Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)- dione derivatives of primaquine: Scope and limitations

Article abstract of DOI:10.1016/j.tet.2004.04.077

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α- protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a] isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.

Full text of DOI:10.1016/j.tet.2004.04.077

Tetrahedron 60 (2004) 5551–5562
Synthesis of imidazolidin-4-one and
1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of
primaquine: scope and limitations
a
a
a
a
Paula Gomes,a Maria Joa˜o Araujo, Manuela Rodrigues, Nuno Vale, Zelia Azevedo,
,
*
´
´
c
Jim Iley,b Paula Chambel,c,d Jose Morais and Rui Moreira
d
´
a
´ ˆ ´
Departamento de Quımica da Faculdade de Ciencias do Porto, Centro de Investigac¸a˜o em Quımica da Universidade do Porto,
Rua do Campo Alegre 687, P-4169-007 Porto, Portugal
bDepartment of Chemistry, The Open University, Milton Keynes MK7 6AA, UK
ˆ ˆ ´
Centro de Estudos de Ciencias Farmaceuticas, Faculdade de Farmacia da Universidade de Lisboa, Av. Forc¸as Armadas,
c
P-1649-019 Lisboa, Portugal
UCTF, Faculdade de Farmacia da Universidade de Lisboa, Av. Forc¸as Armadas, P-1649-019 Lisboa, Portugal
d
´
Received 28 February 2004; revised 28 April 2004; accepted 29 April 2004
Abstract—The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target
compounds were synthesized in three steps: (i) condensation of (^)-primaquine with Na-protected amino acids, (ii) removal of the Na-
protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde.
Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to
excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-
a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t1/2 5–30 d) in pH 7.4
buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their
antimalarial activity are quite encouraging.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
malaria caused by Plasmodium vivax and Plasmodium
ovale1 and the gametocytes from all species of parasite
causing human malaria, including chloroquine-resistant
Plasmodium falciparum.2 However, the clinical use of
primaquine is impaired as a result of a rapid metabolic
inactivation to form carboxyprimaquine 2,3–6 and to serious
blood toxicity, particularly the ability to induce oxidation of
oxyhemoglobin to methemoglobin.7 Several peptide and
amino acid derivatives of primaquine, for example, 3, have
been prepared to reduce toxicity of the parent as well as to
reduce the oxidative deamination metabolic pathway
leading to 2.8–11 Despite the improved activity/toxicity
ratio usually displayed by 3, most of these derivatives are
rapidly hydrolysed to primaquine by aminopeptidases and
endopeptidases,11,12 suggesting that they might undergo
extensive hydrolysis to the parent drug in the intestinal
lumen when given orally. Thus, the design of orally
effective and metabolically stable derivatives of the
antimalarial agents 3 is of obvious interest.
Primaquine, 1, is the only currently available drug that is
active against both the latent liver forms of the relapsing
Keywords: Antimalarial; Imidazolidin-4-one; 1H-Imidazo[2,1-a]isoindole-
2,5(3H,9bH)-diones; Malaria; Primaquine; Stereoselectivity.
Abbreviations: AA, amino acid; HAAPQ, amino acid derivative of
primaquine (unprotected); Ala, alanine residue; Boc, tert-butyloxy-
carbonyl (protecting group); BocAAOH, Na-Boc-protected amino acid;
BocAAPQ, Na-Boc-protected amino acid derivative of primaquine; bs,
broad singlet; Bzl, benzyl; CDCl3, deuterated chloroform; d, doublet; dd,
double doublet; dt, double triplet; d, chemical shift (in ppm); DCCI,
N,N0-dicyclohexylcarbodiimide; DCM, dichloromethane; DCU,
N,N0-dicyclohexylurea; DHB, 2,5-dihydroxybenzoic acid; DIEA,
diisopropylethylamine; DIPCDI, N,N0-diisopropylcarbodiimide; DIU,
N,N0-diisopropylurea; Gly, glycine residue; HOBt, N-hydroxy-
benzotriazole; iBu, isobutyl; iPr, isopropyl; Leu, leucine residue; m,
unresolved multiplet; MALDI-TOF, matrix-assisted laser desorption
ionization—time-of-flight; NOE, nuclear Overhauser effect; PES,
potential energy surface; Phe, phenylalanine residue; ppm, parts per
million (NMR chemical shift unit); PQ, primaquine; q, quartet; s, singlet; t,
triplet; TEA, triethylamine; THF, tetrahydrofuran; TLC, thin layer
chromatography; TMS, tetramethylsilane; Val, valine residue.
Replacement of an amide bond with appropriate isosteres is
a commonly used lead-optimization strategy for enhancing
enzymatic stability of a peptide.13 Alternatively, the peptide
drug can be converted into a prodrug or transport form that
*
Corresponding author. Tel.: þ351-226082863; fax: þ351-226082822;
e-mail address: pgomes@fc.up.pt
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.077

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P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
protects the parent peptide against proteolytic degradation at
the mucosal absorption barrier or in the blood.14 Such a
prodrug must be capable of reverting to the parent peptide
drug following oral absorption via an unspecific plasma
enzyme-catalysed reaction or a non-enzymatic pathway.
Imidazolidin-4-one, 4, formation was introduced as a
useful prodrug approach to protect the N-terminal
amino acid residue of di-, tri- and pentapeptides against
Scheme 1.
Scheme 2. (i) DCCI, HOBt, BocAAOH; (ii) (1) TFA, (2) Na2CO3; (iii) Me2CO or C5, C6 or C7 cyclic ketones or 3,4-(MeO)2–C6H3CHO in refluxing MeOH,
TEA, molecular sieves.

P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
5553
aminopeptidase-catalysed hydrolysis (Scheme 1).15–18 The
synthetic approaches for the preparation of imidazolidin-4-
ones involve the reaction of the peptide with an aldehyde or
ketone followed by intramolecular cyclization. This reac-
tion is catalysed by acids19 or bases20 although no catalyst is
needed with acetone.21 Usually, peptide imidazolidin-4-one
derivatives, 4, were quantitatively hydrolysed to the parent
peptide in physiological conditions (pH 7.4 buffer at 37 8C)
with half-lives ranging from in 1 to 30 h, depending on the
N-terminal dipeptide sequence and on the R3, R4 imidazo-
lidinone substituents (Scheme 1).15–18 The same imidazo-
lidin-4-one strategy was used to improve the bioavailability
of ampicillin, a b-lactam that also contains a peptide
backbone.22 The corresponding imidazolidin-4-one,
hetacillin, is also rapidly hydrolysed to ampicillin in
physiological conditions.
(DCCI)24 or diisopropylcarbodiimide (DIPCDI)25 in com-
bination with the auxiliary nucleophile 1-hydroxybenzo-
triazole (HOBt).26 Products 7b–e were isolated as mixtures
of the two possible diastereomers (13C NMR signal
duplications were observed), even though they could not
be distinguished by the chromatographic techniques
employed. The Na-Boc-protected amino acid derivatives
of primaquine, 7a–e, were treated with neat trifluoroacetic
acid (TFA) to remove the Boc-protecting group.27 After
neutralization of the resulting trifluoroacetates with aqueous
sodium carbonate, the deprotected amino acid derivatives of
primaquine (HAAPQ, 3) were extracted with chloroform
and isolated as yellow-orange waxy oils in 83–97% yields.
All HAAPQ derivatives, 3a–e, were characterized by NMR
and MALDI-TOF-MS.
2.2. Reaction of the N-a-aminoacylprimaquine
derivatives with carbonyl compounds
Here we report the synthesis of compounds 5, incorporating
the imidazolidin-4-one scaffold, as potential peptidase-
stable prodrugs of amino acid derivatives of primaquine, 3
(Scheme 2). As the primaquine starting material was a
racemate, the cyclization reactions of 3 with ketones or
aldehydes yielded compounds 5 as the corresponding dia-
stereomeric mixtures. Reaction of 3 with 2-formylbenzoic
acid leads to 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-
dione production, 6, via a diastereoselective cyclization
(Scheme 3).
The HAAPQ intermediates, 3a–e, reacted with acetone,
cyclopentanone, cyclohexanone and cycloheptanone, by
refluxing both reactants in methanol in the presence of
˚
triethylamine (TEA), 4 A molecular sieves and an excess of
the ketone, to form the expected imidazolidin-4-ones, 5, in
good yields (44–81%). When the reaction of 3 with ketones
˚
was carried out without TEA or 4 A molecular sieves (or
both) only small amounts of condensation products 5 were
isolated. The imidazolidin-4-ones 5, containing a chiral
amino acid residue (e.g., 5b–e, derived from Ala, Val, Leu
and Phe, respectively) were isolated as mixtures of two
co-eluting diastereomers, as detected by the duplication of
some 13C NMR signals. For example, compound 5c derived
from HValPQ, 3c, and acetone presented two signals for the
following reso0nances: C-2, C-5 and C-6 in the quinoline
ring; C-10, C-2 , C-30 and C-40 in the amine side-chain; C-2
and C-4 in the imidazolidin-4-one ring.
2. Results and discussion
2.1. Synthesis of N-a-aminoacylprimaquine derivatives
The target imidazolidin-4-ones 5 were synthesised via the
corresponding amino acid derivatives 3 (Scheme 2). The
Boc-protected amino acid intermediates 7 were prepared
using standard peptide coupling methods23 that involved
Na-Boc protected amino acid (BocAAOH) coupling to (^)-
primaquine (PQ), using either dicyclohexylcarbodiimide
All HAAPQ derivatives, 3, were also reacted with
formaldehyde and ethyl glyoxylate, but, unfortunately,
Scheme 3. (i) 2-CHO–C6H4CO2H in refluxing MeOH, TEA, molecular sieves.

