Optimized synthesis of tetrahydroisoquinoline-hydantoins

Article abstract of DOI:10.1016/j.tetlet.2004.07.112

Several methods have been developed and compared for the solution synthesis of tetrahydroisoquinoline-hydantoin derivatives. The best yields were obtained when the imidazolidine-2,4-dione ring was synthesized in two steps: (1) reaction of Tic-OH with the appropriate amine and (2) cyclization with 1,1′-carbonyldiimidazole.

Full text of DOI:10.1016/j.tetlet.2004.07.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7081–7085
Optimized synthesis of tetrahydroisoquinoline-hydantoins
Julie Charton,* Amaury Cazenave Gassiot, Patricia Melnyk,
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, B.P. 447, 59021 Lille cedex, France
Received 25 June 2004; revised 16 July 2004; accepted 24 July 2004
Abstract—Several methods have been developed and compared for the solution synthesis of tetrahydroisoquinoline-hydantoin (Tic-
hydantoin) derivatives. Starting materials were Tic-OH and amines readily available from commercial sources. The best yields were
observed when the imidazolidine-2,4-dione ring was synthesized in two steps: (1) reaction of Tic-OH with the appropriate amine and
(2) cyclization with 1,10-carbonyldiimidazole.
Ó 2004 Elsevier Ltd. All rights reserved.
O
1. Introduction
N
R
One of the challenges of medicinal chemistry is the
enhancement of the affinity of a given ligand for its tar-
get. A possible solution resides in decreasing its degrees
of freedom and thereby reducing the entropy cost.
Another difficult task is the promotion of structural
diversity attached to such a rigidified molecule. Imidaz-
olidine-2,4-diones, or hydantoins 1 (Fig. 1), common
five-membered rings containing a reactive urea function-
ality, represent a good platform to apply this concept.
This heterocycle is present in a wide range of biologi-
cally active compounds including antiarrhythmics, anti-
convulsivant, antitumor, and anxiolytic agents.1–5
N
O
2
Figure 2. Tetrahydroisoquinoline-hydantoin derivatives 2.
We have previously described a method for preparing
Tic-hydantoins, which were inaccessible by solid phase
synthesis under cyclization/cleavage conditions.8
Compounds were synthesized according to procedure
described in Scheme 1, starting from (S)-(ꢀ)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid 3 (L-Tic-OH).
With the aim of combining bulky pharmacophoric moi-
eties and hydantoins, we focused our efforts on com-
pounds with the following structure 2 (Fig. 2). Indeed,
the tetrahydroisoquinoline ring (Tic) was selected after
screening different combinatorial libraries frequently
containing such molecular structures.6,7
COOH
COOH
NBoc
COOCH3
NBoc
a
b
NH
3
4
5
c-d
O
O
COOCH3
H
e
R
N
R
N
N R
N
N
R''
N
O
O
R'
7
6
O
1
Scheme 1. Reagents and conditions: (a) Boc2O 1.1equiv, NaOH 1M
1.1equiv, dioxane, rt, 12h, 98%; (b) Cs2CO3 1M 0.5equiv, MeOH, rt,
10min, then CH3I 1.1equiv, DMF, rt, 12h, 98%; (c) TFA/DCM 1:1,
rt, 1h, then DIEA 4.5equiv, DCM, rt, 15min, 100%; (d) R-NCO
2.5equiv, DCM, rt, 12h; (e) NaOH 1.1equiv, MeOH or DIEA,
1.1equiv, DCM, rt, 1–24h.
Figure 1. Trisubstituted hydantoins 1.
*
Corresponding author. Tel.: +33 3 20 87 12 20; fax: +33 3 20 87 12
33; e-mail: julie.charton@ibl.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.112

7082
J.Charton et al./ Tetrahedron Letters 45 (2004) 7081–7085
For reasons of reactivity and solubility, two protection
steps were necessary before reaction with the appropri-
ate isocyanate. A final treatment with NaOH/MeOH
or DIEA/DCM solution allowed to achieve cyclization
as expected. This method was suitable for aliphatic
and aromatic isocyanates, which were both tested.
COOH
NH
COOH
NBoc
a
4
3
b
O
O
R
c-d
N
H
8
N
R
N
NBoc
However it remained limited in terms of diversity
because a few isocyanates are commercially available
and their synthesis is not always convenient.
