Efficient one-pot synthesis of 1-alkoxy-2-arylaminoimidazolines from N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides and arylisothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2008.05.098

A new synthetic approach towards 1-alkoxy-2-aminoimidazolines that uses N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides as nucleophile reagents for the reaction with isothiocyanates is reported. Hence, the synthesis of 1-alkoxy-2-aminoimidazolines was performed in high yield with a one-pot procedure involving thiourea formation, nosyl group removal and spontaneous cyclization (42-77% overall yield).

Full text of DOI:10.1016/j.tetlet.2008.05.098

Tetrahedron Letters 49 (2008) 4571–4574
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient one-pot synthesis of 1-alkoxy-2-arylaminoimidazolines
from N-alkoxy-N-(2-aminoethyl)-2-nitrobenzenesulfonamides
and arylisothiocyanates
*
Ainhoa Mascaraque , Lidia Nieto , Christophe Dardonville
Instituto de Química Médica, CSIC, Juan de la Cierva 3, E–28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic approach towards 1-alkoxy-2-aminoimidazolines that uses N-alkoxy-N-(2-aminoethyl)-
2-nitrobenzenesulfonamides as nucleophile reagents for the reaction with isothiocyanates is reported.
Hence, the synthesis of 1-alkoxy-2-aminoimidazolines was performed in high yield with a one-pot
procedure involving thiourea formation, nosyl group removal and spontaneous cyclization (42–77%
overall yield).
Received 8 May 2008
Accepted 21 May 2008
Available online 27 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ester groups, affording less basic molecules that are not protonated
at physiological pH, has been successfully applied to antimicrobi-
Our continuous effort in the search of new antitrypanosomal
agents potentially useful against Trypanosoma brucei rhodesiense,1–3
the protozoan parasite responsible for the acute form of sleeping
sickness in sub-saharian Africa, led us to envisage the synthesis of
compounds bearing 1-alkoxy-2-aminoimidazolyl groups as poten-
tial prodrugs for the 2-aminoimidazoline cation. We previously
showed that the ip administration of a bis(2-aminoimidazoline)
derivative was able to cure two models of acute infection in mice
that is, T. b. brucei STIB 795 and T. b. rhodesiense STIB900).3 However,
our lead compound (X = NH, Chart 1) could not cure the late stage
disease (i.e., with CNS involvement) probably due to a poor blood
brain barrier (BBB) penetration caused by its dicationic nature.
In fact, this kind of guanidine compounds has very basic nitro-
gen atoms (pKa = 9.9 for our lead compound)4 that are charged at
physiological pH and as such potentially poorly liposoluble, lead-
ing to poor diffusion across the BBB.
als. In particular, the amidoxime prodrug strategy developed by
Clement 5 and used by the group of Boykin and Tidwell to improve
the oral bioavailability of a series of 2,5-bis(4-amidinophenyl)furan
derivatives is a very promising approach6–9 that proved also useful
for the CNS delivery of the diamidine antitrypanosomal agents
DB844 and DB289.10–12
Encouraged by these data, we considered the preparation of 1-
alkoxy-2-aminoimidazoline derivatives that could work as poten-
tial prodrugs for the 2-aminoimidazoline group. Since our lead
compounds (Chart 1) are easily accessible via their Boc-protected
precursors, obtained by reaction between primary diamines and
N,N0-bis(tert-butoxycarbonyl)imidazoline-2-thione/HgCl2/Et3N,13 we
were especially interested in a methodology using the same
commercially available aromatic amines as starting materials.
However, and contrary to N-hydroxyguanidines,14–16 only a few
procedures for the preparation of 1-hydroxy-2-aminoimidazolines
and their O-alkyl derivatives could be found, mainly in the patent
literature where no yields were reported.17–22
Amongst the existing strategies to improve the pharmacokinet-
ics of cationic compounds such as amidines or guanidines, the sub-
stitution of the basic N-atom with hydroxyl (or alkoxy group) or
H2N
OR
N
N
H
X
R
R
X
2
N
N
N
OR
N
N
H
ð1Þ
N
R
N
R
1
N
H
N
H
3
(X = CCl2, CBr2, C=S )
R = H, Me, n-Pr, Bn
R = H: Antitrypanosomal lead compounds
R = OH, O-alkyl, OBn: target compounds
Chart 1.
2. Results and discussion
* Corresponding author. Tel.: +34 912587490; fax: +34 915644853.