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P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
only untractable mixtures were obtained. In constrast,
reaction of compounds 3b–e with veratraldehyde (3,4-
dimethoxybenzaldehyde) as described above, afforded the
corresponding imidazolidin-4-ones 5u–x with global
yields of 57–94%. The imidazolidin-4-one derived
from HGlyPQ, 3a, was probably formed, since the correct
molecular weight was detected by MALDI-TOF-MS
analysis of the crude mixture. However, this compound
was too unstable to be satisfactorily isolated and character-
ized by NMR.
Figure 1. NOE effect of the cis-isomer of 6c as observed in CDCl3 at
300 K.
The cyclization of 3b–e with aldehydes generates a new
chiral centre, so four imidazolidin-4-one diastereomeric
pairs are to be expected. In fact, TLC monitoring could
distinguish one to four spots in the reaction of veratralde-
hyde with compounds 3b–e. The closeness between the Rf
values for the different diastereomers was obviously high,
depending on the amino acid involved. Best chromato-
graphic resolution was found for the Phe-derived product 5x
(all four spots, though close, could be distinguished),
whereas for the Leu-derived compound 5y a single fraction
was obtained. Interestingly, the 1H NMR spectra of 5y
presented four well-resolved and equally intense signals at
5.12, 5.20, 5.25 and 5.31 ppm, corresponding to the
imidazolidinone NCHN resonance, suggesting that equal
amounts of all four diastereomers were formed. In contrast,
it was possible to isolate two pure diastereomers of 5x, each
one presenting a singlet at ca. 5.1 ppm, corresponding to the
imidazolidinone NCHN resonance, and three singlets at
3.7–3.9 ppm, corresponding to each of the CH3O reson-
ances. In addition, a 1:1 mixture of the other two
diastereomers of 5x was also isolated, as indicated by the
two equally intense singlets at ca. 5.0 ppm and six singlets
in the 3.7–3.9 ppm region. The compounds derived from
alanine, 5v, and valine, 5w, had an intermediate behaviour:
two fractions could be isolated in both cases, each of which
corresponded to different combinations of the four
diastereomers.
spectra of 6b–e presented duplication for, among others: the
C-5 and C-7 quinoline carbons; the C-10, C-20, C-30 and C-40
amine side-chain carbons; and the C-2, C-3 and C-5 atoms
of the 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione
system.
In order to determine the absolute configuration of the new
chiral center in 6b–e we carried out NOE experiments. For
compound 6c, irradiation of C9b–H of each diastereomer
led to a clear positive NOE-effect for the C3–H (Fig. 1) and
for one of the methyls in the isopropyl side chain. In
contrast, no significant effect was observed for hydrogen
(CH3)2CH in the same group upon irradiation of C9b–H.
Similar results were obtained for 6b and 6d: irradiation of
C9b–H of each 6b diastereomer caused a positive NOE for
the C3–H and had no effect on the hydrogen atoms of the
CH3; irradiation of the C9b proton in compound 6d caused
positive NOEs on C3–H and (CH3)2CHCH2, but no effect
The reactions of compounds 3a–e with 2-formylbenzoic
acid afforded the corresponding 1H-imidazo[2,1-a]iso-
indole-2,5(3H,9bH)-diones, 6a–e in good yields
(44–60%). Mass spectrometric analysis of crude 6e
exhibited a signal at m/z¼538.6 corresponding to the
imidazolidin-4-one intermediate that is formed prior to the
cyclization that leads to the formation of the isoindole ring.
The structural assignment of compounds 6 is based on
spectroscopic data. For the glycine derivative 6a, two
diastereomeric pairs of enantiomers were to be expected,
and it was indeed possible to separately isolate two fractions
from the reaction of 3a and 2-formylbenzoic acid. A
characteristic feature of the 1H NMR spectrum of each
enantiomeric pair of 6a is the resonance of the NCHN
group, which appears as a singlet at 5.6–5.8 ppm. More-
over, the glycine CH2 signal appears as two doublets with
typical geminal coupling constants (2J¼11.7 Hz), reflecting
the diastereotopic nature of the methylene protons. In
contrast, compounds 6b–e were formed as mixtures of non-
Figure 2. AM1-optimised structure of the imine intermediate formed from
2-formylbenzoic acid and the N-acylprimaquine 3b. Small spheres¼H;
black spheres¼O; dark grey spheres¼N; light grey spheres¼C; dotted lines
show intramolecular hydrogen bonds and their lengths are also displayed;
black arrow depicts the favoured orientation for ring closure leading to a
final 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione structure with C3-H
and C9b-H atoms in cis-orientation (see text).
isolable diastereomers. However, the following 1H and 13
C
NMR data suggest the formation of only two diastereomers
in each case, even though a total of four was anticipated.
First, the resonance of the NCHN proton (H9b) appears as
two 1:1 singlets at 5.7–5.9 ppm. Second, the 13C NMR

P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
5555
on (CH3)2CHCH2. These findings suggest that the C3–H
and C9b–H have a cis orientation. This contrasts with results
obtained by Katritzky and co-workers, who found that
stereoselective syntheses of 1H-imidazo[2,1-a]isoindole-
2,5(3H,9bH)-diones led to the trans-orientation of C3–H
and C9b–H.28 The cause of such difference is not clear. The
reaction path leading to 1H-imidazo[2,1-a]isoindole-
2,5(3H,9bH)-diones is essentially the same as for imidazo-
lidin-4-ones, that is, imine formation followed by
intramolecular cyclization to the imidazolidinone structure,
including an additional step for the intramolecular amide
bond formation that generates the final pyrrolidinone
structure. A possible explanation is that the o-carboxyl
substituent in 2-formylbenzoic acid could establish a
hydrogen bond with the amide group, yielding a rigid
conformation that would constrain the stereochemistry of
the subsequent intramolecular cyclization step. The lack of
any such constraint in veratraldehyde would explain its
different behaviour. To evaluate the validity of this
hypothesis, we have performed semi-empirical calculations
at the AM1 level29 to optimise the geometry of the imine
intermediate formed upon reaction with 2-formylbenzoic
acid. The simplest chiral amino acid, alanine, was
considered, and the calculations yielded the optimised
structure depicted in Figure 2. This structure clearly shows
three intramolecular hydrogen bonds that stabilize the
folding of the imine and favours a stereo-controlled
cyclization. This leads to a final 1H-imidazo[2,1-a]iso-
indole-2,5(3H,9bH)-dione structure where atoms C3–H and
C9b–H are cis-oriented, which is in agreement with the
NOE experiments. A final confirmation of this rationale
could be given by X-ray diffraction experiments. Unfortu-
nately, compounds 6 are all oils and all attempts to obtain
crystals have been unsuccessful.
hydrolysed 60 times slower than the Leu-enkephalin
derivative 8.17 The rates of hydrolysis of 5 are largely
affected by the substituents at C-2 of the imidazolidin-4-one
moiety, with those derived from cyclopentanone, 5h and 5j,
being significantly more reactive than those derived from
acetone or cyclohexanone. Unfortunately, derivatives 5
derived from cycloheptanone displayed very low aqueous
solubility precluding their study in the pH 7.4 phosphate
buffer. The results presented herein indicate that imidazo-
lidin-4-ones 5 will likewise hydrolyse slowly in vivo and
thus can be considered as slow-release systems of the amino
acid derivatives of primaquine.
3. Conclusion
In summary, amino acid derivatives, 3, of primaquine can be
converted to the corresponding imidazolidin-4-ones 5 in
good yields by reaction with both cyclic and acyclic ketones
and aromatic aldehydes. Cyclization of 3 with an unsym-
metrical carbonyl (veratraldehyde) yields mixtures of all
four possible stereomers. However, when cyclization was
carried out with an o-carboxylated aldehyde, diastereo-
selectivity was encountered, since only two out of four
possible stereomers of the corresponding 1H-imidazo[2,1-
a]isoindole-2,5(3H,9bH)-diones 6 were formed. The low
rates of hydrolysis of imidazolidin-4-ones 5 in physiological
conditions suggest that they may be useful as slow-release
forms of the parent amino acid derivatives 3.
2.3. In vitro assessment of imidazolidin-4-ones 5 as
potential prodrugs
The reactivity of several imidazolidin-4-ones 5 derived
from ketones in pH 7.4 phosphate buffer at 37 8C was
assessed by HPLC. Quite surprisingly, compounds 5
hydrolyse very slowly, though quantitatively, to the
corresponding amino acid derivative 3 (Table 1). This
behaviour contrasts with the rapid hydrolysis of their
counterparts 4 derived from a dipeptide framework. For
example the 2,2-dimethylimidazolidin-4-one 5a, derived
from HGlyPQ, 3a, is hydrolysed ca. 100 times slower than
their counterparts 4 derived from Gly-Phe or Gly-Tyr.16 The
same trend is observed when comparing derivatives 5 with
imidazolidin-4-ones derived from higher peptides. For
example, compound 5e derived from HPhePQ, 3e, is
4. Experimental
4.1. General details
Na-Protected amino acids were purchased from
NovaBiochem (Switzerland). Solvents were of p.a. quality
and bought from Merck (Germany). Both thin layer
chromatography (TLC) aluminium foil plates covered
with silica 60 F254 (0.25 mm) and silica-gel 60 (70–230
mesh ASTM) for preparative column chromatography were
also purchased from Merck. When required, solvents were
Table 1. Rate of hydrolysis of imidazolidin-4-ones 5 in pH 7.4 phosphate
buffer at 37 8C
˚
previously dried with pre-activated molecular sieves (4 A)
(Merck). Other chemicals were obtained from Sigma-
Aldrich.
Compound
t1/2 (d)
5a
5c
5e
5h
5j
9.8
12
31
8.8
6.4
12
NMR spectra of compounds dissolved in deuterated
chloroform (CDCl3), containing tetramethylsilane (TMS)
as internal reference, were acquired on a Bruker AMX-300
spectrometer. Mass spectrometry (MS) was performed by
the matrix-assisted laser desorption ionization—time-of-
flight (MALDI-TOF) technique on an Applied Biosystems
5l
5m
26