O
7
Scheme 2. Reagents and conditions: (a) Boc2O 1.1equiv, NaOH 1M
1.1equiv, dioxane, rt, 12h, 98%; (b) R-NH2 1.2equiv, HOBt 1.1equiv,
EDCI 1.1equiv, DIEA 2equiv, DCM, rt, 2h; (c) TFA/DCM 1:1, rt,
1h; (d) CDI 1.5equiv, DIEA 4.5equiv, THF, reflux, 6–48h.
2. Chemistry
Therefore, the use of other reagents leading to hydant-
oin cyclization was considered (Fig. 3). In particular,
we investigated the use of 1,10-carbonyldiimidazole
(CDI) as a cyclizing agent. Three complementary strat-
egies were designed around this reagent. They were ap-
plied to the synthesis of compounds of biological
interest.
O
COOH
NH
COOH
NBoc
b
a
O
N
4
O
3
9 (not isolated)
c
O
O
2.1. Strategy 1
N
R
d
H
N
R
NH
N
Boc-protected L-Tic-OH 3 was coupled with a variety of
amines using different coupling reagents (DCC, PyBroP,
HOBt/EDCI). HOBt/EDCI activation using DIEA as a
base was retained due to the good solubility of by-prod-
ucts in the aqueous phase.9 After deprotection of the
secondary amino group using TFA/DCM, the crude
product was dissolved in THF and excess DIEA
(4.5equiv). CDI was added to yield the hydantoins 7
(Scheme 2).10–12
O
7
10
Scheme 3. Reagents and conditions: (a) Boc2O 1.1equiv, NaOH
1M 1.1equiv, dioxane, rt, 12h, 98%; (b) PCl3 1.3equiv, DCM, rt, 3h;
(c) R-NH2 1.2equiv, TEA 2equiv, DCM, rt, 24h; (d) CDI 1.5equiv,
DIEA, THF, reflux, 12h.
2.3. Strategy 3
Another way to introduce diversity on the hydantoin
ring at the 2-position is to synthesize the unsubstituted
hydantoin 11 first and then to carry out nucleophilic
substitutions. These substitutions could be achieved
using an appropriate halide, in acetonitrile, in the pres-
ence of potassium carbonate (Scheme 4).
2.2. Strategy 2
This approach uses the a-amino acid N-carboxyan-
hydride of L-Tic-OH (10,10a-dihydro-5H-oxazolo-[3,
4-b]isoquinoline-1,3-dione 9),13 which can be directly
submitted to a coupling reaction with amines allowing
the direct synthesis of compounds 10. The hydantoins
7 were then synthesized using the conditions described
above (Scheme 3).14
Use of potassium isocyanate followed by cyclization
in acidic conditions was considered as a first method
to obtain compound 11 (Scheme 5). Unfortunately the
yield of the transformation was poor.
Unlike the first strategy, this approach eliminates the
extra Boc-deprotection step and the use of coupling
agent.
Consequently, an alternative method was used for the
preparation of the unsubstituted hydantoin. After Boc
O
N
R
N
strategy 3
strategy 1
COOH
O
O
strategy 2
O
NH
+
R Cl
N
+
R-NH2
NH
O
+
O
R-NH2
N
O
Figure 3. Starting materials used for the synthesis of target compounds.

J.Charton et al./ Tetrahedron Letters 45 (2004) 7081–7085
Table 1. Overall yields for hydantoins 7 by the different strategies
7083
O
O
Product
R
Overall
yield
Scheme 1 strategy 1 strategy 2 strategy 3
Overall
yield
Overall
yield
Overall
yield
N
R
NH
N
N
O
O
7
(%)
(%)
(%)
(%)
11
7a
7b
22
80
26
––
Scheme 4. Reagents and conditions: R-Cl 1.1equiv, K2CO3 1equiv,
CH3CN, 60°C, overnight.
51
16
45
70
88
54
43
58
––
56
––
30
32
30
25
––
7c
7d
7e
O
COOH
a-b
NH
N
NH
O
3
11
Scheme 5. Reagents and conditions: (a) KNCO 2equiv, H2O, reflux,
18h; (b) HCl, H2O, reflux, 2h, 25%.