E-mail address: dardonville@iqm.csic.es (C. Dardonville).
Both authors contributed equally to this work.
None of the methods mentioned above resulted convenient for
the preparation of our target compounds due in part to the
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.098

4572
A. Mascaraque et al. / Tetrahedron Letters 49 (2008) 4571–4574
difficulty to get the N-alkoxyethylenediamine precursors (2) easily
and in high yields. For instance, 4a was obtained satisfactorily from
2-bromoethylphthalimide/O-benzylhydroxylamine following the
reported procedure,20 but several attempts to synthesize the corre-
sponding methyl (4b) and ethyl (4c) analogues [RONH2ꢀHCl
(2 equiv)/ DIPEA (2 equiv)/CH3CN, 80 °C, two days] resulted only
in low yields (20%) of the product together with a major dione
by-product (4d and 4e, respectively). This result is probably due
to the unstability of 4b and 4c in the basic reaction medium, result-
ing in the intramolecular nucleophilic attack of the N-alkoxyamine
at the phthalimide carbonyl group.23
its phthalimide precursor 5b–8b and the amino group is deprotec-
ted immediately before use.
NH
O
NO2
NH2
O
O
S
N
S
O
R1O
N
R1O
5d-8d
5c-8c
Phenylisothiocyanate was chosen as a model compound to test
this synthetic approach (Scheme 2). A screening of the reaction
conditions for the condensation of 5c with phenylisothiocyanate
showed that 1.5 equiv of amine 5c were necessary, whereas the
addition of base (DIPEA), heating of the reaction or changing the
solvent (THF, CH3CN, and toluene) did not modify significantly
the yield of the formation of 9. On the contrary, the dropwise
addition of a dilute solution of the isothiocyanate to the amine
was critical to avoid the formation of large amounts of 1,3-
diphenylthiourea by-product.
RO
N
O
O
O
N
N
H
N
RO
HN
N
OR
OH
O
O
4a: R = Bn
4d: R = Me
4e
4b
: R = Me
: R = Et
: R = Et
4c
The fact that this rearrangement was not observed with 4a is
possibly due to steric factors with the bulkier benzyl group. The
use of a base to deprotonate the hydrochloride salt of the alkoxyl-
amine reagent in the reaction medium may also favour the
rearrangement.23
We found that protecting the secondary amine with the 2-nitro-
benzenesulfonamide (Ns) group24,25 was a very convenient way to
avoid the problem of rearrangement of 4a and 4b through intramo-
lecular cyclization. Thus, O-alkyl-N-nosyl hydroxylamines 5a–8a
were prepared easily, in good yields, by sulfonylation (NsCl/
pyridine/CH2Cl2) of hydroxylamines 5, 6, 726 and 8, respectively,
followed by acidic workup and crystallization from acetone/
hexane27 (Scheme 1).
The 2-nitrobenzenesulfonamides 5a–8a were alkylated at room
temperature with 2-bromoethylphthalimide to give high yield of
the corresponding 2-nitrobenzenesulfonamides 5b–8b as colour-
less solids.28 In most cases, the products were obtained in suffi-
cient purity (>95% by HPLC) by water-mediated precipitation
from the reaction mixture.29 The phthalimide protecting group
was removed easily by treatment with an excess of hydrazine
monohydrate in EtOH affording 5c–8c.30 The non-optimized over-
all yield for the three-step synthesis of the N-alkoxy-N-nosyl-2-
aminoethane derivatives was pretty satisfying (ca. 60%).
It should be noted that, upon storage as free base, these primary
amines tend to rearrange to cyclic secondary amines (5d–8d) via
an intramolecular process. This reaction presumably occurs either
by direct intramolecular aromatic nucleophilic substitution of the
nitro group or possibly through Smiles rearrangement followed
by an annulation process with concomitant loss of nitrous acid.31,32
This drawback can be overcome simply if the reagent is stored as
We were pleased to verify that there is no need to isolate the
thiourea intermediate in order to complete this synthetic route. In-
deed, after checking the complete formation of 9 by HPLC–MS, the
crude reaction mixture was treated with PhSH (5 equiv)/K2CO3
(10 equiv)33 following Fukayamas’ protocol.24 In this way, 9 was
converted directly to the 1-methoxy-2-phenylaminoimidazoline
product 11 via formation of the amine intermediate 10 (77% for
three steps). This new protocol was validated with the synthesis
of the target compounds 12–15 (Scheme 3) in moderate to high
yield (4234–74%).35 It should be noted that in this case, that is, syn-
thesis of symmetric bis-imidazolines, the last step required longer
reaction time (ca. three days) in order to complete the cyclization
of the amino-thiourea intermediate. Alternatively, heating the
reaction vessel at 65 °C allowed the cyclization to occur in approx-
imately 4 h.36
H
N
H
N
NCS
5c
S
Ns
DMF, rt
N
9
OMe
PhSH (5 eq.)
