Convenient synthesis of tetrahydroisoquinoline-hydantoins

Article abstract of DOI:10.1016/S0040-4039(01)01526-X

NaOH/MeOH or DIEA/CH₂Cl₂ were convenient conditions for the synthesis in solution phase of hydantoins derived from Tic-OH and isocyanates.

Full text of DOI:10.1016/S0040-4039(01)01526-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7559–7561
Convenient synthesis of tetrahydroisoquinoline-hydantoins
Julie Charton, Sandrine Delarue, Sandrine Vendeville,† Marie-Ange Debreu-Fontaine,
Sophie Girault-Mizzi and Christian Sergheraert*
UMR CNRS 8525, Universite´ de Lille II, Institut de Biologie et Institut Pasteur de Lille, 1 rue du Professeur Calmette,
BP 447, 59021 Lille cedex, France
Received 21 May 2001; accepted 21 August 2001
Abstract—NaOH/MeOH or DIEA/CH2Cl2 were convenient conditions for the synthesis in solution phase of hydantoins derived
from Tic-OH and isocyanates. © 2001 Elsevier Science Ltd. All rights reserved.
One of the challenges of medicinal chemistry is the
enhancement of the affinity of a given ligand for its
target by decreasing its degrees of freedom and thereby
reducing the cost in entropy. Another difficult task is
the promotion of the structural diversity which can be
achieved by the attachment of pharmacophoric groups
to the rigidified molecule. An example of such a process
includes di- and trisubstituted hydantoins 1 (Fig. 1),
which have been widely used in biological screenings
resulting in numerous pharmaceutical applications.1–3
been required for formation of the hydantoins.6–8 How-
ever, recent reports have described efficient mild
cyclization/cleavage conditions for various linear urea
compounds, employing triethylamine or diisopropyl-
amine at room temperature.9,10 These conditions were
thus applied to the benzyl urea, prepared by reacting
benzyl isocyanate and (S)-(−)-1,2,3,4-tetrahydro-3-iso-
quinolinecarboxylic acid (L-Tic-OH) fixed either to a
Tentagel S-OH or to a Wang resin (Scheme 1).11
As part of our strategy towards the preparation and
biological evaluation of hydantoin-containing hetero-
cycles, we elected to fuse the hydantoin ring by its C-5
and N-1 positions to another ring in order to design a
new series of more constrained derivatives 2 (Fig. 1).
The tetrahydroisoquinoline ring was selected as a phar-
macophoric moiety frequently found in our screenings
of combinatorial libraries.4,5 The subsequent absence of
variation in the C-5 and N-1 positions could be coun-
ter-balanced by the presence of substituents on the
tetrahydroisoquinoline ring and the introduction of a
side chain to the N-3 position capable of generating a
broad structural diversity.
Figure 1. Di- and trisubstituted hydantoins 1 and more con-
strained Tic derivatives 2.
All previous efforts to prepare di- or trisubstituted
hydantoins in solid phase have focused upon the ring
synthesis from acyclic precursors. According to the
literature, strongly acidic (or basic) conditions,
extended reaction times or elevated temperatures have
Keywords: hydantoins; cyclization.
* Corresponding author. Tel.: (33) 3 20 87 12 11; fax: (33) 3 20 87 12
33; e-mail: christian.sergheraert@pasteur-lille.fr
† Present address: Tibotec, L11 Gen. De Wittelaan, B-32800 Meche-
len, Belgium.
Scheme 1. Reagents and conditions: (a) Bzl-NCO, TEA, rt; (b)
TEA, MeOH, rt or TEA, CH2Cl2, rt.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01526-X