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P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
Voyager STR-DE spectrometer, using either anthracene or
2,5-dihydroxibenzoic acid (DHB) as adjuvant matrices.
(7c). dH (CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.05,
1.35 Hz); 7.90 (dd, 1H, J¼8.25, 1.35 Hz); 7.28 (dd, 1H,
J¼7.25, 4.95 Hz); 6.53 (m, 1H); 6.33 (d, 1H, J¼2.10 Hz);
6.27 (d, 1H, J¼2.10 Hz), 5.99 (d, 1H, J¼7.20 Hz); 5.30
(dd, 1H, J¼8.25, 2.00 Hz); 3.92 (m, 1H); 3.87 (s, 3H);
3.59 (m, 1H); 3.25 (m, 2H); 2.05 (m, 1H); 1.63 (m, 4H);
1.39 (s, 9H); 1.27 (d, 3H, J¼6.00 Hz); 0.93 (d, 3H,
J¼6.90 Hz); 0.90 (d, 3H, J¼6.90 Hz). dC (CDCl3,
300 MHz) 171.7; 159.4; 156.0; 144.9; 144.3; 135.3; 134.8;
129.9; 121.8; 96.8; 91.7; 79.7; 60.0; 55.1; 50.8; 50.7; 47.8;
47.7; 44.4; 39.3; 39.2; 33.9; 33.8; 30.9; 28.3; 26.3; 26.2;
20.5; 19.3; 17.9. m/z (MWmonoisotopic)¼458.1214 (Calcd,
458.29).
4.2. Condensation of PQ with Na-Boc protected amino
acids—synthesis of compounds 7a–e
Compounds 7a–e were prepared by condensation of PQ
with Na-Boc-protected amino acids by the carbodiimide/
1-hydroxybenzotriazole (DCCI or DIPCDI/HOBt) method.
Briefly, primaquine bis[dihydrogenophosphate] (3.3 mmol)
was suspended in dichloromethane (DCM, 30 mL), TEA
(14 mmol) was added and the mixture was stirred in an ice-
water–NaCl bath for 30 min. After addition of the
BocAAOH (3.3 mmol) and HOBt (4.0 mmol), the carbo-
diimide (DCCI or DIPCDI, 4.0 mmol) was slowly added to
the mixture, which was kept at 0 8C for 2 h more. The
reaction was allowed to proceed at room temperature for 2
d, with periodic monitoring by TLC. A second stepwise
addition of carbodiimide (4.0 mmol) was made, and the
reaction prolonged for a further 3 d. The solid phase formed
was removed by suction filtration and identified as the
carbodiimide-derived urea (DCU or DIU). The filtrate was
evaporated to dryness and the residue dissolved in the
minimum amount of warm acetone; the resulting solution
was stored overnight at 4 8C and the urea precipitated was
again removed by suction filtration. The filtrate was
evaporated to dryness and the residue submitted to column
chromatography on silica-gel, using DCM/acetone mixtures
as eluents (in the proportions of 5:1 for compounds 7a–c
and 10:1 for compounds 7d–e). Products 7a–e were
isolated as yellow-orange oils in 78–93% yields and
successfully characterized by high-resolution MS and
NMR, as detailed below.
4.2.4. N-{7-[(6-Methoxyquinolin-8-yl)amino]-3-aza-1-
isobutyl-2-oxooctyl}carbamic acid tert-butyl ester (7d).
dH (CDCl3, 300 MHz) 8.53 (dd, 1H, J¼4.10, 1.70 Hz); 7.92
(dd, 1H, J¼7.50, 1.70 Hz); 7.31 (dd, 1H, J¼7.50, 4.10 Hz);
6.34 (d, 1H, J¼2.00 Hz); 6.31 (m, 1H); 6.27 (d, 1H,
J¼2.00 Hz); 5.99 (d, 1H, J¼8.20 Hz); 4.99 (m, 1H); 4.05
(m, 1H); 3.89 (s, 3H); 3.63 (m, 1H); 3.27 (m, 2H); 2.12 (m,
1H); 1.66 (m, 6H); 1.41 (s, 9H); 1.29 (d, 3H, J¼6.00 Hz);
0.92 (d, 3H, J¼6.90 Hz); 0.90 (d, 3H, J¼6.90 Hz). dC
(CDCl3, 300 MHz) 172.5; 159.3; 156.0; 144.8; 144.3;
135.3; 134.8; 129.9; 121.8; 96.8; 91.6; 80.2; 68.7; 55.2;
49.0; 47.8; 47.7; 33.9; 33.7; 33.6; 30.3; 28.2; 26.2; 26.1;
25.6; 24.9; 24.7; 22.9; 20.5. m/z (MWmonoisotopic)¼472.3163
(Calcd, 472.30).
4.2.5. N-{7-[(6-Methoxyquinolin-8-yl)amino]-3-aza-1-
benzyl-2-oxooctyl}carbamic acid tert-butyl ester (7e).
dH (CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.17, 1.55 Hz); 7.91
(dd, 1H, J¼8.31, 1.59 Hz); 7.32–7.12 (m, 6H); 6.33 (d, 1H,
J¼2.90 Hz); 6.25 (d, 1H, J¼2.90 Hz); 6.03 (m, 1H); 5.58
(m, 1H); 4.27 (m, 1H); 3.87 (s, 3H); 3.52 (m, 1H); 3.17 (m,
2H); 3.15 (d, 2H, J¼6.68 Hz); 1.49 (m, 4H); 1.37 (s, 9H);
1.25 (d, 3H, J¼6.33 Hz). dC (CDCl3, 300 MHz) 173.9;
173.8; 159.3; 156.0; 144.8; 144.1; 136.8; 136.7; 135.2;
134.6; 129.7; 129.5; 128.4; 126.7; 121.7; 96.5; 91.4; 75.9;
58.6; 55.0; 47.8; 47.6; 40.1; 40.0; 36.8; 36.7; 33.9;
33.8; 27.8; 26.2; 26.1; 25.9; 25.8; 20.5. m/z
(MWmonoisotopic)¼506.2019 (Calcd, 506.29).
4.2.1. N-{7-[(6-Methoxyquinolin-8-yl)amino]-3-aza-2-
oxooctyl}carbamic acid tert-butyl ester (7a). dH (CDCl3,
300 MHz) 8.50 (dd, 1H, J¼4.20, 1.47 Hz); 7.90 (dd, 1H,
J¼8.22, 1.65 Hz); 7.28 (dd, 1H, J¼8.22, 4.20 Hz); 6.31 (d,
1H, J¼2.56 Hz); 6.24 (d, 1H, J¼2.56 Hz); 6.17 (m, 1H);
5.97 (m, 1H); 5.16 (m, 1H); 3.87 (s, 3H); 3.72 (d, 2H,
J¼5.88 Hz); 3.61 (m, 1H); 3.28 (m, 2H); 1.57 (m, 4H); 1.40
(s, 9H); 1.27 (d, 3H, J¼6.24 Hz). dC (CDCl3, 300 MHz)
169.3; 159.4; 156.0; 144.9; 144.3; 135.3; 134.8; 129.9;
121.9; 96.8; 91.7; 80.2; 55.2; 50.8; 50.7; 47.8; 44.4; 39.3;
37.5; 34.4; 33.7; 30.9; 28.3; 26.2; 20.5. m/z
(MWmonoisotopic)¼416.2107 (Calcd, 416.24).
4.3. Acidic removal of the Na-Boc protecting group—
synthesis of compounds 3a–e
Compounds 7a–e were dissolved in a small volume of neat
trifluoroacetic acid (TFA, ca. 5 mL) and the deprotection
reactions allowed to proceed for 1–2 h at room temperature.
Excess TFA was neutralized by dropwise addition
of aqueous Na2CO3 at 30% until pH 10; the supernatant
oily phase formed in this process was extracted seven
times with 10-mL portions of chloroform and the organic
phases pooled, dried over anhydrous MgSO4 and
evaporated to dryness. Products 3a–e were thus isolated
as yellow-orange oils in 83–97% yields and successfully
characterized by high-resolution MS and NMR, as detailed
below.
4.2.2. N-{7-[(6-Methoxyquinolin-8-yl)amino]-3-aza-1-
methyl-2-oxooctyl}carbamic acid tert-butyl ester (7b).
dH (CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.22, 1.64 Hz); 7.87
(dd, 1H, J¼8.28, 1.60 Hz); 7.30 (dd, 1H, J¼8.25, 4.23 Hz);
6.47 (m, 1H); 6.33 (d, 1H, J¼2.48 Hz); 6.26 (d, 1H,
J¼2.48 Hz); 5.98 (d, 1H, J¼8.25 Hz); 5.19 (m, 1H); 4.13
(m, 1H); 3.68 (s, 3H); 3.61 (m, 1H); 3.26 (m, 2H); 3.28 (m,
2H); 1.64 (m, 4H); 1.39 (s, 9H); 1.33 (d, 3H, J¼6.46 Hz);
1.27 (d, 3H, J¼6.24 Hz). dC (CDCl3, 300 MHz) 172.6;
159.3; 155.5; 144.8; 144.2; 135.3; 134.8; 129.8; 121.8; 96.7;
91.6; 79.9; 55.1; 50.0; 48.9; 47.7; 39.2; 33.9; 33.6; 28.2;
26.1; 25.6; 24.9; 20.5; 18.5. m/z (MWmonoisotopic)¼430.2658
(Calcd, 430.26).
4.3.1. N-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-
aminoacetamide (3a). dH (CDCl3, 300 MHz) 8.48 (dd,
1H, J¼4.23, 1.65 Hz); 7.87 (dd, 1H, J¼9.51, 1.29 Hz); 7.26
(dd, 1H, J¼9.72, 4.23 Hz); 6.30 (d, 1H, J¼2.56 Hz); 6.24
4.2.3. N-{7-[(6-Methoxyquinolin-8-yl)amino]-3-aza-1-
isopropyl-2-oxooctyl}carbamic acid tert-butyl ester