K2CO3 (10 eq.)
DMF, rt
OMe
N
H
N
spontaneous
cyclization
H
N
H
N
24h, rt
N
S
HN
11
10
OMe
Not isolated
Scheme 2.
Br
NPht
Ns
N
H
N
NsCl
CH2Cl2
pyr., rt
NR2R3
R1 NH2
R1
Ns
R1
K2CO3
DMF, rt
OR
N
NH
2
5
: R1 = OMe
: R1 = OEt
NH
1)
5a (75%)
5b
6b
(92%)
(95%)
5c (97%)
6c (81%)
7c (84%)
8c (76%)
6
6a
7a
8a
(76%)
(77%)
(73%)
5c 8c
-
(2.5 equiv), DMF, rt
7: R1 = OTHP
8: R1 = OBn
7b (98%)
8b (97%)
2 = R3 = Pht R2 = R3 = H
N
2) PhSH (10 equiv), K2CO3 (20 equiv)
N
H
SCN
2
3 steps in one pot
R
12: R = Bn (74%)
13: R = Me (48%)
14: R = Et (42%)
NH2NH2
EtOH, rt
15
: R= THP (56%)
Scheme 1.
Scheme 3.

A. Mascaraque et al. / Tetrahedron Letters 49 (2008) 4571–4574
4573
Compound 7b: colourless solid (98%); mp 122.1–123.9 °C; dH (300 MHz;
CDCl3) 8.05 (1H, dd, J 1.3 and 7.7 Hz), 7.86–7.83 (2H, m), 7.77–7.69 (4H, m),
7.58 (1H, dd, J 1.3 and 7.7), 5.1 (1H, m), 4.20–3.65 (4H, m), 3.45 (1H, m, 1/2
AA0BB0), 3.25 (1H, m, 1/2 AA0BB0), 1.9–1.3 (6H m); dC (75 MHz; CDCl3) 168.1
(2 ꢁ CO), 149.4 (C–NO2), 134.8 (CH), 133.9 (CH), 132.3 (CH), 132.1 (CH), 127.3
(C–SO2), 123.9 (CH), 123.2 (CH), 106.1 (OCH), 63.8 (OCH2), 51.4 (NCH2), 36.0
(NCH2), 28.8 (CH2), 24.8 (CH2), 19.7 (CH2); m/z 476.34 (M+H); found: C, 51.90;
H, 4.32; N, 9.06; S, 6.84. C21H21N3O8Sꢀ0.5 H2O requires C, 52.06; H, 4.58; N,
8.67; S, 6.62. Compound 8b: colourless solid (97%); mp 118.5–119.8 °C; two
conformers were observed by 1H and 13C NMR in CDCl3 and DMSO-d6: dH
(300 MHz; CDCl3) 8.01 (1H, dd, J 1.5 and7.9 Hz), 7.89–7.83 (2H, m), 7.78–7.72
(3H, m), 7.65 (1H, td, J 1.1 and 7.9), 7.57–7.53 (3H, m), 7.43 (3H, m), 5.23 (2H,
s), 4.11 (0.1H, t, J 6.8, conformer A, minor), 3.86 (0.9H, br t, J 5.3, conformer B,
major), 3.62 (0.1H, t, J 6.8, conformer A), 3.47 (0.9H, br, conformer B); dC
(75 MHz; CDCl3) 168.0 (CO), 149.8 (C–NO2), 134.96 (C), 134.7 (CH), 134.1 (CH),
132.5 (CH), 131.9 (C), 131.1 (CH), 129.9 (CH), 128.9 (CH), 128.6 (CH), 125.6 (C),
123.8 (CH), 123.4 (CH), 80.5 (OCH2), 51.3 (CH2, conformer B), 39.1 (CH2,
conformer A), 35.1 (CH2, conformer B), 28.0 (CH2, conformer A); m/z 482.28
(M+H); found: C, 57.08; H, 4.06; N, 8.71; S, 6.47. C23H19N3O7S requires C, 57.37;
H, 3.98; N, 8.73; S, 6.66.
