 121.4

(CF3); 126.4-128.6 (CH ); 145.7 (C); 160.8 (C-O) ppm; Anal. Calcd for C48H41N2OF3: C, 80.22; H, 5.71;
N, 3.90; F, 7.94. Found: C, 80.28; H, 5.66; N, 3.87; F, 8.00.
N,N’-Di(triphenylmethyl)-2-decyloxy-1,3-diaminopropane (11h) :
Sodium hydride (dry, 95%) (351 mg, 14.6 mmol) was added in small portions to a solution of N,N’-
di(triphenylmethyl)-2-hydroxy-1,3-diaminopropane (10) (2.51 g, 4.4 mmol) in dry DMF (20 mL). After
¼ h stirring, 1-bromodecane (1.3 mL, 6.54 mmol) was added and the reaction mixture was stirred for 96 h
at rt. DMF was removed under vacuum, the residue poured into water and extracted with CH2Cl2. The
organic layer was washed with an aqueous saturated NaHCO3 solution (2x), dried over Na2SO4 and
evaporated under reduce pressure. Yield: 2.15 g (69%) of 11h as a yellow oil. 1H-NMR (CDCl3) : 1.00 (t,
3H, CH3, J=6.0 Hz); 1.42 (m, 16H, CH2); 2.56 (d, 4H, CH2-N, J=5.0 Hz); 3.26 (t, 2H, CH2-O, J=6.0 Hz);
13
3.38 (t, 1H, CH, J=5.0 Hz); 7.37-7.69 (m, 30H, C6H5) ppm ; C-NMR: 14.2 (CH3); 22.7 (CH2-CH3);
26.3; 29.6; 30.1; 31.9 (CH2); 45.0 (CH2-N); 69.5 (CH2-O); 70.6 (C(C6H5)3); 79.4 (CH); 126.2; 127.8;
128.7 (C6H5); 146.1 (C) ppm; Anal. Calcd for C51H58N2O: C, 85.72; H, 8.12; N, 3.92. Found: C, 85.75;
H, 8.11; N, 3.91.
N,N’-Di(triphenylmethyl)-2-octadecyloxy-1,3-diaminopropane (11i ) :
11i was prepared according to procedure of 11h. Yield: 62% (white oil). 1H-NMR (CDCl3) : 1.00 (t, 3H,
CH3, J=6.0 Hz); 1.42 (m, 32H, CH2); 2.56 (d, 4H, CH2-N, J=5.0 Hz); 3.26 (t, 2H, CH2-O, J=6.0 Hz); 3.38
13
(t, 1H, CH, J=5.0 Hz); 7.37-7.69 (m, 30H, C6H5) ppm ; C-NMR: 14.2 (CH3); 22.7 (CH2-CH3); 26.3;
29.5; 29.8; 30.1; 32.0; 33.9 (CH2); 45.1 (CH2-N); 69.5 (CH2-O); 70.6 (C(C6H5)3); 79.4 (CH); 126.2;
127.8; 128.7 (C6H5); 146.1 (C) ppm; Anal. Calcd for C59H74N2O: C, 85.71; H, 8.96; N, 3.39. Found: C,
85.72; H, 8.98; N, 3.36.
Synthesis of propanediamines (2g-i): typical procedure.
Trityl derivatives (11g-i) were treated with trifluoroacetic acid (TFA) in methylene chloride (50/50) and
allowed to stir 1 h. Methylene chloride and excess of TFA were removed under vacuum and the residue
was triturated in ether affording respectively diammonium salts (2g-i) as hygroscopic white powders.
NMR analyses were done in CD3OD.
1
2g : 92%; mp 169°C (ethanol/ether); H-NMR : 3.10 (m, 2H, CH2N) ; 4.8 (m, 1H, CH) ; 7.12 (d, 2H, o-
13
C6H5, A2B2, J=8.8 Hz) ; 7.51 (d, 2H, m- C6H5, A2B2, J=8.8 Hz) ppm ; C-NMR: 40.8 (CH2N) ; 72.0
(CH) ; 117.4 (o-C6H5) ; 112.3 ;123.9 (CF3) ; 128.2 ;128.3 (m-C6H5, CCF3) ; 160.2 (C-O) ppm; Anal.
Calcd for C14H15N2O5F9: C, 36.36; H, 3.25; N, 6.06; F, 37.01. Found: C, 36.28; H, 3.26; N, 6.04; F,
37.08.
2h : 73%; mp 236-238°C (ethanol/ether); 13C-NMR: 14.4 (CH3) ; 23.7 (CH2CH3) ; 26.8 ;30.6 ; 33.0
(CH2) ; 40.8 (CH2N) ; 71.8 (CH2O) ; 73.5 (CH) ppm; Anal. Calcd for C17H32N2O5F6: C, 44.54; H, 6.99;
N, 6.11; F, 24.89. Found: C, 44.53; H, 6.97; N, 6.10; F, 24.92.
2i: 56%; mp 100-102°C (ethanol/ether); 13C-NMR: 14.7 (CH3) ; 23.7 (CH2CH3) ; 26.7 ;30.8 ; 33.1 (CH2) ;
40.7 (CH2N) ; 71.7 (CH2O) ; 73.2 (CH) ppm; Anal. Calcd for C25H48N2O5F6: C, 52.63; H, 8.42; N, 4.91;
F, 20.00. Found: C, 52.57; H, 8.40; N, 4.91; F, 20.06.