P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
5557
(d, 1H, J¼2.56 Hz); 5.92 (m, 1H); 3.83 (s, 3H); 3.53 (m,
1H); 3.39 (m, 2H); 3.19 (m, 2H); 1.59 (m, 4H); 1.20 (d, 3H,
J¼6.21 Hz). dC (CDCl3, 300 MHz) 159.4; 144.9;
144.3; 137.4; 135.3; 134.8; 129.9; 121.9; 96.9; 91.7; 78.1;
77.2; 55.2; 48.2; 47.9; 47.8; 43.7; 43.3; 40.2; 39.7; 39.5;
39.2; 39.1; 26.4; 26.3; 26.1; 20.6; 20.5. m/z
(MWmonoisotopic)¼316.1992 (Calcd, 316.19).
(4 mmol) of the appropriate ketone (acetone, cyclopenta-
none, cyclohexanone or cycloheptanone) and TEA
(2 mmol) in dry methanol (10 mL) and the mixture refluxed
˚
for 3 d in the presence of 4 A molecular sieves (1 g). The
reaction was monitored by TLC and ketone was re-added
(2 mmol) once per day. The molecular sieves were removed
by decantation and the solution evaporated to dryness.
The oily residue was submitted to column chromatography
on silica-gel, eluted with DCM/THF (varying solvent
proportions) or, for compound 5a, DCM/ethanol 15:1
(v/v). Fractions containing the chromatographically homo-
geneous product were pooled and evaporated to dryness,
yielding 5a–t as yellow-orange oils (44–81%) that were
analyzed by high-resolution MS and NMR, as detailed
below.
4.3.2. N-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-
aminopropanamide (3b). dH (CDCl3, 300 MHz) 8.53 (dd,
1H, J¼4.20, 1.53 Hz); 7.92 (dd, 1H, J¼8.25, 1.51 Hz); 7.31
(dd, 1H, J¼8.22, 4.20 Hz); 6.34 (d, 1H, J¼2.45 Hz); 6.28
(d, 1H, J¼2.45 Hz); 6.00 (d, 1H, J¼8.29 Hz); 3.89 (s, 3H);
3.63 (m, 1H); 3.46 (m, 1H); 3.27 (m, 2H); 1.80 (m, 2H); 1.63
(m, 4H); 1.31 (d, 3H, J¼6.19 Hz); 1.29 (d, 3H, J¼6.72 Hz).
dC (CDCl3, 300 MHz) 159.4; 144.9; 144.2; 135.3; 134.8;
129.9; 121.9; 96.8; 91.6; 55.2; 50.7; 47.8; 38.9; 33.8; 26.3;
21.7; 20.5. m/z (MWmonoisotopic)¼330.1082 (Calcd, 330.21).
4.4.1. 3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2,2-
dimethylimidazolidin-4-one (5a). dH (CDCl3, 300 MHz)
8.50 (dd, 1H, J¼4.20, 1.80 Hz); 7.89 (dd, 1H, J¼8.40,
1.80 Hz); 7.27 (dd, 1H, J¼8.40, 4.20 Hz); 6.31 (d, 1H,
J¼2.40 Hz); 6.26 (d, 1H, J¼3.00 Hz); 5.99 (d, 1H,
J¼7.80 Hz); 3.86 (s, 3H); 3.62 (m, 1H); 3.40 (s, 2H); 3.16
(m, 2H); 2.05 (m, 1H); 1.69 (m, 4H); 1.27 (m, 9H). dC
(CDCl3, 300 MHz) 173.6; 159.3; 144.9; 144.2; 135.2;
134.7; 129.8; 121.8; 96.7; 91.6; 78.1; 55.1; 48.1; 47.8;
4.3.3. N-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-
amino-3-methylbutanamide (3c). dH (CDCl3, 300 MHz)
8.52 (dd, 1H, J¼3.60, 0.90 Hz); 7.90 (dd, 1H, J¼8.10,
1.20 Hz); 7.28 (dd, 1H, J¼7.50, 5.10 Hz); 6.32 (d, 1H,
J¼1.95 Hz); 6.28 (d, 1H, J¼1.95 Hz), 6.01 (d, 1H,
J¼8.10 Hz); 3.87 (s, 3H); 3.62 (m, 1H); 3.28 (m, 2H);
3.16 (m, 1H); 2.25 (m, 1H); 1.65 (m, 4H); 1.53 (s, 2H); 1.29
(d, 3H, J¼6.60 Hz); 0.95 (d, 3H, J¼7.20 Hz); 0.78 (dd, 3H,
J¼6.90, 2.40 Hz). dC (CDCl3, 300 MHz) 174.3; 159.4;
144.9; 144.3; 135.3; 134.8; 129.9; 121.8; 96.8; 91.7; 77.3;
63.9; 60.1; 55.2; 47.8; 47.7; 38.9; 38.8; 33.9; 33.8; 30.8;
26.4; 26.3; 20.5; 19.7; 16.0. m/z (MWmonoisotopic)¼358.1878
(Calcd, 358.24).
40.1;
33.9;
26.3;
26.2;
26.1;
20.5.
m/z
(MWmonoisotopic)¼356.1004 (Calcd, 356.22).
4.4.2. 3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-
2,2,5-trimethylimidazolidin-4-one (5b). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.23, 1.66 Hz); 7.92 (dd, 1H,
J¼8.28, 1.66 Hz); 7.30 (dd, 1H, J¼8.28, 4.23 Hz); 6.33 (d,
1H, J¼2.50 Hz); 6.28 (d, 1H, J¼2.50 Hz); 6.00 (d, 1H,
J¼7.16 Hz); 3.88 (s, 3H); 3.64 (m, 1H); 3.50 (q, 1H,
J¼6.87 Hz); 3.32 (m, 1H); 3.04 (m, 1H); 1.93 (m, 1H); 1.72
(m, 4H); 1.32 (m, 12H). dC (CDCl3, 300 MHz) 175.6; 159.3;
144.9; 144.2; 135.3; 134.7; 129.8; 121.8; 96.7; 91.6; 75.7;
55.2; 53.6; 47.8; 45.0; 40.3; 33.8; 28.1; 26.2; 25.8; 25.6;
20.5; 17.4. m/z (MWmonoisotopic)¼370.2809 (Calcd, 370.24).
4.3.4. N-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-
(CDCl3,
amino-4-methylpentanamide
(3d).
dH
300 MHz) 8.52 (dd, 1H, J¼4.90, 1.60 Hz); 7.91 (dd, 1H,
J¼6.80, 1.60 Hz); 7.38 (m, 1H); 7.30 (dd, 1H, J¼8.20,
4.90 Hz); 6.33 (d, 1H, J¼2.60 Hz); 6.28 (d, 1H,
J¼2.60 Hz); 6.00 (d, 1H, J¼8.20 Hz); 3.88 (s, 3H); 3.62
(m, 1H); 3.35 (m, 2H); 3.28 (m, 1H); 1.86 (m, 5H); 1.66 (m,
4H); 1.29 (d, 3H, J¼6.33 Hz); 0.93 (d, 3H, J¼6.09 Hz);
0.90 (d, 3H, J¼5.79 Hz). dC (CDCl3, 300 MHz) 172.5;
159.3; 156.0; 144.8; 144.3; 135.3; 134.8; 129.9; 121.8; 96.8;
91.6; 80.2; 68.7; 55.2; 49.0; 47.8; 47.7; 33.9; 33.7; 33.6;
30.3; 28.2; 26.2; 26.1; 25.6; 24.9; 24.7; 22.9; 20.5. m/z
(MWmonoisotopic)¼372.3335 (Calcd, 372.25).
4.4.3. 3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-5-
isopropyl-2,2-dimethylimidazolidin-4-one
(5c).
dH
(CDCl3, 300 MHz) 8.51 (d, 1H, J¼3.60 Hz); 7.90 (d, 1H,
J¼7.80 Hz); 7.29 (dd, 1H, J¼7.80, 3.60 Hz); 6.31 (d, 1H,
J¼2.10 Hz); 6.29 (d, 1H, J¼2.10 Hz), 6.01 (m, 1H); 3.87 (s,
3H); 3.63 (m, 1H); 3.46 (m, 3H); 2.96 (m, 1H); 2.18 (m,
1H); 1.71 (m, 4H); 1.29 (m, 9H); 1.03 (d, 3H, J¼6.90 Hz);
0.91 (d, 3H, J¼6.30 Hz). dC (CDCl3, 300 MHz) 174.2;
166.0; 159.4; 145.5; 145.0; 144.3; 135.4; 134.7; 129.9;
121.8; 96.8; 91.7; 75.7; 65.8; 62.8; 55.2; 48.0; 47.7; 40.2;
40.0; 34.1; 34.0; 30.3; 28.9; 28.3; 26.6; 26.5; 26.2; 26.1;
20.6; 19.3; 16.7; 15.3. m/z (MWmonoisotopic)¼398.2293
(Calcd, 398.27).
4.3.5. N-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-2-
amino-3-phenylacetamide (3e). dH (CDCl3, 300 MHz)
8.53 (dd, 1H, J¼4.22, 1.56 Hz); 7.93 (dd, 1H, J¼8.36,
1.42 Hz); 7.34–7.16 (m, 6H); 6.33 (d, 1H, J¼2.51 Hz); 6.27
(d, 1H, J¼2.51 Hz); 3.88 (s, 3H); 3.57 (m, 2H); 3.28 (m,
2H); 3.21 (m, 1H); 2.66 (dd, 1H, J¼13.7, 9.31 Hz); 1.62 (m,
6H); 1.30 (d, 3H, J¼6.35 Hz). dC (CDCl3, 300 MHz) 174.0;
159.3; 156.0; 144.8; 144.2; 137.8; 135.2; 134.6; 129.8;
129.2; 128.5; 126.7; 121.8; 96.6; 91.5; 56.3; 55.1; 47.7;
4.4.4. 3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-5-
(5d).
isobutyl-2,2-dimethylimidazolidin-4-one
dH
40.9;
38.9;
36.8;
33.7;
26.1;
20.4.
m/z
(CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.20, 2.10 Hz); 7.90
(dd, 1H, J¼8.40, 2.10 Hz); 7.38 (m, 1H); 7.28 (dd, 1H,
J¼8.40, 4.20 Hz); 6.32 (d, 1H, J¼2.40 Hz); 6.29 (d, 1H,
J¼2.40 Hz); 6.10 (d, 1H, J¼6.60 Hz); 3.88 (s, 3H); 3.63 (m,
1H); 3.44 (dd, 1H, J¼9.90, 3.30 Hz); 3.33 (m, 1H); 3.02 (m,
1H); 1.84 (m, 3H); 1.71 (m, 4H); 1.34 (d, 3H, 6.90 Hz), 1.30
(d, 3H, J¼6.30 Hz); 0.96 (d, 3H, J¼6.00 Hz); 0.94 (d, 3H,
(MWmonoisotopic)¼406.2477 (Calcd, 406.24).
4.4. Reaction of 3a–e with symmetrical ketones:
synthesis of imidazolidin-4-ones 5a–t
Compounds 3a–e (2 mmol) were mixed with an excess