In summary, we have reported a new methodology that is very
convenient for the synthesis of 1-alkoxy-2-aminoimidazoline
derivatives starting from N-alkoxy-N-(2-aminoethyl)-2-nitroben-
zenesulfonamides that are easily obtained in high yield in three
steps from commercial hydroxylamines. This method proved prac-
tical for the one-pot synthesis of mono- and bis(1-alkoxy-2-aryl-
amino)imidazolines in good yield (42–77% total yield from the
starting isothiocyanate).
Acknowledgements
This work was supported by the ‘Proyecto Intramural Especial’
Grant 200680I121 from the CSIC (LN and AM) and the ‘Programa
Nacional de Biomedicina’ Grant SAF2006–04698 from the Spanish
‘Ministerio de Educación y Ciencia’.
29. In some experiments, a minor by-product (Scheme 1, 5b–8b: R1 = H) resulting
from the cleavage of the alkoxyl group was observed. H.-G. H. Pablo Wessig,
Liebigs Ann. Chem., 1991, 1991, 983–986.
References and notes
30. Procedure for the deprotection of the Pht group: Excess (10 equiv) hydrazine
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monohydrate (25% in H2O) was added to
a stirred suspension of the
phthalimide derivative (1.4 mmol) in EtOH (5 mL). The reaction mixture,
which became clear after ca. 20 min, was stirred at room temperature
overnight. The precipitate was filtered off and rinsed with EtOH. The filtrate
was concentrated to dryness and the resulting solid was taken up in CH2Cl2.
The unsoluble white flocculent solid (2,3-dihydrophthalazine-1,4-dione) was
filtered off and the filtrate evaporated under vacuum to afford the crude amine
as a yellowish oil that solidified on standing. The amine was dried under
vacuum and used directly in the reaction with isothiocyanates in order to avoid
the formation of the cyclic dione by-product upon standing. Compound 5c:
yellowish oil (97%); dH (300 MHz, CDCl3) 8.03 (1H, dd, J 1.5 and 7.9 Hz, Ar, o-
NO2), 7.79 (1H, td, J 1.5 and 7.9, Ar, p-NO2), 7.71 (1H, td, J 1.5 and 7.9, Ar, p-SO2),
7.57 (1H, dd, J 1.5 and 7.9, Ar, o-SO2), 3.87 (3H, s, OCH3), 3.14 (2H, t, J 5.6, NCH2),
2.95 (2H, t, J 5.6, CH2NH2), 1.60 (2H, br, NH2); dC (75 MHz, CDCl3) 149.8 (C–
NO2), 134.9 (CH, p-NO2), 132.4 (CH, o-NO2), 130.9 (CH, p-SO2), 125.7 (C–SO2),
123.6 (CH, o-SO2), 65.6 (CH3), 56.3 (NCH2), 39.1 (CH2NH2); m/z 276.19 (M+H,
100%). Compound 6c: yellowish oil (81%); dH (300 MHz; CDCl3) 8.04 (1H, dd, J
1.1 and 7.9 Hz, Ar), 7.77 (1H, ddd, J 1.5, 7.9 and 7.5, Ar), 7.72 (1H, ddd, J 1.5, 7.9
and 7.5, Ar), 7.57 (1H, dd, J 1.1 and 7.9, Ar), 4.15 (2H, t, J 7.2, OCH2), 4.10 (2H, m,
NCH2), 3.2 (2H, br, NH2), 2.93 (2H, t, J 5.7, CH2NH2), 1.23 (3H, t, J 7.2, CH3); dC
(75 MH; CDCl3) 149.8, 146.6, 134.9, 132.5, 130.9, 123.7, 73.9, 56.5, 39.2, 13.5;
m/z (ES+) 290.2 (M+H, 100%). Compound 7c: yellowish oil (84%); dH (300 MHz,
CDCl3) 8.02 (1H, dd, J 1.3 and 7.7 Hz, Ar), 7.79 (1H, td, J 1.3 and 7.7, Ar), 7.71
(1H, td, J 1.3 and 7.7, Ar), 7.58 (1H, dd, J 1.3 and 7.7, Ar), 5.29 (2H, s, NH2), 5.16–
5.13 (1H, br s, OCH), 3.93 (1H, 1/2 AA0BB0), 3.64–3.46 (2H, m), 3.1–3.0 (1H, m),
2.88–2.79 (2H, m), 1.91–1.53 (6H, m); dC (75 MHz, CDCl3) 150.0 (C–NO2), 135.4
(CH, p-NO2), 132.9 (CH, o-NO2), 131.4 (CH, p-SO2), 126.8 (C–SO2), 124.2 (CH, o-