Synthesis of cyclic thioureas (12b-i): typical procedure.
To a solution of propanediamine derivatives (2b-i) (83 mmol) in absolute ethanol (50 mL) were added
carbon disulfide (167 mmol) and EDC (83 mmol). The mixture was stirred 3 h at rt. Ethanol was removed
under vacuum, the residue poured into water, extracted with CH2Cl2, dried over Na2SO4 and evaporated
under reduced pressure affording 12b-i.
12b : white powder (93%); mp 225-227°C (acetone); 1H-NMR (CDCl3) : 0.91 (s, 6H, CH3); 2.88 (d, 4H,
CH2, J=2.1 Hz); 7.46 (s, 2H, NH) ppm ; 13C-NMR : 24.2 (CH3); 26.3 (C); 52.0 (CH2); 174.8 (C=S) ppm;
Anal. Calcd for C6H12N2S: C, 50.00; H, 8.33; N, 19.45; S, 22.22. Found: C, 49.96; H, 8.32; N, 19.44; S,
22.27.

1
12c : yellow solid (64%) which was recrystallized (acetone); mp 187°C; MS-ES+: [M+H]+: 235; H-
NMR (DMSO-d6) : 1.63 (m, 2H, CH2-CH) ; 1.94 (m, 1H, CH) ; 2.62 (m, 2H, CH2-C6H5) ; 2.94 (m, 2H,
13
Ha, CH2N) ; 3.17 (m, 2H, He, CH2N) ; 7.20 (m, 5H, C6H5) ppm ; C-NMR : 28.8 (CH2- C6H5) ; 32.4
(CH) ; 32.8 (CH2-CH) ; 45.6 (CH2N) ; 126.2 (p-C6H5) ; 128.2 (o-C6H5) ; 128.6 (m-C6H5) ; 141.0 (C) ;
176.1 (C=S) ppm; Anal. Calcd for C12H16N2S: C, 65.45; H, 7.27; N, 12.73; S, 14.55. Found: C, 65.40; H,
7.25; N, 12.74; S, 14.61.
12d : white solid (62%) which was recrystallized (ethanol); mp 115-117°C; 1H-NMR (CDCl3) : 0.84 (m,
3H, CH3, J=5.8 Hz) ; 1.28 (m, 10H, CH2) ; 1.90 (m, 1H, CH) ; 2.91 (m, 2H, Ha, CH2N) ; 3.28 (m, 2H, He,
CH2N) ; 7,0 (s, 2H, NH) ppm ; 13C-NMR : 13.3 (CH3) ; 21.4 ; 25.5 ; 28.3 ; 29.6 (CH2) ; 30.5 (CH) ; 44.4
(CH2N) ; 174.9 (C=S) ppm; Anal. Calcd for C10H20N2S: C, 59.96; H, 10.07; N, 13.99; S, 15.98. Found: C,
59.98; H, 10.06; N, 13.95; S, 16.01.
1
12e : white fluffy solid (65%); mp 126°C (ethanol) ; H-NMR (CDCl3) : 0.84 (m, 3H, CH3, J=5.8 Hz) ;
1.22 (m, 18H, CH2) ; 1.89 (m, 1H, CH) ; 2.90 (m, 2H, Ha, CH2N) ; 3.26 (m, 2H, He, CH2N) ; 7.00 (s, 2H,
13
NH) ppm ; C-NMR : 14.1 (CH3) ; 22.7 ; 26.7 ; 29.6 (CH2) ; 30.8 (CH) ; 45.9 (CH2N) ; 176.4 (C=S)
ppm; Anal. Calcd for C14H28N2S: C, 65.62; H, 10.94; N, 10.94; S, 12.50. Found: C, 65.65; H, 10.92; N,
10.90; S, 12.53.
12f : white solid (67%); mp 106°C (ethanol) ; 1H-NMR (CDCl3) : 0.92 (m, 3H, CH3, J=5.8 Hz) ; 1.30 (m,
18H, CH2) ; 1.92 (m, 1H, CH) ; 2.93 (m, 2H, Ha, CH2N) ; 3.32 (m, 2H, He, CH2N) ; 7.00 (s, 2H, NH)
13
ppm ; C-NMR : 14.1 (CH3) ; 22.7 ; 26.5 ; 29.4 ; 29.7 (CH2) ; 31.5 (CH) ; 45.9 (CH2N) ; 176.4 (C=S)
ppm; Anal. Calcd for C22H44N2S: C, 71.74; H, 11.96; N, 7.61; S, 8.69. Found: C, 71.80; H, 11.93; N,
7.59; S, 8.72.
12g : white solid (52%) after chromatography over silica gel (CH2Cl2:CH3OH 95:5); mp 221-223°C
(ethanol) ; 1H-NMR (DMSO-d6) : 3.54 (m, 4H, CH2N) ; 5.02 (m, 1H, CH) ; 7.18 (d, 2H, o-OC6H5, A2B2,
13
J=8.2 Hz) ; 7.64 (d, 2H, m-OC6H5, A2B2, J=8.2 Hz) ppm ; C-NMR : 43.2 (CH2N) ; 64.6 (CH) ; 116.3
(CH o-OC6H4) ; 121.2 ;122.5 (C-CF3) ; 108.5 ; 119.3 ; 130.0 ;140.8 (CF3) ; 127.2 ; 127.3 (CH m-O
C6H4) ; 159.6 (C-O) ; 175.7 (C=S) ppm; Anal. Calcd for C11H11N2 F3OS: C, 47.83; H, 3.99; N, 10.14; F,
20.65; S, 11.59. Found: C, 47.89; H, 3.98; N, 10.12; F, 20.59; S, 11.62.