5558
P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
J¼6.00 Hz). dC (CDCl3, 300 MHz) 175.7; 165.9; 159.4;
145.0; 144.3; 135.3; 134.7; 129.9; 121.8; 96.7; 91.6; 76.1;
56.3; 55.2; 47.9; 47.8; 41.7; 40.3; 40.2; 33.9; 28.2; 26.2;
26.1; 25.9; 25.3; 23.4; 21.5; 20.6; 20.5. m/z
(MWmonoisotopic)¼412.1843 (Calcd, 412.28).
J¼8.40, 1.50 Hz); 7.29 (dd, 1H, J¼8.40, 4.20 Hz); 6.32 (d,
1H, J¼2.40 Hz); 6.28 (m, 1H); 6.02 (m, 1H); 3.88 (s, 3H);
3.64 (m, 1H); 3.37 (dd, 1H, J¼9.90, 3.90 Hz); 3.32 (m, 1H);
2.93 (m, 1H); 2.00–1.50 (m, 16H); 1.30 (d, 3H, J¼6.30 Hz),
0.94 (m, 6H). dC (CDCl3, 300 MHz) 176.4; 159.6;
145.1; 144.4; 135.4; 134.9; 130.0; 121.9; 96.9; 93.8; 91.8;
86.2; 56.6; 55.3; 48.1; 47.9; 41.4; 40.4; 40.3; 37.7;
35.2; 35.0; 34.1; 34.0; 26.3; 26.2; 25.3; 23.5; 23.4; 23.3;
21.9; 20.8; 20.7. m/z (MWmonoisotopic)¼438.3199 (Calcd,
438.30).
4.4.5. 3-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-5-
benzyl-2,2-dimethylimidazolidin-4-one (5e). dH (CDCl3,
300 MHz) 8.52 (m, 1H); 7.90 (d, 1H, J¼8.18 Hz); 7.22 (m,
6H); 6.32 (d, 1H, J¼2.46 Hz); 6.28 (d, 1H, J¼2.46 Hz);
6.00 (dd, 1H, J¼8.24, 5.66 Hz); 3.87 (s, 3H); 3.75 (t, 1H,
J¼5.39 Hz); 3.61 (m, 1H); 3.33 (m, 1H); 3.07 (d, 2H,
J¼5.24 Hz); 2.94 (m, 1H); 1.63 (m, 5H); 1.28 (dd, 3H,
J¼6.34, 2.12 Hz); 1.20 (d, 3H, J¼2.45 Hz); 1.08 (s, 3H). dC
(CDCl3, 300 MHz) 174.0; 159.4; 156.0; 145.0; 144.3;
136.9; 135.3; 134.7; 129.9; 129.6; 128.5; 126.6; 121.6;
96.7; 91.6; 76.1; 58.8; 55.2; 53.9; 47.9; 47.8; 40.3; 36.9;
34.0; 30.7; 29.3; 28.0; 26.4; 26.3; 26.1; 26.0; 20.6. m/z
(MWmonoisotopic)¼446.3802 (Calcd, 446.27).
4.4.10. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
benzyl-1,4-diazaspiro[4.4]nonan-2-one (5j). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.36, 2.85 Hz); 7.92 (dd, 1H,
J¼8.26, 1.62 Hz); 7.32–7.17 (m, 6H); 6.33 (d, 1H,
J¼2.39 Hz); 6.28 (d, 1H, J¼2.88 Hz); 6.00 (t, 1H,
J¼8.24 Hz); 3.88 (s, 3H); 3.68 (t, 1H, J¼5.28 Hz); 3.61
(m, 1H); 3.36 (m, 1H); 3.12 (dd, 1H, J¼14.3, 5.64 Hz); 3.07
(dd, 1H, J¼14.3, 4.84 Hz); 2.86 (m, 1H); 1.79–1.48 (m,
12H); 1.29 (dd, 3H, J¼6.35, 2.39 Hz). dC (CDCl3,
300 MHz) 174.6; 174.5; 159.4; 159.3; 144.9; 144.2; 144.1;
136.8; 136.7; 135.3; 135.2; 134.7; 129.8; 129.6; 128.5;
126.8; 121.8; 96.6; 96.5; 91.5; 85.9; 77.2; 58.9; 58.8;
55.1; 47.9; 47.6; 40.2; 40.1; 37.3; 36.4; 36.3; 35.1;
34.9; 33.9; 33.8; 30.9; 26.1; 25.9; 20.6.; 20.5 m/z
(MWmonoisotopic)¼472.3531 (Calcd, 472.28).
4.4.6. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-1,4-
diazaspiro[4.4]nonan-2-one (5f). dH (CDCl3, 300 MHz)
8.52 (m, 1H); 7.91 (d, 1H, J¼8.40 Hz); 7.29 (dd, 1H,
J¼7.80, 4.20 Hz); 6.33 (m, 1H); 6.28 (m, 1H); 6.01 (d, 1H,
J¼8.10 Hz); 3.89 (s, 3H); 3.66 (m, 1H); 3.36 (s, 2H); 3.13
(m, 2H); 1.89 (bs, 1H); 1.72 (m, 8H); 1.54 (m, 4H); 1.30 (d,
3H, J¼6.30 Hz). dC (CDCl3, 300 MHz) 174.3; 159.4; 145.0;
144.3; 135.3; 134.8; 129.9; 121.9; 96.7; 91.6; 88.1; 77.3;
76.8; 55.2; 48.3; 47.8; 40.1; 35.5; 35.4; 33.8; 26.2; 23.0;
20.6; 20.7. m/z (MWmonoisotopic)¼382.2637 (Calcd, 382.24).
4.4.11. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-
1,4-diazaspiro[4.5]decan-2-one
(5k).
dH
(CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.20, 1.50 Hz); 7.92 (dd, 1H,
J¼8.10, 2.70 Hz); 7.30 (dd, 1H, J¼8.10, 4.20 Hz); 6.33 (d,
1H, J¼2.70 Hz); 6.29 (d, 1H, J¼2.70 Hz); 6.01 (d, 1H,
J¼8.40 Hz); 3.89 (s, 3H); 3.64 (m, 1H); 3.37 (s, 2H); 3.14
(m, 2H); 1.80 (bs, 1H); 1.74–1.48 (m, 14H); 1.30 (d, 3H,
J¼6.30 Hz). dC (CDCl3, 300 MHz) 173.9; 159.4; 145.0;
144.2; 135.3; 134.7; 129.9; 121.8; 96.6; 91.5; 80.1; 77.2;
55.2; 48.0; 47.8; 39.8; 34.9; 34.8; 33.8; 30.3; 26.4; 25.6;
24.7; 22.5; 20.7. m/z (MWmonoisotopic)¼396.0727 (Calcd,
396.25).
4.4.7. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
methyl-1,4-diazaspiro[4.4]nonan-2-one (5g). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.35, 1.65 Hz); 7.92 (dd, 1H,
J¼8.40, 1.20 Hz); 7.30 (dd, 1H, J¼8.10, 4.20 Hz); 6.33 (d,
1H, J¼2.40 Hz); 6.28 (d, 1H, J¼2.40 Hz); 6.01 (m, 1H);
3.88 (s, 3H); 3.66 (m, 1H); 3.44 (q, 1H, J¼10.0 Hz); 3.32
(m, 1H); 2.93 (m, 1H); 1.69 (m, 12H); 1.33 (d, 3H,
J¼6.30 Hz); 1.30 (d, 3H, J¼5.40 Hz). dC (CDCl3,
300 MHz) 176.3; 159.4; 145.0; 144.9; 144.3; 135.3; 134.8;
129.9; 121.8; 96.8; 96.7; 91.6; 85.9; 77.2; 55.2; 53.9; 48.0;
47.7; 40.4; 40.2; 37.5; 33.8; 30.3; 26.2; 23.2; 23.0; 20.7;
20.6; 17.0. m/z (MWmonoisotopic)¼396.3026 (Calcd, 396.25).
4.4.12. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
methyl-1,4-diazaspiro[4.5]decan-2-one (5l). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.31, 1.68 Hz); 7.92 (dd, 1H,
J¼8.24, 1.61 Hz); 7.30 (dd, 1H, J¼8.28, 4.26 Hz); 6.33 (d,
1H, J¼2.51 Hz); 6.28 (d, 1H, J¼2.51 Hz); 6.01 (d, 1H,
J¼8.22 Hz); 3.88 (s, 3H); 3.63 (m, 1H); 3.44 (q,
J¼7.05 Hzþq, J¼6.84 Hz, 1H); 3.32 (m, 1H); 2.96 (m,
1H); 1.76–1.40 (m, 14H); 1.32 (d, 3H, J¼4.70 Hz); 1.30 (d,
3H, J¼4.23 Hz). dC (CDCl3, 300 MHz) 175.9; 159.3; 145.0;
144.9; 144.2; 135.3; 134.7; 129.8; 121.8; 96.7; 96.6; 91.5;
78.0; 77.4; 55.1; 53.4; 47.9; 47.6; 40.0; 39.8; 37.8; 37.7;
33.7; 33.6; 33.3; 33.2; 30.2; 26.4; 24.8; 22.9; 22.2; 20.7;
17.7; 15.2. m/z (MWmonoisotopic)¼410.3247 (Calcd, 410.27).
4.4.8. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isopropyl-1,4-diazaspiro[4.4]nonan-2-one
(5h).
dH
(CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.35, 1.35 Hz); 7.91
(dd, 1H, J¼8.25, 1.35 Hz); 7.28 (dd, 1H, J¼7.95, 4.35 Hz);
6.32 (d, 1H, J¼2.70 Hz); 6.29 (d, 1H, J¼2.85 Hz), 6.02 (d,
1H, J¼8.70 Hz); 3.88 (s, 3H); 3.64 (m, 1H); 3.37 (m, 1H);
3.32 (d, 1H, J¼4.2 Hz); 2.87 (m, 1H); 2.15 (m, 1H); 1.80–
1.50 (m, 12H); 1.30 (d, 3H, J¼6.90 Hz); 1.02 (d, 3H,
J¼6.75 Hz); 0.90 (d, 3H, J¼6.75 Hz). dC (CDCl3,
300 MHz) 174.9; 174.8; 159.5; 159.4; 145.0; 144.3; 144.2;
135.4; 134.7; 129.9; 121.8; 96.8; 96.7; 91.6; 85.7; 77.3;
63.0; 55.2; 48.0; 47.6; 40.2; 39.9; 37.7; 35.5; 35.4; 34.1;
33.9; 28.9; 26.2; 26.0; 25.6; 23.1; 22.9; 20.7; 20.6; 19.3;
19.2; 17.1; 17.0. m/z (MWmonoisotopic)¼424.1883 (Calcd,
424.28).
4.4.13. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isopropyl-1,4-diazaspiro[4.5]decan-2-one
(5m).
dH
(CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.14, 1.50 Hz); 7.92
(dd, 1H, J¼8.24, 1.59 Hz); 7.30 (dd, 1H, J¼8.21, 4.20 Hz);
6.33 (d, 1H, J¼2.50 Hz); 6.28 (d, 1H, J¼2.50 Hz), 6.01 (d,
1H, J¼8.38 Hz); 3.89 (s, 3H); 3.63 (m, 1H); 3.36 (d, 1H,
J¼3.99 Hz); 3.32 (m, 1H); 3.00 (m, 1H); 2.10 (m, 1H);
1.75–1.37 (m, 15H); 1.30 (d, 3H, J¼6.36 Hz); 1.01 (d, 3H,
J¼6.94 Hz); 0.88 (d, 3H, J¼6.80 Hz). dC (CDCl3,
4.4.9. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isobutyl-1,4-diazaspiro[4.4]nonan-2-one (5i). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.20, 1.50 Hz); 7.92 (dd, 1H,