SO2), 106.0 (OCH), 65.1 (OCH2), 57.0 (NCH2), 39.2 (CH2NH2), 29.3 (OCHCH2),
25.4 (OCH2CH2), 20.8 (CH2CH2CH2); m/z 346.11 (M+H, 100%). Compound 8c:
yellowish oil (76%); dH (300 MHz, CDCl3) 8.03 (1H, d, J 7.8 Hz), 7.76 (1H, dd, J
1.9 and 7.8), 7.66 (1H, t, J 7.8), 7.60–7.51 (1H, m), 7.46–7.38 (5H, m), 5.09 (2H,
s), 3.15 (2H, br m), 2.75 (2H, t, J 5.9), 1.48 (2H, br, NH2); dC (125 MHz, CDCl3)
149.8 (C–NO2), 134.9 (C, Ar), 134.6 (C–SO2), 132.6 (CH, Ar, p-NO2), 130.9 (CH,
Ar, o-NO2), 130.1 (CH, Ar, p-SO2), 129.2 (CH, Ar), 128.7 (CH, Ar), 123.7 (CH, Ar, o-
SO2), 80.1 (OCH2), 56.6 (NCH2), 39.0 (CH2NH2); m/z 352.31 (M+H, 100%).
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35. General method for the one-pot synthesis of 1-alkoxy-2-arylaminoimidazolines: A
solution of phenylisothiocyanate (0.4 mmol, 1 equiv) in dry DMF (2 mL) was
27. Reddy, P. A.; Schall, O. F.; Wheatley, J. R.; Rosik, L. O.; McClurg, J. P.; Marshall, G.
R.; Slomczynska, U. Synthesis 2001, 1086–1092.
added dropwise to
a stirred solution of amine (1.25 equiv/0.5 mmol, or
2.5 equiv/1 mmol for the reaction with diamines) in dry DMF (5 mL) under
an argon atmosphere. The resulting solution was stirred at room temperature
until the starting material was consumed. Formation of the thiourea
intermediate was checked by TLC and HPLC–MS. The deprotection–
cyclization step was carried out by adding successively PhSH (5 equiv/nosyl
group) and K2CO3 (10 equiv/nosyl group) to the crude reaction. The resulting
mixture was stirred at room temperature (typically 36 h) checking the total
disappearance of the starting material and the cyclization of the thiourea
intermediate to the 1-alkoxy-2-imidazoline product by HPLC. In some cases,
the cyclization step required mild heating (65 °C) during a few hours to go to
completion. The solvent was removed in vacuo and the crude residue was
dissolved in CH2Cl2 and washed successively with saturated NaHCO3 solution
(2ꢁ) and brine. The organic extracts were dried (MgSO4) and evaporated in
vacuo. The crude product was purified by silica chromatography with CH2Cl2/
MeOH–NH3satd Compound 12: brownish amorphous solid (148 mg, 74%);
mp > 93 °C; dH (300 MHz, CDCl3) 7.47–7.30 (10H, m, Ar), 7.09 (4H, d, J 8.5 Hz,
Ar), 6.92 (4H, d, J 8.5, Ar), 6.57 (1H, s, NH), 5.29 (2H, br s, NH), 4.94 (4H, s,
OCH2), 3.45 (4H, br t, J 7.2), 3.25 (4H, br t, J 7.2); dC (75 MHz, CDCl3) 159.5
28. General procedure for the synthesis of 5b–8b: K2CO3 (709 mg, 5.1 mmol, 2 equiv)
was added to a stirred solution of sulfonamide 5a–8a27 (2.57 mmol, 1 equiv)
and 2-bromoethylphthalimide (718 mg, 2.8 mmol, 1.1 equiv) in dry DMF
(4 mL). The reaction mixture was stirred 24 h at room temperature and
diluted with water (45 mL). The precipitate was collected by filtration, rinsed
thoroughly with water and dried under high vacuum, affording the 5b–8b as
colourless solids. Compound 5b: colourless solid (92%); mp 175.1–176.7 °C; dH
(300 MHz; CDCl3) 8.0 (1H, dd, J 1.5 and 7.5 Hz), 7.89–7.68 (6H, m), 7.56 (1H, dd,
J 1.1 and 7.9), 3.99 (3H, s), 3.93 (2H, t, J 5.6), 3.42 (2H, br); dC (75 MHz; CDCl3)
168.0, 149.9, 135.1, 134.2, 132.3, 131.9, 130.9, 125.6, 123.8, 123.5, 65.8, 51.1,
35.2; m/z 406.21 (M+H, 100%); found: C, 50.54; H, 3.80; N, 10.27; S, 8.02.