1
12h : orange thick oil (61%) after chromatography over silica gel (CH2Cl2:CH3OH 95:5); H-NMR
(CDCl3) : 1.06 (t, 3H, CH3, J=5.8 Hz) ; 1.45-1.66 (m, 16H, CH2) ; 3.48-3.74 (m, 6H, CH2N, CH2O) ; 3.97
(m, 1H, CH) ppm ; 13C-NMR : 14.1 (CH3) ; 22.6 (CH2-CH3) ; 26.0 ; 29.3 ; 29.4 ; 29.5 ; 29.7 ; 31.8
(CH2) ; 44.4 (CH2N) ; 66.4 (CH) ; 69.2 (CH2O) ; 176.1 (C=S) ppm; Anal. Calcd for C14H28N2OS: C,
61.76; H, 10.29; N, 10.29; S, 11.77. Found: C, 61.82; H, 10.26; N, 10.27; S, 11.82.
12i : precipitate formed in the reaction mixture was filtered, washed with ethanol and ether affording 12i
(80%) as a white solid. mp 125°C (acetone) ; 1H-NMR (CDCl3) : 1.06 (t, 3H, CH3, J=5.8 Hz) ; 1.45-1.66
(m, 32H, CH2) ; 3.48-3.74 (m, 6H, CH2N, CH2O) ; 3.97 (m, 1H, CH) ; 6.75 (s, 2H, NH) ppm ; 13C-NMR :
14.1 (CH3) ; 22.6 (CH2-CH3) ; 26.0 ; 29.3 ; 29.4 ; 29.7 ; 31.8 (CH2) ; 44.4 (CH2N) ; 66.4 (CH) ; 69.2
(CH2O) ; 176.1 (C=S) ppm; Anal. Calcd for C22H44N2S: C, 68.75; H, 11.46; N, 7.29; S, 8.33. Found: C,
68.80; H, 11.42; N, 7.30; S, 8.36.
Synthesis of isothioureas (3a-i): typical procedure.
Respectively thiourea (12a-i) (0.1 mol) and methyl iodide (0.12 mol) in methanol (10 mL/g) were heated
5 h under reflux. After cooling, methanol and excess of methyl iodide were removed under vacuum
affording quantitatively 3a-i, as solids which were washed with acetone and petroleum ether.
1
3a : brown powder; mp 146-148°C (ethanol/ether); H-NMR (DMSO-d6) : 1.94 (m, 2H, CH2) ; 2.66 (s,
3H, SCH3) ; 3,44 (t, 4H, CH2N, J=5.7 Hz) ; 9.53 (s, 2H, NH) ppm ; 13C-NMR : 13.1 (SCH3) ; 17.6 (CH2) ;
39.4 (CH2N) ; 162.1 (C=N) ppm ; Anal. Calcd for C5H11N2IS: C, 23.26; H, 4.26; N, 10.85; S, 12.40.
Found: C, 23.16; H, 4.28; N, 10.84; S, 12.38.
1
3b : yellow amorphous solid; H-NMR (CDCl3) : 0.95 (s, 6H, CH3); 2.62 (s, 3H, SCH3); 3.11 (s, 4H,
CH2), 8.76 (s, 2H, NH) ppm ; 13C-NMR : 13.6 (SCH3) ; 23.2 (CH3) ; 25.7 (C(CH3)2) ; 50.5 (CH2) ; 162.0

(C=N) ppm ; Anal. Calcd for C7H15N2IS: C, 29.37; H, 5.24; N, 9.79; S, 11.19. Found: C, 29.31; H, 5.25;
N, 9.77; S, 11.17.
3c : white powder; mp 161-162°C (ethanol/ether); 1H-NMR (CD3OD) : 1.70 (m, 2H, CH2-CH) ; 2.04 (m,
1H, CH) ; 2.63 (s, 3H, SCH3) ; 2.74 (m, 2H, CH2C6H5) ; 3.24 (m, 2H, CH2N) ; 3.59 (m, 2H, CH2N) ; 7.28
13
(m, 5H, C6H5) ppm ; C-NMR : 13.1 (SCH3) ; 29.7 (CH2-CH) ; 33.1 (CH2-C6H5) ; 33.6 (CH) ; 46.3
(CH2N) ; 127.1 (p-C6H5) ; 129.4 (m-C6H5) ; 129.5 (o-C6H5) ; 142.6 (C) ; 165.7 (C=N) ppm ; Anal. Calcd
for C13H19IN2S: C, 43.09; H, 5.25; N, 7.73; S, 8.84. Found: C, 42.99; H, 5.25; N, 7.74; S, 8.86.
3d : brown thick oil; 1H-NMR (CD3OD) : 0.89 (t, 3H, CH3, J=6.0 Hz) ; 1.34 (m, 10H, CH2) ; 2.06 (m,
13
1H, CH) ; 2.65 (s, 3H, SCH3) ; 3.04-3.67 (m, 4H, CH2N) ppm ; C-NMR : 13.1 (SCH3) ; 14.4 (CH3) ;
23.5 (CH2CH3) ; 29.9 (CH) ; 27.4 ; 30.2 ; 31.3 ; 32.6 (CH2) ; 46.4 (CH2N) ; 165.3 (C=N) ppm; Anal.