P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
5559
300 MHz) 174.3; 159.4; 145.0; 144.2; 135.3; 129.9; 121.8;
96.7; 91.5; 77.2; 62.5; 55.2; 48.0; 47.6; 39.8; 39.6; 37.6;
34.5; 34.0; 33.9; 29.3; 26.5; 24.8; 23.1; 22.9; 22.2; 20.7;
20.6; 19.2; 17.0; 16.9. m/z (MWmonoisotopic)¼438.4114
(Calcd, 438.30).
6.32 (d, 1H, J¼2.70 Hz); 6.29þ6.28 (dþd, 1H, J¼2.70 Hz),
6.01 (dd, 1H, J¼7.95, 3.15 Hz); 3.88 (s, 3H); 3.64 (m, 1H);
3.41 (m, 1H); 3.32 (d, 1H, J¼4.50 Hz); 3.01 (m, 1H); 2.12
(m, 1H); 1.89 (m, 1H); 1.71–1.34 (m, 16H); 1.30 (d, 3H,
J¼6.60 Hz); 1.01 (d, 3H, J¼6.90 Hz); 0.89 (d, 3H,
J¼6.30 Hz). dC (CDCl3, 300 MHz) 174.3; 174.2; 159.5;
159.4; 145.1; 145.0; 144.3; 144.2; 135.4; 134.7; 129.9;
121.8; 96.8; 96.7; 91.6; 80.9; 80.8; 77.3; 62.3; 55.2; 47.9;
47.5; 41.0; 40.9; 40.2; 40.1; 38.2; 38.1; 34.0; 30.3;
29.5; 29.4; 29.3; 29.2; 26.2; 26.1; 25.6; 22.5; 22.4;
22.1; 21.9; 20.7; 20.6; 19.3; 19.2; 17.1; 17.0. m/z
(MWmonoisotopic)¼452.3847 (Calcd, 452.32).
4.4.14. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isobutyl-1,4-diazaspiro[4.5]decan-2-one (5n). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.20, 1.50 Hz); 7.92 (dd, 1H,
J¼8.40, 1.50 Hz); 7.30 (dd, 1H, J¼8.40, 4.20 Hz); 6.32 (d,
1H, J¼2.40 Hz); 6.29 (d, 1H, J¼1.80 Hz); 6.02 (m, 1H);
3.88 (s, 3H); 3.64 (m, 1H); 3.38 (m, 1H); 3.30 (m, 1H); 2.98
(m, 1H); 1.98–1.29 (m, 18H); 1.30 (d, 3H, J¼6.30 Hz),
0.94 (m, 6H). dC (CDCl3, 300 MHz) 176.0; 159.4; 145.0;
144.2; 135.3; 134.8; 129.9; 121.8; 96.8; 96.7; 91.6; 78.2;
56.1; 55.2; 48.0; 47.7; 42.0; 41.9; 40.0; 39.8; 37.8; 37.7;
33.9; 33.8; 33.7; 26.5; 25.4; 25.3; 24.8; 23.2; 22.9; 22.2;
21.8; 20.7; 20.6. m/z (MWmonoisotopic)¼452.3154 (Calcd,
452.32).
4.4.19. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isobutyl-1,4-diazaspiro[4.6]undecan-2-one
(5s).
dH
(CDCl3, 300 MHz) 8.52 (dd, 1H, J¼4.20, 1.80 Hz); 7.91
(dd, 1H, J¼8.40, 1.80 Hz); 7.29 (dd, 1H, J¼8.40, 4.20 Hz);
6.32 (d, 1H, J¼2.40 Hz); 6.28 (m, 1H); 6.02 (m, 1H); 3.88
(s, 3H); 3.64 (m, 1H); 3.36 (m, 2H); 3.05 (m, 1H); 1.93–
1.24 (m, 20H); 1.30 (d, 3H, J¼6.60 Hz), 0.94 (m, 6H). dC
(CDCl3, 300 MHz) 175.6; 159.5; 145.0; 144.2; 144.1;
135.3; 135.2; 134.8; 134.7; 130.0; 129.9; 121.8; 96.8;
96.7; 918; 81.5; 55.9; 55.2; 47.8; 47.6; 41.7; 41.6; 41.0;
40.4; 40.3; 37.4; 37.2; 33.9; 33.8; 33.7; 29.6; 29.5; 29.3;
29.2; 26.1; 25.4; 25.3; 23.2; 22.5; 22.4; 22.2; 22.0; 21.8;
20.7; 20.6. m/z (MWmonoisotopic)¼466.3315 (Calcd, 466.33).
4.4.15. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
benzyl-1,4-diazaspiro[4.5]decan-2-one (5o). dH (CDCl3,
300 MHz) 8.52 (dd, 1H, J¼4.20, 1.83 Hz); 7.92 (dd, 1H,
J¼8.22, 1.47 Hz); 7.32–7.15 (m, 6H); 6.33 (m, 1H); 6.28
(m, 1H); 6.00 (m, 1H); 3.88 (s, 3H); 3.71 (m, 1H); 3.60 (m,
1H); 3.31 (m, 1H); 3.05 (dd, 2H, J¼5.3, 2.75 Hz); 1.75–
1.40 (m, 14H); 1.29 (dd, 3H, J¼6.39, 1.83 Hz). dC (CDCl3,
300 MHz) 175.4; 173.9; 159.2; 144.8; 144.7; 144.0; 137.1;
137.0; 135.0; 134.9; 134.5; 129.6; 129.5; 128.2; 126.5;
121.7; 96.4; 96.3; 91.4; 72.5; 58.5; 58.4; 55.0; 47.7; 47.6;
40.2; 40.1; 37.4; 37.3; 37.2; 37.1; 34.4; 34.2; 33.7; 33.6;
26.1; 24.4; 22.5; 22.0; 21.9; 20.5; 20.4 m/z
(MWmonoisotopic)¼486.7263 (Calcd, 486.30).
4.4.20. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
dH
benzyl-1,4-diazaspiro[4.6]undecan-2-one
(5t).
(CDCl3, 300 MHz) 8.52 (dq, 1H, J¼50, 1.80 Hz); 7.91
(dt, 1H, J¼8.40, 1.80 Hz); 7.32–7.14 (m, 6H); 6.32 (m,
1H); 6.27 (m, 1H); 5.99 (t, 1H, J¼8.70 Hz); 3.88 (s, 3H);
3.67 (t, 1H, J¼5.40 Hz); 3.61 (m, 1H); 3.37 (m, 1H); 3.11
(m, 3H); 1.64–1.18 (m, 20H); 1.29 (dd, 3H, J¼6.36,
3.38 Hz). dC (CDCl3, 300 MHz) 173.9; 173.8; 159.4; 145.0;
144.9; 144.2; 144.1; 136.9; 136.8; 135.3; 134.7; 129.8;
129.7; 128.4; 126.8; 121.8; 96.6; 96.5; 91.5; 81.3; 77.2;
58.3; 58.2; 55.1; 47.8; 47.5; 40.6; 40.4; 40.3; 37.9; 37.7;
36.6; 36.5; 33.9; 33.8; 29.5; 29.2; 26.1; 25.8; 25.6; 22.3;
22.0; 20.7;20.6 m/z (MWmonoisotopic)¼500.3246 (Calcd,
500.32).
4.4.16. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-
1,4-diazaspiro[4.6]undecan-2-one (5p). dH (CDCl3,
300 MHz) 8.52 (m, 1H); 7.91 (d, 1H, J¼8.40 Hz); 7.29
(dd, 1H, J¼7.80, 4.20 Hz); 6.33 (m, 1H); 6.28 (m, 1H); 6.01
(d, 1H, J¼8.10 Hz); 3.89 (s, 3H); 3.66 (m, 1H); 3.36 (s, 2H);
3.13 (m, 2H); 1.89 (bs, 1H); 1.72–1.40 (m, 14H); 1.30 (d,
3H, J¼6.30 Hz). dC (CDCl3, 300 MHz) 174.3; 159.4; 145.0;
144.3; 135.3; 134.8; 129.9; 121.9; 102.2; 96.7; 91.6; 88.1;
77.3; 76.8; 55.2; 48.3; 47.8; 40.1; 35.5; 35.4; 33.8; 26.2;
23.0; 20.6; 20.7. m/z (MWmonoisotopic)¼410.3558 (Calcd,
410.27).
4.5. Reaction of compounds 3a–e with veratraldehyde—
synthesis of imidazolidin-4-ones 5u–x
Compounds 3a–e (2 mmol) were mixed with a small excess
(2.2 mmol) of veratraldehyde and TEA (2 mmol) in dry
methanol (10 mL). The mixture was refluxed for 3 d in the
4.4.17. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
methyl-1,4-diazaspiro[4.6]undecan-2-one
(5q).
dH
˚
(CDCl3, 300 MHz) 8.49 (m, 1H); 7.89 (m, 1H); 7.28 (m,
1H); 6.30 (m, 1H); 6.26 (m, 1H); 6.01 (m, 1H); 3.86 (s, 3H);
3.65 (m, 1H); 3.43–3.23 (m, 2H); 3.03 (m, 1H); 1.68 (m,
6H); 1.51 (m, 5H); 1.40–1.17 (m, 9H). dC (CDCl3,
300 MHz) 175.5; 175.4; 159.3; 144.9; 144.8; 144.1; 135.2;
134.8; 129.8; 121.7; 96.7; 96.6; 91.6; 91.5; 81.2; 55.1;
53.1; 47.7; 47.6; 47.5; 40.9; 40.8; 40.3; 40.2; 36.9; 36.8;
33.7; 33.6; 29.6; 29.5; 29.1; 26.0; 22.4; 22.1; 22.0; 20.6;
20.5; 20.4; 17.2. m/z (MWmonoisotopic)¼424.2835 (Calcd,
424.28).
presence of 4 A molecular sieves (1 g) with periodic
monitoring by TLC. One to four new TLC spots could be
detected in the different reaction mixtures. The molecular
sieves were removed by decantation and the solution
evaporated to dryness. The oily residue was submitted to
column chromatography on silica-gel, eluted with DCM/
THF (varying solvent proportions). Chromatographically
homogeneous fractions were pooled and evaporated to
dryness, yielding different combinations of the four possible
diastereomers for each one of the imidazolidin-4-ones
5u–x. Global yields ranged from 57 to 95%. The different
fractions of 5u–x were analyzed by MALDI-TOF MS and
NMR, and spectral data are detailed below. The product
derived from glycine could not be isolated and further
characterized by NMR, but the expected molecular weight
4.4.18. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isopropyl-1,4-diazaspiro[4.6]undecan-2-one (5r). dH
(CDCl3, 300 MHz) 8.51 (dd, 1H, J¼3.90, 1.35 Hz); 7.91
(dd, 1H, J¼8.25, 1.35 Hz); 7.29 (dd, 1H, J¼8.25, 3.90 Hz);