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J. Charton et al. / Tetrahedron Letters 42 (2001) 7559–7561
results and carried out the subsequent synthesis of our
Tic-hydantoin derivatives in solution phase.
The final treatment (TEA/MeOH with Tentagel resin or
TEA/CH2Cl2 with Wang resin) led to a very low yield
of the free cyclized derivative or, as in the second case,
to the total absence of the desired compound. Since we
had obtained, under the same conditions, the high
yields reported for the hydantoin derived from phenyl-
alanine and benzyl isocyanate, we concluded that the
Tic residue was responsible for these disappointing
The starting material was commercial
L
-Tic-OH 3
whose secondary amine function was protected by a
Boc group, using Boc2O in aqueous dioxane, before its
transformation into methyl ester 5 by reacting the
cesium salt of Boc- -Tic-OH 4 with methyl iodide
L
(Scheme 2). After deprotection of the secondary amino
group by treatment with a 1:1 mixture of TFA/CH2Cl2,
evaporation
followed
by
addition
of
dry
dichloromethane and an excess of DIEA (4.5 equiv.),
benzyl isocyanate was introduced to the solution of
crude -Tic-OMe to yield the urea 6 (Scheme 2). This
L
latter, assessed by HPLC, was obtained as a very pure
sample following a simple brine washing.12
Several bases (TEA, diisopropylamine, DIEA, DBU,
pyridine, NaOH, Na2CO3 and AcOK,) in a variety of
solvents (CH2Cl2, THF, DMF and MeOH) were com-
pared for the cyclization step of the benzyl urea 6
(Scheme 2, Table 1). First, the two bases (triethylamine
or diisopropylamine) and the solvent (CH2Cl2), used in
solid phase, were tested. Then, the nature of the solvent
was optimized in the presence of diisopropylamine and
finally the nature of the base in the solvent selected.
The hydantoin derived from
L-Tic-OH was obtained
quantitatively and quickest from the use of an organic
or mineral base (except DIEA and pyridine) in
methanol.
Scheme 2. Reagents and conditions: (a) Boc2O 1.1 equiv.,
dioxane, NaOH 1 M 1.1 equiv., rt, 12 h, 98%; (b) Cs2CO3 1
M 0.5 equiv., MeOH, rt, 10 min then CH3I 1.1 equiv., DMF,
rt, 12 h, 98%; (c) TFA/CH2Cl2 1:1, rt, 1 h then DIEA 4.5
equiv., CH2Cl2, rt, 15 min, 100%; (d) Bzl-NCO 2.5 equiv.,
CH2Cl2, rt, 12 h, 68%; (e) base 1.1 equiv., solvent, rt, 1–24 h.
Using sodium hydroxide in methanol, the final com-
pound 7 was isolated with a high level of purity follow-
ing evaporation of methanol, dichloromethane
extraction and simple brine washing. A sample for
analysis was obtained by thick layer chromatography.12
This method of cyclization was applied to other ureas
obtained from aliphatic (ethyl, tert-butyl, allyl) and
phenyl isocyanates with similar results (data not
shown). The same behavior was also observed in each
Table 1. Optimization of synthesis of hydantoin 7 by
cyclization of urea 6
Entry
Solvent
Basea 1.1
equiv.
Reaction time
(h)
Conversion rate
in HPLC (%)
step of Scheme 2 when
D-Tic-OH was used, while no
cyclization occurred from urea derived from
and benzyl isocyanate.
L-Pro-OH
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
DMF
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TEA
TEA
TEA
1
2
24
1
2
24
2
24
2
24
1
1
1
12
1
24
1
1
1
15
20
50
40
65
85
75
75
75
With the aim of decreasing the number of steps without
changing the conditions of synthesis for urea 6, we have
demonstrated that the isolation of this latter compound
was unnecessary. Indeed, the addition of benzyl isocya-
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
DIPA
TEA
DIEA
DIEA
DBU
Pyridine
NaOHb
Na2CO3
AcOK
nate to a solution of intermediate
L-Tic-OMe in dry
9
dichloromethane and in the presence of a large excess
of DIEA (15 equiv.), led directly to the formation of
hydantoin 7. With a reaction time of 14 h, despite the
use of CH2Cl2 as solvent and DIEA as base, the yield
of this ‘one-pot’ reaction was found to be similar (60%)
to that observed via isolation of the intermediate urea 6
and cyclization of this latter in an NaOH/MeOH mix-
ture (65%). Similar results were obtained with other
aliphatic and aromatic isocyanates. Application of the
optimum conditions for the ‘one-pot’ reaction (DIEA
15 equiv. in CH2Cl2), in solid phase (Tentagel or Wang
resin), did not enable us to obtain hydantoin 7.
10
11
12
13
14
15
16
17
18
19
75
100
100
30
100
100
30
100
100
100
a DIPA: diisopropylamine.
b 1 M aqueous solution NaOH was used.

J. Charton et al. / Tetrahedron Letters 42 (2001) 7559–7561
7561
In conclusion, we have described a convenient and
efficient method to prepare Tic-hydantoins not other-
wise accessible using cyclization/cleavage conditions in
solid-phase synthesis. This ‘one-pot’ method is suitable
for both aliphatic and aromatic isocyanates and will be
mined on a Bu¨chi melting point apparatus and are uncor-
1
rected. H and 13C NMR spectra were obtained using a
Brucker 300 MHz spectrometer, chemical shifts (l) were
expressed in ppm relative to TMS used as an internal
standard. Mass spectra were recorded on a ‘time-of-flight’
plasma mass desorption spectrometer (TOF-PDMS)
using a Californium source. The purity of final com-
pounds was checked by high-pressure liquid chromato-
graphy (HPLC) with a C18 Vydac column. Analytical
HPLC was performed on a Shimadzu system equipped
with a UV detector set at 254 nm. Compounds were
dissolved in MeOH and injected through a 50 mL loop.
The following eluent systems were used: A (H2O/TFA,
100:0.05) and B (CH3CN/H2O/TFA, 80:20:0.05). HPLC
retention times (HPLC tR) were obtained, at flow rates of
0.5 mL/min, using the following conditions: a gradient
run from 100% eluent A during 1 min, then to 100%
eluent B over the next 29 min.
(3S) - 2 - (tert - Butoxycarbonyl) - 1,2,3,4 - tetrahydro - 3 - iso-
quinolinecarboxylic acid (4): white solid (98% yield); mp
110–112°C; Rf 0.8 (CH2Cl2/MeOH, 9:1); HPLC tR 20.81
min, purity 100%; lH (DMSO-d6): 12.60 (bs, 1H,
COOH), 7.19–7.16 (m, 4H, Ar-H), 4.90–4.80 (m, 1H, CH
cis or trans), 4.64–4.41 (m, 3H, CH cis or trans and CH2),
3.20–3.00 (m, 2H, CH2), 1.46 (s)+1.38 (s) (9H, C(CH3)3);
TOF-PDMS m/z 177 (M+−Boc).
extended to
L-Tic-OH derivatives substituted on the
tetrahydroisoquinoline ring in order to introduce
another site of structural diversity.
Acknowledgements
We express our thanks to Ge´rard Montagne for NMR
experiments and Dr. Steve Brooks for proof reading.
This work was supported by CNRS (UMR CNRS
8525) and Universite´ de Lille II. S. D. is the recipient of
a fellowship from the CNRS and Region Nord/Pas de
Calais.
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0.27 mmol/g). Wang resin was from Novabiochem (initial
loading: 0.63 mmol/g).
12. Thick-layer chromatography (TLC) was performed using
silica gel from Merck, the compounds were extracted
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CH2Cl2/MeOH, 80:20. All melting points were deter-
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COOCH3), 3.30 (dd, J=15.9, 2.8 Hz, 1H, CH2), 3.17 (dd,
J=16.3, 6.1 Hz, 1H, CH2); TOF-PDMS m/z 325 (M+).
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