Calcd for C11H22N2IS: C, 38.60; H, 6.72; N, 8.19; S, 9.36. Found: C, 38.58; H, 5.26; N, 8.16; S, 9.34.
1
3e : yellow oil; H-NMR (CD3OD) : 0.89 (t, 3H, CH3, J=6.0 Hz) ; 1.30 (m, 20H, CH2) ; 2.06 (m, 1H,
13
CH) ; 2.66 (s, 3H, SCH3) ; 3.04-3.37 (m, 4H, CH2N) ppm ; C-NMR : 13.1 (SCH3) ; 14.4 (CH3) ; 23.5
(CH2CH3) ; 29.9 (CH) ; 27.4 ; 29.0 ; 30.2 ; 30.7 ; 31.4 ; 32.6 (CH2) ; 46.4 (CH2N) ; 165.3 (C=N) ppm ;
Anal. Calcd for C15H31N2IS: C, 45.23; H, 7.79; N, 7.03; S, 8.04. Found: C, 45.15; H, 7.81; N, 7.03; S,
8.02.
3f : beige amorphous solid; 13C-NMR (CD3OD) : 13.1 (SCH3) ; 14.4 (CH3) ; 23.3 (CH2CH3) ; 29.9 (CH) ;
27.4 ; 30.2 ; 31.3 ; 32.6 (CH2) ; 46.4 (CH2N) ; 165.4 (C=N) ppm ; Anal. Calcd for C23H47N2IS: C, 54.12;
H, 9.22; N, 5.49; S, 6.27. Found: C, 54.05; H, 9.25; N, 5.49; S, 6.26.
3g : yellow amorphous solid; 1H-NMR (DMSO-d6) : 2.71 (s, 3H, SCH3) ; 3.78 (m, 4H, CH2N) ; 5.40 (m,
1H, CH) ; 7.35 (d, 2H, o-OC6H4CF3, A2B2, J=8.0 Hz) ; 7.75 (d, 2H, m-OC6H4CF3, A2B2, J=8.0 Hz) ; 9.39
(s, 2H, NH) ppm ; 13C-NMR : 13.0 (SCH3) ; 42.9 (CH2N) ; 64.4 (CH) ; 115.9 (CH o-OC6H4) ;
121.2 ;122.5 (C-CF3) ; 108.5 ; 119.3 ; 130.0 ;140.8 (CF3) ; 126.5 ; 126.6 (CH m-C6H4) ; 158.2 (C-O) ;
162.8 (C=N) ppm ; Anal. Calcd for C11H22N2OF3IS: C, 34.45; H, 3.35; N, 6.70; S, 7.66. Found: C, 34.43;
H, 3.36; N, 6.71; S, 7.66.
1
3h : orange solid; mp 55°C (ethanol/ether); H-NMR (CD3OD) : 0.97 (t, 3H, CH3, J=5.8 Hz) ; 1.37-1.63
13
(m, 16H, CH2) ; 2.72 (s, 3H, SCH3) ; 3.64 (m, 6H, CH2N, CH2O) ; 4.15 (m, 1H, CH) ppm ; C-NMR :
14.0 (SCH3) ; 14.5 (CH3) ; 23.7 (CH2-CH3) ; 27.2 ; 30.5 ; 30.7 ; 33.0 (CH2) ; 45.2 (CH2N) ; 66.2 (CH) ;
69. 8 (CH2O) ;165.6 (C=N) ppm ; Anal. Calcd for C15H31N2OIS: C, 43.48; H, 7.49; N, 6.76; S, 7.73.
Found: C, 43.44; H, 7.50; N, 6.75; S, 7.71.
1
3i : colorless amorphous solid; H-NMR (DMSO-d6) : 0.97 (t, 3H, CH3, J=5.8 Hz) ; 1.37-1.63(m, 32H,
CH2) ; 2.72 (s, 3H, SCH3) ; 3.64 (m, 6H, CH2N, CH2O) ; 4.15 (m, 1H, CH) ; 7.88 (s, 1H, NH ppm ; 13C-
NMR : 14.0 (SCH3) ; 14.5 (CH3) ; 23.7 (CH2-CH3) ; 27.2 ; 30.5 ; 30.7 ; 33.0 (CH2) ; 45.2 (CH2N) ; 66.2
(CH) ; 69. 8 (CH2O) ;165.6 (C=N) ppm ; Anal. Calcd for C23H47N2OIS: C, 52.47; H, 8.94; N, 5.32; S,