5560
P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
(464.24) could be detected in the reaction mixture by
MALDI-TOF MS (m/z 464.2755).
109.0; 108.9; 97.0; 96.9; 96.8; 96.7; 91.8; 91.7; 91.6; 91.5;
76.6; 76.5; 74.8; 74.7; 68.0; 64.2; 64.1; 64.0; 63.8; 56.0;
55.9; 55.8; 55.7; 55.2; 47.8; 47.7; 47.6; 47.5; 40.2; 40.1;
40.0; 33.9; 33.8; 31.2; 30.3; 29.3; 29.2; 25.6; 25.5; 23.8;
23.7; 23.6; 23.3; 22.7; 20.7; 20.6; 20.5; 20.4; 19.5; 19.4;
16.8; 16.7; 16.6. m/z (MWmonoisotopic)¼506.2887 (Calcd,
506.29).
4.5.1. 2-(3,4-Dimethoxyphenyl)-3-{4-[(6-methoxyquino-
lin-8-yl)amino]pentyl}-5-methylimidazolidin-4-one (5u).
Fraction 1. dH (CDCl3, 300 MHz) 8.53 (dd, 1H, J¼4.20,
1.50 Hz); 7.93 (dd, 1H, J¼8.40, 1.50 Hz); 7.32 (dd, 1H,
J¼8.40, 4.20 Hz); 6.80–6.65 (m, 3H); 6.34 (m, 1H); 6.25
(m, 1H); 5.95 (m, 1H); 5.39þ5.00 (sþs, 1H); 3.88 (s, 3H),
3.85 (s, 3H), 3.78 (s, 3H); 3.61 (m, 3H); 2.67 (m, 1H); 1.68–
1.60 (m, 5H); 1.38–1.27 (m, 6H). dC (CDCl3, 75 MHz)
175.7; 175.6; 159.2; 149.6; 149.5; 149.4; 144.7; 144.6;
144.1; 135.1; 134.6; 134.5; 131.3; 131.2; 129.7; 128.0;
121.7; 119.1; 119.0; 111.0; 110.9; 108.9; 108.8; 96.8; 96.6;
91.6; 91.5; 74.8; 74.7; 55.7; 55.6; 54.9; 54.3; 54.1; 47.4;
47.3; 40.0; 34.0; 33.4; 32.5; 23.4; 22.8; 21.0; 20.5; 20.2;
18.1; 17.8. m/z (MWmonoisotopic)¼478.3069 (Calcd, 478.26).
4.5.3. 2-(3,4-Dimethoxyphenyl)-3-{4-[(6-methoxyquino-
lin-8-yl)amino]pentyl}-5-isobutylimidazolidin-4-one
(5w). dH (CDCl3, 300 MHz) 8.53 (dd, 1H, J¼4.25,
1.40 Hz); 7.92 (dd, 1H, J¼8.24, 1.41 Hz); 7.31 (dd, 1H,
J¼8.22, 4.23 Hz); 6.82–6.68 (m, 3H); 6.34 (m, 1H); 6.24
(m, 1H); 5.96 (m, 1H); 5.37þ5.30þ5.22þ5.15 (d,
J¼1.12 Hzþd, J¼1.01 Hzþd, J¼0.98 Hzþd, J¼1.00 Hz;
1H); 3.97–3.72 (m, 11H); 3.59 (m, 2H); 2.66 (m, 1H); 1.94
(m, 2H); 1.58–1.50 (m, 5H); 1.25 (m, 3H); 0.94 (m, 6H). dC
(CDCl3, 75 MHz) 175.8; 175.7; 175.6; 165.7; 165.5; 159.3;
149.8; 149.6; 149.5; 149.4; 144.9; 144.8; 144.7; 144.2;
135.2; 134.7; 131.6; 130.8; 129.8; 121.8; 119.9; 119.8;
119.4; 119.3; 111.1; 111.0; 110.3; 109.5; 109.4; 108.9;
108.8; 96.8; 96.6; 96.5; 91.6; 91.5; 91.4; 75.4; 75.3;
75.2; 75.1; 57.7; 57.2; 57.1; 55.8; 55.7; 55.1; 47.6; 47.5;
42.0; 41.6; 40.3; 40.2; 40.1; 39.9; 33.7; 33.6; 33.1; 33.0;
30.2; 25.5; 25.2; 25.1; 23.5; 23.4; 23.2; 23.1; 21.4;
20.6; 20.5; 20.4. m/z (MWmonoisotopic)¼520.4108 (Calcd,
520.30).
Fraction 2. dH (CDCl3, 300 MHz) 8.53 (m, 1H); 7.92 (dd,
1H, J¼8.40, 1.50 Hz); 7.32 (m, 1H); 6.81–6.74 (m, 3H);
6.33 (d, 1H, J¼2.40 Hz); 6.25 (d, 1H, J¼2.70 Hz); 5.94 (m,
1H); 5.18þ5.17 (mþms, 1H); 3.88 (s, 3H), 3.87 (s, 3H),
3.82 (s, 3H); 3.59 (m, 3H); 2.70 (m, 1H); 1.66–1.58 (m,
5H); 1.32–1.23 (m, 6H). dC (CDCl3, 75 MHz) 175.6; 175.5;
168.1; 159.3; 159.0; 149.8; 149.7; 149.4; 144.8; 144.7;
144.1; 135.2; 134.6; 134.5; 130.8; 130.7; 129.7; 128.1;
121.7; 119.9; 119.8; 119.7; 111.0; 110.9; 109.4; 109.3; 96.7;
96.5; 91.5; 91.4; 75.1; 75.0; 55.7; 55.6; 55.0; 54.9; 47.5;
47.4; 40.3; 40.1; 34.1; 33.6; 33.2; 32.5; 23.5; 23.3; 21.0;
20.5; 20.3; 18.0; 17.9. m/z (MWmonoisotopic)¼478.3083
(Calcd, 478.26).
4.5.4. 2-(3,4-Dimethoxyphenyl)-3-{4-[(6-methoxyquino-
lin-8-yl)amino]pentyl}-5-benzylimidazolidin-4-one (5x).
Fraction 1. dH (CDCl3, 300 MHz) 8.50 (m, 1H); 7.92 (dd,
1H, J¼8.30, 0.90 Hz); 7.34–7.12 (m, 6H); 6.78–6.64 (m,
3H); 6.33 (d, 1H, J¼2.80 Hz); 6.23 (d, 1H, J¼2.80 Hz);
5.93 (m, 1H); 5.05þ4.97 (mþm, 1H); 4.05 (m, 1H);
3.87þ3.85 (sþs, 3H); 3.84þ3.82 (sþs, 3H), 3.80þ3.75
(sþs, 3H); 3.55 (m, 2H); 3.10 (m, 1H); 2.97 (m, 1H); 2.56
(m, 1H); 2.15 (bs, 1H); 1.58–1.43 (m, 4H); 1.22 (d, 3H,
J¼6.70 Hz). dC (CDCl3, 75 MHz) 173.9; 173.8; 159.4;
149.7; 149.6; 145.0; 144.9; 144.3; 137.5; 137.4; 135.3;
134.8; 134.7; 131.7; 129.9; 129.8; 128.5; 128.4; 126.8;
126.7; 121.9; 119.5; 111.1; 111.0; 109.1; 109.0; 96.8;
96.6; 91.6; 91.5; 75.5; 75.4; 60.1; 56.0; 55.9; 55.8; 55.2;
47.7; 47.6; 40.2; 40.0; 38.5; 33.6; 33.4; 30.3; 23.4;
23.3; 20.6; 20.4. m/z (MWmonoisotopic)¼554.6603 (Calcd,
554.29).
4.5.2. 2-(3,4-Dimethoxyphenyl)-3-{4-[(6-methoxyquino-
lin-8-yl)amino]pentyl}-5-isopropylimidazolidin-4-one
(5v). Fraction 1. dH (CDCl3, 300 MHz) 8.52 (m, 1H); 7.92
(d, 1H, J¼7.80 Hz); 7.30 (dd, 1H, J¼7.80, 4.20 Hz); 6.82–
6.71 (m, 3H); 6.32 (d, 1H, J¼2.40 Hz); 6.24 (d, 1H,
J¼2.10 Hz); 5.96 (m, 1H); 5.34þ5.24þ5.12 (d,
J¼1.20 Hzþd, J¼1.20 Hzþd, J¼1.50 Hz; 1H); 3.84–3.49
(m, 11H); 2.67 (m, 1H); 2.18 (m, 1H); 2.02 (bs, 1H); 1.68–
1.42 (m, 5H); 1.24 (d, 3H, J¼2.10 Hz); 1.05–0.92 (m, 6H).
dC (CDCl3, 75 MHz) 174.3; 174.2; 159.4; 159.3; 149.7;
149.5; 145.0; 144.9; 144.8; 144.2; 135.3; 134.8; 134.7;
132.4; 132.3; 129.9; 121.9; 121.8; 119.6; 119.5; 119.4;
111.2; 111.1; 111.0; 109.0; 108.9; 97.0; 96.9; 96.8; 91.7;
91.6; 91.5; 76.6; 76.6; 63.9; 63.8; 55.9; 55.8; 55.2; 47.8;
47.6; 47.5; 40.3; 40.2; 40.1; 40.0; 33.9; 33.8; 33.1; 31.2;
31.1; 25.6; 23.7; 23.5; 20.7; 20.5; 19.5; 16.7; 16.6. m/z
(MWmonoisotopic)¼506.2897 (Calcd, 506.29).
Fraction 2. dH (CDCl3, 300 MHz) 8.52 (dd, 1H, J¼3.90,
1.80 Hz); 7.91 (dd, 1H, J¼8.40, 1.80 Hz); 7.32–7.16 (m,
6H); 6.68 (d, 1H, J¼8.40 Hz); 6.42 (dd, 1H, J¼8.40,
2.10 Hz); 6.32 (m, 2H); 6.24 (d, 1H, J¼2.40 Hz); 5.94 (m,
1H); 5.06 (d, 1H, J¼0.90 Hz); 3.87 (s, 3H); 3.81 (s, 3H);
3.80 (m, 1H); 3.63 (s, 3H); 3.58 (m, 1H); 3.42 (dt, 1H,
J¼14.1, 7.10 Hz); 3.26 (dd, 1H, J¼14.1, 5.70 Hz); 3.10
(dd, 1H, J¼13.9, 4.50 Hz); 2.71 (dt, 1H, J¼13.8, 6.90 Hz);
1.86 (bs, 1H); 1.58–1.43 (m, 4H); 1.24 (d, 3H, J¼6.30 Hz).
dC (CDCl3, 75 MHz) 174.4; 166.1; 149.9; 149.4; 144.9;
144.2; 136.9; 135.3; 134.8; 130.6; 129.9; 129.8; 126.9;
121.8; 120.2; 111.0; 109.2; 96.9; 91.6; 75.6; 60.2;
55.9; 55.8; 55.2; 47.6; 40.6; 36.6; 34.2; 33.4; 30.3;
23.5; 20.6; 20.4. m/z (MWmonoisotopic)¼554.6391 (Calcd,
554.29).
Fraction 2. dH (CDCl3, 300 MHz) 8.53 (dd, 1H, J¼4.20,
2.10 Hz); 7.92 (dd, 1H, J¼8.40, 1.50 Hz); 7.30 (dd, 1H,
J¼8.40, 4.20 Hz); 6.86–6.70 (m, 3H); 6.33 (d, 1H,
J¼2.10 Hz); 6.24 (m, 1H); 5.96 (m, 1H);
5.34þ5.31þ5.24þ5.13 (d, J¼2.10 Hzþd, J¼1.50 Hzþd,
J¼1.80 Hzþd, J¼1.50 Hz; 1H); 3.88–3.74 (m, 10H);
3.71–3.49 (m, 3H); 2.66 (m, 1H); 2.25 (m, 1H); 1.96 (bs,
2H); 1.68–1.44 (m, 4H); 1.24 (m, 3H); 1.07–0.92 (m, 6H).
dC (CDCl3, 75 MHz) 174.4; 174.3; 174.2; 174.1; 159.5;
159.4; 149.9; 149.8; 149.7; 149.6; 149.5; 145.1; 145.0;
144.9; 144.8; 144.3; 135.4; 134.8; 134.7; 132.4; 131.6;
131.5; 129.9; 130.0; 121.9; 121.8; 120.2; 120.1; 119.6;
119.5; 119.4; 111.3; 111.2; 111.1; 111.0; 109.8; 109.7;
Fraction 3. dH (CDCl3, 300 MHz) 8.53 (dd, 1H, J¼3.90,