O
O
COOH
COOH
NBoc
a
N
n
N
N
n
NHBoc
NH
N
N
3
4
O
O
b
17 a n = 2
17 b n = 3
17 c n = 4
17 d n = 5
19 a n = 3
19 b n = 4
19 c n = 5
O
O
c-d
NH2
NH
N
NBoc
Figure 4. Compounds 17a–d and 19a–c.
O
11
12
Scheme 6. Reagents and conditions: (a) Boc2O 1.1equiv, NaOH 1M
1.1equiv, dioxane, rt, 12h, 98%; (b) NH4Cl 1.3equiv, HOBt 1.1equiv,
EDCI 1.1equiv, NMM 1.3equiv, DMF, rt, overnight, 98%; (c) HCl
(2M in Et2O), THF, rt, 12h, 100%; (d) CDI 2equiv, DIEA 2equiv,
THF, reflux, overnight, 45%.
cyanates, followed by substitution of the chloride by
N-benzylmethylamine. Unfortunately overall yields
were not satisfactory (respectively, 15% and 9% for
n = 2and 3). To improve efficiency, strategy 1 was thus
investigated. The diversity of the side chain of hydantoin
core was directly introduced on the amine before the
coupling step. Protected amines 15a–d were synthesized
in a three step process from commercially available ami-
no-alcohols.16 After deprotection of the amines using
TFA/DCM, the coupling and cyclization steps were
performed according to strategy 1 to obtain desired
protection of the starting material L-Tic-OH 3, the pri-
mary amide 12 was obtained by reaction of compound
4 with ammonium chloride using HOBt/EDCI activa-
tion, in DMF, in presence of N-methylmorpholine
(NMM).15 After removal of the Boc-group by HCl/
THF treatment, use of CDI and DIEA in THF led to
a better overall yield of the unsubstituted hydantoin 11
(Scheme 6).
3. Results and discussion
O
S
O
b
a
HO
HO
O
NH2
NHBoc
NHBoc
n
n
n
The efficiency of the different strategies is compared in
Table 1, in the case of a phenyl or a phenylalkyl
substituent.
13 a-d
14 a-d
c
O
d-e
N
H
n
N
n
N
NHBoc
As summed up in Table 1, the best yields were obtained
using strategy 1. However, availability of the starting
materials is a determining factor in the choice of one
of the four routes.
NBoc
15 a-d
16 a-d
f-g
O
As part of our program aimed at the design of biologi-
cally active compounds, we needed preparations of
[(benzyl-methyl-amino)-alkyl]-10,10a-dihydro-5H-imid-
azo[1,5-b]isoquinoline-1,3-diones 17a–d and [(1,3-dioxo-
1,5,10,10a-tetrahydro-imidazo[1,5-b]isoquinolin-2-yl)-
alkyl]carbamic acid tert-butyl esters 19a–c (Fig. 4).
n
N
N
N
O
17 a-d
Scheme 7. Reagents and conditions: (a) Boc2O 1.1equiv, DCM, rt,
12h; (b) MsCl 1.3equiv, TEA 2equiv, DCM, 0 °C, 2h; (c) N-
benzylmethylamine 3equiv, DIEA 10equiv, CH3CN, 35°C, 24–72h;
(d) TFA/DCM 1:1, rt, 30min; (e) N-Boc-L-Tic-OH 4 1equiv, HOBt
1.1equiv, EDCI 1.1equiv, DIEA 2equiv, DCM, rt, 2h; (f) TFA/DCM
1:1, rt, 30min; (g) CDI 1.5equiv, DIEA 4.5equiv, THF, reflux, 6–24h.
In order to obtain compounds 17a–d, our original
method (Scheme 1) was tried first, with chloroalkyl iso-

7084
J.Charton et al./ Tetrahedron Letters 45 (2004) 7081–7085
Table 2. Overall yield of steps d–g for compounds 17a–d
References and notes
Product
n
Overall yield (steps d–g) Scheme 7 (%)
1. Karolak-Wojciechowska, J.; Kwiatkowski, W.; Kieckon-
ono, K. Pharmazie 1995, 50, 114–117.