6.08. Found: C, 52.40; H, 8.97; N, 5.32; S, 6.05.
N-tert-Butyloxycarbonyl-2,2-dimethyl-1,3-propanediamine (13b)
Di-tert-butyldicarbonate (7.59 g, 34.8 mmol) in dioxane (80 mL) was added dropwise to a solution of 2,2-
dimethyl-1,3-propanediamine (2b) (15.1 mL, 174 mmol) in dioxane (90 mL) over a period of 2 h. The
reaction mixture was stirred 16 h at rt and dioxane was removed under reduce pressure. The residue was
poured into water and the formed precipitate, di-Boc derivative (0.25 g, 2%), was filtered. The filtrate was
extracted with CH2Cl2 (4x), the organic layer washed with a saturated NaCl aqueous solution, dried over
Na2SO4 and evaporated to give compound 13b as a colorless oil which solidified on standing and was
recrystallized (hexane-ether). Yield: 6.74 g (96%). mp 78°C; 1H-NMR (CDCl3) : 0.75 (s, 6H, CH3) ; 1.36
13
(s, 9H, (CH3)3C) ; 2.37 (m, 2H, CH2NH2) ; 2.90 (m, 2H, CH2NH) ppm ; C-NMR : 23.1 ((CH3)2)C) ;
28.2 ((CH3)3)C) ; 35.6 (C(CH3)2) ; 48.2 (CH2NH) ; 50.5 (CH2NH2) ; 78.8 (C(CH3)3) ; 156.3 (C=O) ppm ;
Anal. Calcd for C10H22N2O2: C, 59.41; H, 10.89; N, 13.86. Found: C, 59.45; H, 10.88; N, 13.82.

N-tert-Butyloxycarbonyl-2-decyloxy-1,3-propanediamine (13h)
13h was prepared according to procedure of 13b. Yield: 63% (yellow oil). 1H-NMR (CDCl3) : 0.85 (t,
3H, CH3, J=5.1 Hz) ; 1.22-1.40 (m, 25H, (CH3)3, CH3(CH2)8) ; 3.11-3.59 (m, 6H, CH2N, CH2O) ppm ;
13C-NMR : 14.1 (CH3) ; 22.7 (CH2-CH3) ; 28. 4 ((CH3)3C) ; 26.0 ; 29.4 ; 29.8 ; 29.9 ; 31.9 (CH2) ; 40.3
(CH2NH2) ; 40.4 (CH2NH) ; 70.4 (CH2O) ; 73.9 (CH) ; 79.9 (C(CH3)3) ; 156.4 (C=O) ppm ; Anal. Calcd
for C18H38N2O3: C, 65.45; H, 11.52; N, 8.48. Found: C, 65.48; H, 11.49; N, 8.47.
Synthesis of compounds (14xy) : typical procedure
Isothiourea hydroiodide (3y) (3.1 mmol) was added to amine (13x) (3.1 mmol) in dry acetonitrile (10
mL). The reaction mixture was heated 72 h under reflux, CH3CN was removed under vacuum and the
residue poured into water. 1N NaOH was added up to basic pH and these solution was extracted with
CH2Cl2. The organic layer was dried over Na2SO4, evaporated under reduce pressure affording 14xy
obtained after chromatography over silica gel (CH2Cl2 :CH3OH :NH4OH 90 :10 :1).
1
14bg : yellow oil; 60%; H-NMR (CDCl3) : 0.78 (s, 6H, CH3) ; 1.33 (s, 9H, (CH3)3C) ; 2.88 (m, 4H,
CH2N) ; 3.48 (m, 4H, CH2Ncyc) ; 4.56 (m, 1H, CH) ; 7.35 (d, 2H, o-OC6H4CF3, A2B2, J=8.0 Hz) ; 7.75 (d,
2H, m-OC6H4CF3, A2B2, J=8.0 Hz) ppm ; 13C-NMR : 23.6 (CH3) ; 28.4 ((CH3)3C) ; 36.3 (C(CH3)2) ; 44.7
(CH2Ncyc) ; 46.8 (CH2NHBoc) ; 47.6 (CH2N) ; 68,2 (CH) ; 79.4 (C(CH3)3) ; 115.7 (CH, o-OC6H4) ; 123.2
(CF3) ; 126.9 (CH, m-OC6H4) ; 127.0 (C-CF3) ; 151.9 (C=N) ; 157.0 (C=O) ; 159.9 (C-O) ppm ; Anal.
Calcd for C20H30N4O3F3I: C, 43.01; H, 5.38; N, 10.04. Found: C, 43.07; H, 5.39; N, 10.08.
1
14bh : yellow oil; 67%; H-NMR (CDCl3) : 0.85 (s, 3H, CH3(CH2)9, J=5.1 Hz) ; 0.94 (s, 6H, (CH3)2C) ;
1.21-1.38 (m, 25H, (CH2)8CH3, (CH3)3C) ; 2.93 (m, 2H, CH2NHBoc) ; 3.08 (m, 2H, CH2NH) ; 3.42 (m,
13
6H, CH2Ncyc, CH2O) ; 3.75 (m, 1H, CH) ppm ; C-NMR : 14.1 (CH3-(CH2)9) ; 22.6 (CH2-CH3) ; 23.5
((CH3)2C) ; 26.0 ; 28.4 ; 29.3 ; 31.7 (CH2) ; 29.5 ((CH3)3C) ; 36.7 (C(CH3)2) ; 42.3 (CH2N cycle) ; 47.7
(CH2NHBoc) ; 49.2 (CH2NH) ; 66.5 (CH) ; 67.9 (CH2O) ; 79.4 (C(CH3)3) ; 153.2 (C=N) ; 156.8 (C=O)
ppm ; MS-ES+ : [M+H]+ : 441 ; Anal. Calcd for C20H30N4O3I: C, 49.81; H, 8.48; N, 10.11. Found: C,
49.78; H, 8.50; N, 10.13.