P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
5561
1.50 Hz); 7.92 (dd, 1H, J¼8.40, 1.20 Hz); 7.32–7.19 (m,
6H); 6.60 (d, 1H, J¼8.40 Hz); 6.44 (dd, 1H, J¼7.80,
1.80 Hz); 6.32 (m, 2H); 6.21 (d, 1H, J¼2.40 Hz); 5.94 (m,
1H); 5.20 (d, 1H, J¼1.50 Hz); 3.87 (s, 3H); 3.84 (m, 1H);
3.80 (s, 3H); 3.57 (s, 3H); 3.48 (m, 2H); 3.28 (dd, 1H,
J¼14.1, 5.40 Hz); 3.12 (dd, 1H, J¼13.8, 4.50 Hz); 2.66 (m,
1H); 1.86 (bs, 1H); 1.64–1.43 (m, 4H); 1.22 (d, 3H,
J¼6.60 Hz). dC (CDCl3, 75 MHz) 174.4; 166.1; 149.9;
149.4; 144.9; 144.2; 136.9; 135.3; 134.8; 130.6; 129.9;
129.8; 126.9; 121.8; 120.2; 111.0; 109.2; 96.9; 91.6; 75.6;
60.2; 55.9; 55.8; 55.2; 47.6; 40.6; 36.6; 34.2; 33.4; 30.3;
23.5; 20.6; 20.4. m/z (MWmonoisotopic)¼554.7268 (Calcd,
554.29).
34.0; 33.4; 23.9; 20.5. m/z (MWmonoisotopic)¼430.2315
(Calcd, 430.20).
4.6.2. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
methyl-1,9b-dihydroimidazo[2,1-a]isoindole-2,5-dione
(6b). dH (CDCl3, 300 MHz) 8.50 (m, 1H); 7.88 (m, 1H);
7.78 (m, 1H); 7.48–7.24 (m, 4H); 6.32 (m, 2H); 6.04 (m,
1H); 5.76 (s, 0.7H); 5.59 (s, 0.3H); 4.52 (m, 1H); 3.85 (s,
3H), 3.65 (m, 2H), 3.30 (m, 1H); 1.79-1.60 (m, 4H); 1.50-
1.42 (m, 3H); 1.27-1.24 (m, 3H). dC (CDCl3, 75 MHz)
173.1; 173.0; 172.7; 172.6; 159.1; 159.0; 144.4; 143.9;
141.7; 141.6; 135.1; 134.9; 134.4; 132.3; 132.0; 130.5;
130.0; 129.5; 129.4; 124.5; 123.5; 123.4; 121.5; 96.7; 96.6;
91.5; 91.4; 72.7; 72.6; 54.1; 54.0; 46.9; 46.8; 40.1; 39.7;
38.2; 33.8; 33.0; 32.6; 23.6; 20.3; 20.1; 16.7; 16.6. m/z
(MWmonoisotopic)¼444.2428 (Calcd, 444.22).
4.6. Reaction of compounds 3a–e with 2-formylbenzoic
acid—synthesis of 1H-imidazo[2,1-a]isoindole-2,5(3H,
9bH)-diones 6a–e
4.6.3. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isopropyl-1,9b-dihydroimidazo[2,1-a]isoindole-2,5-
dione (6c). dH (CDCl3, 300 MHz) 8.52 (m, 1H); 7.94 (m,
1H); 7.86 (m, 1H); 7.52–7.23 (m, 4H); 6.37 (m, 1H); 6.32
(m, 1H); 6.01 (m, 1H); 5.80þ5.71 (sþs, 1H); 4.28 (m, 1H);
3.90 (s, 3H), 3.70 (m, 2H), 3.30 (m, 1H); 2.34 (m, 1H); 1.80-
1.62 (m, 4H); 1.31 (m, 3H); 1.19 (m, 3H); 0.99 (m, 3H). dC
(CDCl3, 75 MHz) 173.1; 171.5; 171.4; 158.8; 144.1;
143.6; 142.1; 142.0; 134.6; 134.1; 132.0; 131.9; 131.7;
129.6; 129.3; 129.2; 124.0; 123.2; 123.1; 121.2; 96.3;
91.2; 91.1; 74.1; 73.9; 64.1; 54.4; 46.8; 46.3; 39.9; 39.4;
32.9; 32.8; 23.6; 23.2; 20.0; 19.9; 19.0; 17.0. m/z
(MWmonoisotopic)¼472.3159 (Calcd, 472.25).
Compounds 3a–e (2 mmol) were mixed with a small excess
of 2-formylbenzoic acid (2.2 mmol) and TEA (2 mmol) in
dry methanol (10 mL). The mixture was refluxed for 3 d in
˚
the presence of 4 A molecular sieves (1 g) with periodic
monitoring by TLC. In the syntheses of compounds 6b–d
only one new spot could be detected in the reaction
mixtures, whereas two spots could be distinguished in the
reaction mixtures for the syntheses of 6a and 6e. Molecular
sieves were removed by decantation and the solution
evaporated to dryness. The oily residue was submitted to
column chromatography on silica-gel, eluted with DCM/
THF (varying solvent proportions). Chromatographically
homogeneous fractions were pooled, evaporated to dryness
and analyzed by NMR and MALDI-TOF MS. Global yields
ranged from 44 to 60% and compounds 6b–e were found to
be mixtures of two diastereomers (NMR), whereas it was
possible to isolate each of the two diastereomers of 6a. In
the purification of compound 6e, a second fraction of impure
product was collected and analyzed by MALDI-TOF MS,
showing the presence of an m/z peak (538.34) compatible
with the imidazolidin-4-one structure (Calcd, 538.26).
4.6.4. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
isobutyl-1,9b-dihydroimidazo[2,1-a]isoindole-2,5-dione
(6d). dH (CDCl3, 300 MHz) 8.52 (m, 1H); 7.94 (m, 1H);
7.85 (m, 1H); 7.51–7.24 (m, 4H); 6.38-6.30 (m, 2H); 6.01
(t, 1H, J¼8.70 Hz); 5.82þ5.70 (sþs, 1H); 4.48 (dt, 1H,
J¼11.4, 3.30 Hz); 3.89 (s, 3H), 3.87 (m, 1H); 3.69 (m, 2H),
3.40 (m, 1H); 1.92 (m, 2H); 1.80–1.67 (m, 4H); 1.31þ1.29
(d, J¼1.80 Hzþd, J¼1.80 Hz; 3H); 1.12 (d, J¼6.60 Hz,
3H); 1.02þ0.99 (d, J¼1.80 Hzþd, J¼1.80 Hz; 3H). dC
(CDCl3, 75 MHz) 173.4; 173.3; 173.2; 159.4; 159.3; 144.8;
144.7; 144.3; 144.2; 142.1; 142.0; 135.2; 134.7; 134.3;
132.6; 130.8; 130.4; 129.9; 129.8; 125.3; 124.9; 123.8;
123.7; 123.3; 121.9; 121.8; 96.9; 96.8; 91.8; 91.7; 73.3;
73.1; 58.0; 57.9; 55.1; 47.4; 47.1; 40.5; 40.0; 39.8; 39.1;
33.4; 33.2; 24.1; 23.9; 23.2; 23.1; 20.7; 20.6. m/z
(MWmonoisotopic)¼486.2896 (Calcd, 486.26).
4.6.1. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-
1,9b-dihydroimidazo[2,1-a]isoindole-2,5-dione
(6a).
Fraction 1. dH (CDCl3, 300 MHz) 8.50 (dd, 1H, J¼4.20,
1.20 Hz); 7.92 (dd, 1H, J¼8.40, 1.20 Hz); 7.83 (d, 1H,
J¼7.80 Hz); 7.50–7.24 (m, 4H); 6.36 (d, 1H, J¼2.40 Hz);
6.32 (d, 1H, J¼2.40 Hz); 5.95 (m, 1H); 5.69 (s, 1H); 4.42 (d,
1H, J¼16.2 Hz); 3.88 (s, 4H), 3.74 (d, 1H, J¼16.2 Hz), 3.60
(m, 1H); 3.40 (m, 1H); 1.92-1.65 (m, 4H); 1.27 (d, 3H,
J¼6.60 Hz). dC (CDCl3, 75 MHz) 173.1; 170.5; 159.2;
144.6; 144.2; 142.0; 135.1; 134.7; 132.7; 130.4; 129.8;
124.9; 123.6; 121.7; 96.8; 91.7; 74.7; 55.1; 47.7; 47.2; 40.5;
34.0; 33.1; 24.0; 20.4. m/z (MWmonoisotopic)¼430.2296
(Calcd, 430.20).
4.6.5. 1-{4-[(6-Methoxyquinolin-8-yl)amino]pentyl}-3-
benzyl-1,9b-dihydroimidazo[2,1-a]isoindole-2,5-dione
(6e). dH (CDCl3, 300 MHz) 8.54þ8.52 (dd, J¼4.20,
1.20 Hzþdd, J¼4.20, 1.50 Hz; 1H); 7.95 (dd, 1H, J¼8.40,
1.90 Hz); 7.84 (m, 1H); 7.45 (m, 1H); 7.34-7.14 (m, 9H);
6.37þ6.35 (dþd, 1H, J¼2.40 Hz); 6.29þ6.26 (dþd, 1H,
J¼2.40 Hz); 5.95 (m, 1H); 4.84þ4.80 (sþs, 1H); 4.77 (t,
1H, J¼4.50 Hz); 3.90 (s, 3H), 3.62-2.96 (m, 5H); 1.61-1.31
(m, 4H); 1.26 (m, 3H). dC (CDCl3, 75 MHz) 173.6; 173.5;
172.0; 171.8; 159.5; 144.9; 144.8; 144.4; 144.3; 134.8;
132.7; 132.6; 130.4; 130.3; 130.2; 130.1; 127.2; 125.1;
125.0; 123.8; 123.7; 122.0; 121.9; 96.9; 96.8; 91.9;
91.8; 74.3; 74.1; 60.2; 60.1; 55.2; 47.7; 47.1; 40.7; 40.2;
37.4; 37.3; 33.6; 33.5; 23.9; 23.4; 20.7; 20.6. m/z
(MWmonoisotopic)¼520.3128 (Calcd, 520.258).
Fraction 2. dH (CDCl3, 300 MHz) 8.49 (dd, 1H, J¼4.50,
1.50 Hz); 7.90 (dd, 1H, J¼8.10, 1.50 Hz); 7.80 (d, 1H,
J¼7.80 Hz); 7.50–7.24 (m, 4H); 6.34 (d, 1H, J¼2.10 Hz);
6.27 (d, 1H, J¼2.10 Hz); 6.01 (m, 1H); 5.80 (s, 1H); 4.44 (d,
1H, J¼16.2 Hz); 3.86 (s, 4H), 3.78 (d, 1H, J¼16.2 Hz), 3.64
(m, 1H); 3.28 (m, 1H); 1.90-1.60 (m, 4H); 1.26 (d, 3H,
J¼6.30 Hz). dC (CDCl3, 75 MHz) 173.1; 170.4; 159.2;
144.6; 144.2; 141.9; 135.1; 134.6; 132.6; 130.3; 129.8;
124.9; 123.6; 121.8; 96.8; 91.8; 74.6; 55.0; 47.7; 47.1; 40.1;

5562
P. Gomes et al. / Tetrahedron 60 (2004) 5551–5562
3. Baker, J. K.; Bedford, J. A.; Clark, A. M.; McChesney, J. D.
4.7. Kinetics of hydrolysis
Pharm. Res. 1984, 1, 98.
4. Mihaly, G. W.; Ward, S. A.; Edwards, G.; Orme, M. L’E;
Breckenridge, A. M. Br. J. Clin. Pharmacol. 1984, 17, 441.
5. Brossi, A.; Millet, P.; Landau, I.; Bembenek, M. E.; Abell,
C. W. FEBS Lett. 1987, 214, 291.
The kinetics of hydrolysis of imidazolidin-4-ones were
studied by HPLC using a Watersw assembly equipped with
a model 600 controlled pump and a model 991 photodiode-
array detector set at 265 nm. The separation was performed
on a Purospherw, 250£4.0-mm i.d. 5 mm analytical column.
The mobile phase consisted of a mixture of acetonitrile and
sodium acetate buffer (pH 4.75; 0.05 M) containing 1023 M
triethylamine. Two gradients were developed: one for the
imidazolidin-4-one derivatives of phenylalanine and the
other for the derivatives of valine. A gradient method using
50–90% (v/v) acetonitrile over 20 min was used for
compounds 5a, 5e, 5j and 5l, while a gradient using 60–
90% (v/v) acetonitrile over 20 min was used for compounds
5c, 5h and 5m. Usually, a 10 mL aliquot of a 1022 M stock
solution of substrate in acetonitrile was added to 10 mL of
the appropriate thermostatted buffer solution. At regular
intervals, samples of the reaction mixture were analysed by
HPLC. All reactions followed first-order kinetics over four
half-lives.
6. Constantino, L.; Paixa˜o, P.; Moreira, R.; Portela, M. J.;
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Rosario, V. E.; Iley, J. Exp. Toxicol. Pathol. 1999, 51, 299.
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4.8. Computational details
´
13. Pauletti, G. M.; Gangwar, S.; Siahaan, T. J.; Aube, J.;
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The geometry of the imine intermediate has been optimised
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GAMESS-US suite of programs.29 Several different starting
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the PES was reached. Harmonic vibrational frequencies
were calculated through construction and diagonalisation of
the Hessian matrices at the obtained optimised molecular
geometries. The absence of negative wavenumbers allowed
us to characterize the equilibrium geometries as true
minima.
19. Zehavi, U.; Ben-Ishai, D. J. Org. Chem. 1961, 26, 1097.
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Acknowledgements
PG is greatly indebted to Drs. Eliandre de Oliveira
(University of Barcelona) and J. R. B. Gomes (University
of Porto) for helpful discussions. The authors thank
24. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1959, 77, 1067.
25. Izdebsky, J.; Kunce, D.; Drabarek, S. Pol. J. Chem. 1980, 54,
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Fundac¸a˜o para a Ciencia e Tecnologia (Portugal) for
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27. Anderson, G. W.; McGregor, A. C. J. Am. Chem. Soc. 1957,
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financial support through research project POC-
TI/FCB/39218/2001.
28. Katritzky, A. R.; Xu, Y-J.; He, H-Y.; Steel, P. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 1767.
References and notes
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