2. Brouillette, W. J.; Brown, G. B.; DeLorey, T. M.; Liang,
G. J.Pharm.Sci. 1990, 79, 871–874.
3. Brouillette, W. J.; Jestkov, V. P.; Brown, M. L.; Akhtar,
M. S.; DeLorey, T. M.; Brown, G. B. J.Med.Chem. 1994,
37, 3289–3293.
17a
17b
17c
17d
2
22
3
2
6
4
30
10
5
´
´
´
4. Lopez-Rodrıguez, M. L.; Rosado, M. L.; Benhamu, B.;
Morcillo, M. J.; Sanz, A. M.; Orensanz, L.; Beneitez, M.
E.; Fuentes, J. A.; Manzanares, J. J.Med.Chem. 1996, 39,
4439–4450.
O
COOH
a
O
N
NBoc
´
´
5. Lopez-Rodrıguez, M. L.; Morcillo, M. J.; Rosado, M. L.;
Benhamu´, B.; Sanz, A. M. Bioorg.Med.Chem.Lett. 1996,
6, 689–694.
O
4
9
b
6. Vendeville, S.; Buisine, E.; Williard, X.; Schrevel, J.;
Grellier, P.; Santana, J.; Sergheraert, C. Chem.Pharm.
Bull. 1999, 47, 194–198.
O
O
c
N
H
n
NHBoc
n NHBoc
19 a-c
N
N
NH
´
7. Deprez, B.; Williard, X.; Bourel, L.; Coste, H.; Hyafil, F.;
18 a-c
Tartar, A. J.Am.Chem.Soc. 1995, 117, 5405–5406.
8. Charton, J.; Delarue, S.; Vendeville, S.; Debreu-Fontaine,
M.-A.; Girault-Mizzi, S.; Sergheraert, C. Tetrahedron
Lett. 2001, 42, 7559–7561.
9. Damour, D.; Barreau, M.; Blanchard, J.-C.; Burgevin,
M.-C.; Doble, A. Chem.Lett. 1998, 9, 943–944.
O
Scheme 8. Reagents and conditions: (a) PCl3 1.3equiv, DCM, rt, 3h;
(b) Boc-NH-(CH2)n-NH2 1.2equiv, TEA 2equiv, DCM, rt, 24h; (c)
CDI 1.5equiv, DIEA 4.5equiv, THF, rt, overnight.
10. Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P.
E.; Oates, B.; MacCoss, M.; Mills, S. G.; Malkowitz, L.;
Gould, S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda,
D.; Miller, M.; Kessler, J.; Danzeisen, R.; Carver, G.;
Carella, A.; Holmes, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Bioorg.Med.Chem.Lett. 2001, 11, 3099–3102.
11. De Laszlo, S. E.; Allen, E. E.; Li, B.; Ondeyka, D.; Rivero,
R.; Malkowitz, L.; Molineaux, C.; Siciliano, S. J.; Sringer,
M. S.; Greenlee, W. J.; Mantlo, N. Bioorg.Med.Chem.
Lett. 1997, 7, 213–218.
Table 3. Overall yields for compounds 19a–c
Product
n
Overall yield Scheme 8 (%)
19a
19b
19c
3
4
5
2
0
40
39
compounds 17a–d (Scheme 7) with pretty good overall
yields as shown in Table 2.17
12. Liverton, N. J.; Armstrong, D. J.; Claremon, D. A.;
Remy, D. C.; Baldwin, J. J.; Lynch, R. J.; Zhang, G.;
Gould, R. J. Bioorg.Med.Chem.Lett.
486.
13. Ha¨tzelt, A.; Laschat, S.; Jones, P. G.; Grunenberg, J. Eur.
J.Org.Chem. 2002, 23, 3936–3943.
14. Durham, T. B.; Miller, M. J. J.Org.Chem.
27–34.
15. Njoroge, F. G.; Vibulbhan, B.; Pinto, P.; Strickland, C. L.;
Bishop, W. R.; Kirschmeir, P.; Girijavallabhan, V.;
1998, 8, 483–
To obtain compounds 19a–c, a Boc aminoalkyl moiety
was introduced using strategy 2. Strategy 1 was indeed
inappropriate in this case because the Tic-deprotection
(cf. Scheme 2, step c) was incompatible with the presence
of the Boc protection on the side chain (Scheme 8).