14bc : yellow thick oil; 83%; 1H-NMR (CDCl3) : 0.90 (s, 6H, (CH3)3) ; 1.53 (m, 2H, CH2-CH) ; 1.82 (m,
13
1H, CH) ; 2.56 (m, 2H, CH2-C6H5) ; 2.88-3.42 (m, 8H, CH2N) ; 7.11 (m, 5H, C6H5) ppm ; C-NMR :
23.0 (CH3) ; 28.1 ((CH3)3) ; 29.4 (CH) ; 31.9 (CH2-CH) ; 32.4 (CH2-C6H5) ; 36.4 (C(CH3)2) ; 43.1
(CH2Ncyc) ; 47.7 (CH2NHBoc) ; 49.3 (CH2NH) ; 79.4 (C(CH3)3) ; 126.0 (p-C6H5) ; 127.9 (o-C6H5) ; 128.3
(m-C6H5) ; 140.5 (C) ; 153.3 (C=N) ; 156.8 (C=O) ppm ; Anal. Calcd for C22H37N4O2I: C, 51.16; H, 7.17;
N, 10.85. Found: C, 51.09; H, 7.18; N, 10.83.
14bi : yellow thick oil; 61%; 1H-NMR (CDCl3) : 0.85 (t, 3H, CH3, J=5.1 Hz) ; 0.94 (s, 6H, (CH3)2) ; 1.13-
1.38 (m, 41H, CH3(CH2)16, C(CH3)3) ; 2.93 (m, 2H, CH2NHBoc) ; 3.08 (m, 2H, CH2NH) ; 3.42 (m, 6H,
CH2Ncyc, CH2O) ; 3.75 (m, 1H, CH) ppm ; 13C-NMR : 14.1 (CH3) ; 22.6 (CH3CH2) ; 23.5 ((CH3)2) ; 29.4
((CH3)3) ; 25.8 ; 28.1 ; 29.0 ; 31.6 ((CH2)15CH2O) ; 36.5 (C(CH3)3) ; 42.0 (CH2Ncyc) ; 47.7 (CH2NHBoc) ;
49.2 (CH2NH) ; 66.2 (CH) ; 68.8 (CH2O) ; 79.4 (C(CH3)3) ; 153.2 (C=N) ; 156.8 (C=O) ppm ; Anal.
Calcd for C32H65N4O3I: C, 56.47; H, 9.56; N, 8.23. Found: C, 56.42; H, 9.55; N, 8.21.
1
14bd : brown oil; 85%; H-NMR (CDCl3) : 0.88 (m, 9H, CH3, (CH3)2) ; 1.12-1.26 (m, 19H, CH2,
13
(CH3)3) ; 1.83 (m, 1H, CH) ; 2.81-3.42 (m, 8H, CH2N) ppm ; C-NMR : 14.1 (CH3) ; 22.6 (CH3CH2) ;
23.5 ((CH3)2) ; 26.9 ; 28.8 ; 29.6 ; 32.0 ((CH2)4CH) ; 31.0 (CH) ; 36.5 (C(CH3)3) ; 44.0 (CH2Ncyc) ; 47.7
(CH2NHBoc) ; 49.3 (CH2NH) ; 79.4 (C(CH3)3) ; 153.3 (C=N) ; 156.9 (C=O) ppm ; Anal. Calcd for
C20H41N4O2I: C, 48.39; H, 8.27; N, 11.29. Found: C, 48.34; H, 8.27; N, 11.27.
1
14ba : colorless oil; 60% ; H-NMR (CDCl3) : 0.92 (s, 6H, (CH3)2C) ; 1.35 (s, 9H, (CH3)3C) ; 1.98 (m,
2H, CH2) ; 3.00-3.10 (m, 4H, CH2NH) ; 3.33 (m, 4H, CH2Ncyc) ppm ; 13C-NMR : 19.2 (CH2) ; 23.3
((CH3)2C) ; 28.3 ((CH3)3C) ; 36.6 (C(CH3)2) ; 39.8 (CH2Ncyc) ; 48.1 (CH2NHBoc) ; 49.5 (CH2NH) ; 79.8
(C(CH3)3) ; 152.8 (C=N) ; 156.8 (C=O) ppm ; Anal. Calcd for C14H29IN4O2: C, 40.78; H, 7.04; N, 13.59;
O, 7.67. Found: C, 40.73; H, 7.07; N, 13.57; O, 7.66.
14bb : yellow oil; 85%; 1H-NMR (CDCl3) : 0.89 (s, 3H, (CH3)2Ccyc) ; 0.94 (s, 6H, (CH3)2C) ; 1.30 (s, 9H,
(CH3)3C) ; 2.90 (m, 8H, CH2N) ppm ; 13C-NMR : 23.2 ((CH3)2C) ; 23.9 ((CH3)2Ccyc) ; 27.1 ((CH3)2Ccyc) ;

28.3 ((CH3)3C) ; 36.6 (C(CH3)2) ; 44.6 (CH2Ncyc) ; 48.0 (CH2NHBoc) ; 49.2 (CH2NH) ; 79.5 ((CH3)3C) ;
152.8 (C=N) ; 156.8 (C=O) ppm ; MS-ES+ : [M+H]+ : 313 ; Anal. Calcd for C16H33N4O2I: C, 43.64; H,
7.50; N, 12.73. Found: C, 43.56; H, 7.51; N, 12.70.