C
17H15N3O7S requires C, 50.37; H, 3.73; N, 10.37; S, 7.91. Compound 6b:
colourless solid (95%); mp 141.5–142.1 °C; dH (300 MHz; CDCl3) 8.02 (1H, dd, J
1.5 and 7.5 Hz), 7.87–7.83 (2H, m), 7.78–7.71 (4H, m), 7.57 (1H, dd, 1.5 and
7.9), 4.26 (2H, q, J 7.2), 3.93 (2H, t, J 5.6), 3.46 (2H, br s), 1.28 (3H, t, J 7.2); dC
(75 MHz; CDCl3) 168.1, 149.8, 134.9, 134.1, 132.5, 131.9, 131.0, 125.8, 123.9,
123.5, 74.2, 51.1, 35.4, 13.6; m/z 420.3 (M+H); found: C, 51.84; H, 4.31; N,
10.27; S, 7.86. C18H17N3O7S requires C, 51.55; H, 4.09; N, 10.02; S, 7.65.

4574
A. Mascaraque et al. / Tetrahedron Letters 49 (2008) 4571–4574
(C@N), 140.3 (C), 136.3 (C), 129.6 (CH), 128.8 (CH), 128.7 (CH), 122.3 (CH), 118.2
(CH), 70.4 (CH2), 52.0 (CH2), 44.5 (br, CH2), 13.8 (CH3); m/z 424 (M+H); HPLC:
97%. Compound 15: brownish amorphous solid (47 mg, 56%); mp >80 °C; dH
(300 MHz, CDCl3) 7.33 (4H, d, J 8.7 Hz, Ar), 6.94 (4H, d, J 8.7, Ar), 5.55 (1H, br s,
NH), 5.28 (2H, s, NH), 4.86 (2H, br m, OCH), 4.13 (2H, m, OCH2), 3.75–3.55 (8H,
m, NCH2CH2N + OCH2), 3.30 (2H, d, J 8.3, CH2N), 1.89–1.81 (4H, m), 1.57 (8H, br
m); dC (75 MHz, CDCl3) 159.6 (C@N), 138.6 (C), 133.6 (C), 119.8 (CH), 118.4
(CH), 104.6 (OCH), 65.8 (OCH2), 53.9 (NCH2), 49.2 (NCH2), 29.3 (CH2), 24.8 (CH2),
21.4 (CH2); m/z 536.51 (M+H); HPLC: 93%.
(CH), 78.2 (OCH2), 52.7 (NCH2), 45.8 (NCH2); m/z 548.52 (M+H); HPLC: 93%;
found: C, 65.21; H, 6.38; N, 16.21.C32H33N7O2ꢀ2.3 H2O requires C, 65.18; H,
6.44; N, 16.63. Compound 13: brownish amorphous solid (174 mg, 48%); mp
103–105 °C; dH (300 MHz, CD3OD) 7.01 (4H, d, J 8.7 Hz, Ar), 6.88 (4H, d, J 8.7,
Ar), 3.67 (6H, s, OCH3), 3.32 (4H, m), 3.2 (4H, m); dC (75 MHz, CD3OD) 160.4
(C@N), 140.5 (C), 135.3 (C), 122.5 (CH), 117.9 (CH), 62.2 (CH3), 51.1 (CH2), 43.7
(CH2); m/z 396.4 (M+H); HPLC: 98%. Compound 14: brownish solid (83 mg,
42%); mp 78–82 °C; dH (300 MHz, DMSO-d6) 7.99 (1H, br s, NH), 7.34 (4H, d, J
8.7 Hz, Ar), 6.96 (4H, d, J 8.7, Ar), 3.98 (4H, q, J 7), 3.5–3.4 (8H, m), 1.23 (6H, t, J
7); dC (75 MHz, DMSO-d6) 159.1 (C@N), 139.8 (C), 133.0 (C), 122.3 (CH), 117.2
36. In this case, the reaction should be carefully monitored (i.e., avoid high
temperature and prolonged reaction times) to avoid the formation of
dealkylation products.