Commercially available mono-protected a–x-diamino-
alkanes were used as amines.
2003, 68,
Ganguly, A. K. Bioorg.Med.Chem.
143.
16. Young, B. L.; Folk, J. E. Bioorg.Med.Chem. 1998, 6,
253–270.
2003, 11, 139–
This method was found to be simple and efficient, with
overall yields between 20% and 40% (Table 3).
17. (3S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydro-3-isoquino-
linecarboxylic acid (4): white solid; mp 110–112°C; dH
(300MHz, DMSO-d6): 12.6 (br s, 1H, COOH), 7.2–7.1 (m,
4H, Ar-H), 4.9–4.4 (m, 3H, CH, CH2), 3.2—3.0 (m, 2H,
CH2), 1.4 (2s, 9H, C(CH 3)3); MALDI-TOF m/z 278
[M+H]+.
4. Conclusion
In summary, we have described versatile and efficient
methods to prepare tetrahydroisoquinoline-hydantoin
derivatives using Tic-OH and amines or halides. These
procedures will allow an easy access to further diversi-
fied hydantoin based products.
(10aS)-2-Benzyl-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]-
isoquinoline-1,3-dione (7b): white solid; mp 122–124°C;
dH (300MHz, DMSO-d6): 7.3–7.2(m, 9H, Ar-H), 4.8 (d,
J = 17Hz, 1H, CH2), 4.6 (s, 2H, CH2-Ph), 4.4 (d,
J = 17Hz, 1H, CH2), 4.3 (dd, J = 11 and 5Hz, 1H, CH),
3.2(dd, J = 15 and 5Hz, 1H, CH2 (H trans)), 2.8 (dd,
J = 15 and 11Hz, 1H, CH2 (H cis)); dC (300MHz, DMSO-
d6): 173, 155, 137, 132, 130, 129, 128.5, 128.1, 127.6, 127.5,
55, 42.1, 42.0, 30.6; MALDI-TOF m/z 293 [M+H]+.
10,10a-Dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione
(11): white solid; mp 227–230°C; dH (300MHz, DMSO-
d6): 10.3 (br s, 1H, NH), 7.2–7.0 (m, 4H, Ar-H), 4.7 (d,
J = 15Hz, 1H, CH2), 4.2(d, J = 15Hz, 1H, CH2), 4.1 (dd,
Acknowledgements
Thanks are due to Marie-Ange Debreu-Fontaine for
´
technical assistance, Gerard Montagne for NMR spec-
tra and Herve Drobecq for Maldi-Tof experiments.
`
J.C. is a recipient of fellowships from the Ministere de
lÕEducation Nationale et de la Recherche.
´

J.Charton et al./ Tetrahedron Letters 45 (2004) 7081–7085
7085
J = 11 and 5Hz, 1H, CH), 3.0 (dd, J = 15 and 5Hz, 1H,
CH2 (H trans)), 2.8 (dd, J = 15 and 11Hz, 1H, CH2 (H
cis)); dC (300MHz, DMSO-d6): 175, 133–127, 56, 42, 31;
MALDI-TOF m/z 203 [M+H]+.
2-[2-(Benzyl-methyl-amino)-ethyl]-10,10a-dihydro-5H-
imidazo[1,5-b]isoquinoline-1,3-dione (17a): yellow oil; dH
(300MHz, DMSO-d6): 7.3–7.1 (m, 9H, Ar-H), 4.8 (d,
J = 17Hz, 1H, CH2), 4.4 (d, J = 17Hz, 1H, CH2), 4.3 (dd,
J = 11 and 5Hz, 1H, CH), 3.5 (t, J = 6Hz, 2H, CH2), 3.3
(s, 2H, CH2-Ph), 3.1 (dd, J = 16 and 5Hz, 1H, CH2 (H
trans)), 2.8 (dd, J = 16 and 11Hz, 1H, CH2 (H cis)), 2.5 (t,
J = 6Hz, 2H, CH2), 2.1 (s, 3H, CH3); dC (300MHz,
DMSO-d6): 174, 156, 140–127, 62, 59, 55, 43, 42, 37, 31;
MALDI-TOF m/z 350 [M+H]+.