14hc : brown oil; 87%; 1H-NMR (CDCl3) : 0.85 (t, 3H, CH3, J=5.1 Hz) ; 1.18 (m, 16H, CH3(CH2)8) ; 1.36
(s, 9H, (CH3)3) ; 1.58 (m, 2H, CH2-CH) ; 1.92 (m, 1H, CH) ; 2.60 (m, 2H, CH2-C6H5) ; 2.92-3.69 (m,
13
11H, CH2N, CH2O, CH-O) ; 7.12 (m, 5H, C6H5) ppm ; C-NMR : 14.1 (CH3) ; 22.6 (CH3CH2) ; 28.3
((CH3)3) ; 26.0 ; 29.6 ; 31.1 ((CH2)7CH2O) ; 29.4 (CH) ; 31.9 (CH2-CH) ; 32.4 (CH2-C6H5) ; 41.6
(CH2Ncyc) ; 45.1 (CH2NHBoc) ; 53.5 (CH2NH) ; 70.3 (CH2O) ; 73.9 (CH-O) ; 79.4 (C(CH3)3) ; 126.0 (p-
C6H5) ; 127.9 (o-C6H5) ; 128.3 (m-C6H5) ; 141.0 (C) ; 154.6 (C=N) ; 156.8 (C=O) ppm ; Anal. Calcd for
C30H53N4O3I: C, 55.90; H, 8.23; N, 8.70. Found: C, 55.86; H, 8.21; N, 8.69.
Synthesis of compounds (1xy): typical procedure
Compound (14xy) (0.167 mol) was stirred 2 h in 10 mL of a CH2Cl2:TFA 9:1 mixture. CH2Cl2 and excess
of TFA were then removed under reduce pressure; residual thick oil was tritured (3x) with ether, followed
by drying in vacuo, affording quantitatively 1xy.
1
1bg : yellow thick oil; H-NMR (CD3OD) : 1.08 (s, 6H, CH3) ; 2.91 (m, 2H, CH2NH2) ; 3.17 (m, 2H,
CH2NH) ; 3.64 (m, 4H, CH2Ncyc) ; 3.96 (m, 1H, CH) ; 7.13 (d, 2H, o-OC6H4CF3, A2B2, J=8.0 Hz) ; 7.61
13
(d, 2H, m-OC6H4CF3, A2B2, J=8.0 Hz) ppm ; C-NMR : 22.5 (CH3) ; 36.0 (C(CH3)2) ; 43.0 (CH2Ncyc) ;
47.9 (CH2NH2) ; 49.2 (CH2NH) ; 66.1 (CH) ; 117.3 (o-OC6H4) ; 117.8 (CF3) ; 128.1 (m-OC6H4) ; 128.2
(C-CF3) ; 154.8 (C=N) ; 160.3 (C-O) ppm ; MS-ES+ : [M+H]+ : 345 ; [M+2H]++/2 : 173 ; Anal. Calcd for
C20H25F9N4O5: C, 41.96; H, 4.37; N, 9.79. Found: C, 41.94; H, 4.32; N, 9.77.
1bh : brown oil; 1H-NMR (CD3OD) : 0.89 (s, 3H, CH3(CH2)9, J=5.1 Hz) ; 1.06 (s, 6H, (CH3)2C) ; 1.29
(m, 16H, (CH2) ; 2.90 (s, 2H, CH2NH2) ; 3.14 (s, 2H, CH2NH) ; 3.45 (m, 6H, CH2Ncyc, CH2O) ; 3.91 (m,
13
1H, CH) ppm ; C-NMR : 14.5 (CH3-(CH2)9) ; 22.6 ((CH3)2C) ; 23.7 ; 27.2 ; 30.7 ; 30.9 ; 33.1 (CH2) ;
36.0 (C(CH3)2) ; 43.3 (CH2Ncyc) ; 47.9 (CH2NH2) ; 49.3 (CH2NH) ; 67.6 (CH) ; 69.7 (CH2O) ; 154.9
(C=N) ppm ; MS-ES+ : [M+H]+ : 341 ; [M+2H]++/2 : 171 ; Anal. Calcd for C22H40N4O5F6: C, 47.65; H,
7.22; N, 10.11. Found: C, 47.82; H, 7.18; N, 10.03.
1bc : brown thick oil; ; 1H-NMR (CD3OD) : 1.05 (s, 6H, (CH3)2) ; 1.69 (m, 2H, CH2-CH) ; 1.93 (m, 1H,
13
CH) ; 2.69 (m, 2H, CH2-C6H5) ; 2.88-3.49 (m, 8H, CH2N) ; 7.21 (m, 5H, C6H5) ppm ; C-NMR : 22.4
((CH3)2) ; 30.9 (CH) ; 33.0 (CH2-CH) ; 33.6 (CH2-C6H5) ; 35.6 (C(CH3)2) ; 44.3 (CH2Ncyc) ; 48.2
(CH2NH2) ; 50.0 (CH2NH) ; 126.9 (p-C6H5) ; 129.2 (o-C6H5) ; 129.3 (m-C6H5) ; 142.4 (C) ; 154.7 (C=N)
ppm ; MS-ES+ : [M+H]+ : 289 ; [M+2H]++/2 : 145 ; Anal. Calcd for C21H30N4O4F6: C, 48.84; H, 5.81; N,
10.85. Found: C, 48.74; H, 5.62; N, 10.80.
1bi : yellow powder; mp 88°C; 1H-NMR (DMSO-d6) : 1.31 (m, 9H, CH3) ; 1.66 (m, 32H, (CH2)16CH3) ;
2.96 (s, 2H, CH2NH2) ; 3.18 (s, 2H, CH2NH) ; 3.76-3.88 (m, 6H, CH2Ncyc, CH2O) ; 4.47 (m, 1H, CH) ;
13
8.08 (sl, 1H, NH) ; 8.37 (ls, 2H, NH2) ppm ; C-NMR : 13.4 (CH3) ; 21.5 ((CH3)2C) ; 21.7 (CH3CH2) ;
25.3 ; 28.4 ; 28.7 ; 31.0 ((CH2)15CH2O) ; 34.4 (C(CH3)2) ; 41.3 (CH2Ncyc) ; 45.6 (CH2NH2) ; 47.0
(CH2NH) ; 65.3 (CH) ; 67.3 (CH2O) ; 152.6 (C=N) ppm ; MS-ES+ : [M+H]+ : 453 ; [M+2H]++/2 : 227 ;
Anal. Calcd for C31H58N4O5F6: C, 54.71; H, 8.53; N, 8.24. Found: C, 54.50; H, 8.41; N, 8.20.
1
1bd : brown oil; H-NMR (CD3OD) : 0.87 (t, 3H, CH3, J=5.3 Hz) ; 1.04 (s, 6H, (CH3)2) ; 1.31 (m, 10H,
CH2) ; 1.96 (m, 1H, CH) ; 2.87-3.50 (m, 8H, CH2N) ppm ; 13C-NMR : 14.3 (CH3) ; 22.6 (CH3CH2) ; 23.5
((CH3)2) ; 27.6 ; 30.3 ; 31.4 ; 32.7 (CH2) ; 33.2 (CH) ; 35.6 (C(CH3)3) ; 44.6 (CH2Ncyc) ; 47.8 (CH2NH2) ;
49.2 (CH2NH) ; 154.8 (C=N) ppm ; MS-ES+ : [M+H]+ : 269 ; [M+2H]++/2 : 135 ; Anal. Calcd for
C19H34N4O4F6: C, 45.97; H, 6.85; N, 11.29. Found: C, 45.85; H, 6.83; N, 11.17.
1ba : yellow oil; 1H-NMR (CD3OD) : 0.92 (s, 6H, (CH3)2C) ; 1.98 (m, 2H, CH2) ; 2.29 (s, 2H, CH2NH2) ;
2.83 (s, 2H, CH2NH) ; 3.33 (m, 4H, CH2Ncyc) ppm ; 13C-NMR : 19.2 (CH2) ; 23.3 (CH3) ; 36.6
(C(CH3)2) ; 39.8 (CH2Ncyc) ; 46.8 (CH2NH2) ; 49.5 (CH2NH) ; 153.8 (C=N) ppm ; MS-ES+ : [M+H]+ :
185 ; [M+2H]++/2 : 93 ; Anal. Calcd for C13H22N4O4F6: C, 37.86; H, 5.34; N, 13.59. Found: C, 37.84; H,
5.32; N, 13.57.

1
13
1bb : yellow oil; H-NMR (CD3OD) : 1.06 (s, 12H, CH3) ; 2.90-3.15 (m, 8H, CH2N) ppm ; C-NMR :
22.5 ((CH3)2C) ; 24.0 ((CH3)2Ccyc) ; 28.0 ((CH3)2Ccyc) ; 35.9 (C(CH3)2) ; 48.0 (CH2Ncyc) ; 49.4
(CH2NH2) ; 50.8 (CH2NH) ; 154.3 (C=N) ppm ; MS-ES+ : [M+H]+ : 213 ; [M+2H]++/2 : 107 ; Anal.
Calcd for C15H26N4O4F6: C, 40.91; H, 5.91; N, 12.73. Found: C, 40.75; H, 5.80; N, 12.70.
1hc : brown oil; 1H-NMR (CD3OD) : 0.88 (t, 3H, CH3, J=5.1 Hz) ; 1.18 (m, 16H, CH3(CH2)8) ; 1.60 (m,
2H, CH2-CH) ; 1.92 (m, 1H, CH) ; 2.66 (m, 2H, CH2-C6H5) ; 2.92-3.64 (m, 11H, CH2N, CH2O, CH-O) ;
13
7.13 (m, 5H, C6H5) ppm ; C-NMR : 14.1 (CH3) ; 22.6 (CH3CH2) ; 26.0 ; 29.6 ; 31.1 ((CH2)7CH2O) ;
29.4 (CH) ; 31.9 (CH2-CH) ; 32.4 (CH2-C6H5) ; 41.6 (CH2Ncyc) ; 45.1 (CH2NH2) ; 53.5 (CH2NH) ; 70.3
(CH2O) ; 73.8 (CH-O) ; 126.0 (p-C6H5) ; 127.9 (o-C6H5) ; 128.3 (m-C6H5) ; 141.0 (C) ; 154.6 (C=N)
ppm ; MS-ES+ : [M+H]+ : 417 ; [M+2H]++/2 : 209 ; Anal. Calcd for C29H46N4O5F6: C, 54.04; H, 7.14; N,
8.70. Found: C, 53.82; H, 7.10; N, 8.67.
ACKNOWLEDGEMENT
This work was supported by the Ministère de l’enseignement supérieur et de la recherche (aide DPST
n°5) and the Commission of the European Communities (INCO-DC, PL-950529).
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