General and versatile entry to 4,5-fused polycyclic imidazolones systems. Use of the tandem transposition/π-cyclization of N-acyliminium species

Article abstract of DOI:10.1021/jo060616s

A simple and efficient methodology for the synthesis of 4,5-fused imidazolidin-2-ones from bicyclic and tricyclic ketones in a four-step sequence was described, by successive spirohydantoin Bucherer-Berg formation, mono- and dialkylation of the nitrogen atom of the hydantoin ring, regioselective reduction of one carbonyl function, and cationic cyclization associated with ring expansion. The key step of this sequential reaction was based on a tandem transposition/intramolecular amidoalkylation of cyclic spiro-N-acyliminium species. The process seems to be easy, general, regiospecific, resulted in the formation of polyheterocyclic systems containing an imidazolidin-2-one nucleus in good to excellent yields (67-99%), and is compatible with a large-scale production (up to 3 g of product 14, for example). Also, this method allows the preparation of the novel heterocycles 14 and 15 that have pharmaceutically interesting profiles, which are not accessible through short current synthetic methods. Finally, products 15 bear a secondary amide function crucial for further transformations, including the introduction of various pharmacophore groups either at the C or the N atoms of the imidazole ring.

Full text of DOI:10.1021/jo060616s

General and Versatile Entry to 4,5-Fused Polycyclic Imidazolones
Systems. Use of the Tandem Transposition/π-Cyclization of
N-Acyliminium Species
Anthony Pesquet,† Adam Da¨ıch,*,† and Luc Van Hijfte‡
URCOM, EA 3221, UFR des Sciences & Techniques, UniVersite´ du HaVre, 25 rue Philippe Lebon,
B.P. 540, F-76058 Le HaVre Cedex, France, and Johnson & Johnson, Pharmaceutical Research
and DeVelopment, DiVision of Janssen-Cilag, Campus de Maigremont, B.P. 615,
F-27106 Val-de-Reuil Cedex, France
adam.daich@uniV-lehaVre.fr
ReceiVed March 21, 2006
A simple and efficient methodology for the synthesis of 4,5-fused imidazolidin-2-ones from bicyclic and
tricyclic ketones in a four-step sequence was described, by successive spirohydantoin Bucherer-Berg
formation, mono- and dialkylation of the nitrogen atom of the hydantoin ring, regioselective reduction of
one carbonyl function, and cationic cyclization associated with ring expansion. The key step of this
sequential reaction was based on a tandem transposition/intramolecular amidoalkylation of cyclic spiro-
N-acyliminium species. The process seems to be easy, general, regiospecific, resulted in the formation
of polyheterocyclic systems containing an imidazolidin-2-one nucleus in good to excellent yields
(67-99%), and is compatible with a large-scale production (up to 3 g of product 14, for example). Also,
this method allows the preparation of the novel heterocycles 14 and 15 that have pharmaceutically
interesting profiles, which are not accessible through short current synthetic methods. Finally, products
15 bear a secondary amide function crucial for further transformations, including the introduction of
various pharmacophore groups either at the C or the N atoms of the imidazole ring.
Introduction
have received increasing attention, in the pharmaceutical
industry and the medicinal chemistry community, due to their
application in several major pathologies. As representative
structures, N-substituted pyridin-4-yl-imidazole derivatives SB-
235699 (1a),2 SB-216995 (1b),2 SB-203580 (1c),4 SB-210313
Polysubstituted 4,5-diarylimidazoles are common heterocyclic
components in biologically important small molecules, and
consequently they constitute an interesting class of pharmaceu-
ticals and investigational drugs.1 During the past few years, they
(1) Boehm, J. C.; Smietana, J. M.; Sorenson, M. E.; Garigipati, R. S.;
Gallagher, T. F.; Sheldrake, P. L.; Bradbeer, J.; Badger, A. M.; Laydon, J.
T.; Lee, J. C.; Hillegass, L. M.; Griswold, D. E.; Breton, J. J.; Chabot-
Fletcher, M. C.; Adams, J. L. J. Med. Chem. 1996, 39, 3929-3937.
* To whom correspondence should be addressed. Phone: (+33) 02-32-74-
44-03. Fax: (+33) 02-32-74-43-91.
† Universite´ du Havre.
‡ Johnson & Johnson.
10.1021/jo060616s CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/08/2006
J. Org. Chem. 2006, 71, 5303-5311
5303

Pesquet et al.
FIGURE 1. Inhibitors of p38R MAP kinase and cytokine release 1-4, and inhibitors of other kinases 5,6 and our targets 4,5-fused polycyclic
imidazoles 7.
(1d),5 ML-3163 (1e),4 and ML-3375 (1f)5 are potent and highly
selective p38R MAP (mitogen activated protein) kinase inhibi-
tors and involved in cytokine release.2 Several other lead
molecules (e.g., SB-242235 (2),6 RWJ-67657 (3),7 and L-790070
(4)8) have been advanced to proclinical and clinical studies.
Interestingly, in the precedent year, two disclosures present
scaffolds with structures related to the prototypical inhibitor
(SB-203580 (1c)),9 and structures of type 510 containing re-
placements of the pyridine ring and substituents on the benzene
and imidazole nucleuses have shown a distinct profile because
they act as the native Emieria tenella cGMP-dependent protein
kinases (PKGs) inhibitors in vitro, as anti-coccidial agents in
chickens in vitro, and as anti-obesity agents, respectively. In
the latter case, products 5 act as human CB1 (Cannabinoid
receptor of type 1) receptor inverse agonist, which was im-
plicated in both the energy balance and the control of weight
via a dual mechanism of the regulation of energy expenditure
and food intake modification.11
Interestingly, only one structure bearing all nucleuses present
in the above prototype components (Figure 1) is mentioned in
the literature. This product, as a pyridone-containing tetracycle
6 in which the pyridine and benzene rings are connected, inhibits
efficaciously the Jak family of protein tyrosine kinase, which
transduce extra-cellular signals by phosphorylating cytoplasmic
proteins.12
The general synthesis of these kinds of products was built
around substituted imidazole-2-thiones as the key intermediates
followed by subsequent modification of the thioamide function
via the corresponding 2-chloroimidazole using classical chem-
istry. These derivatives could be obtained using two different
synthetic pathways starting from common ketones.
A first general method was based on the construction of
imidazol-2-ones according to the Lettau procedure13 using the
‘‘ketonefnitrosation into R-hydroxyiminoketonefcyclization”
strategy. Because this protocol has been initially limited to the
synthesis of monosubstituted imidazole with a simple alkyl
substituent at the C4- or C5-position of the imidazole ring, serious
modifications in the reaction conditions were introduced by
(2) For a recent review in this area, see: Jackson, P. F.; Bullington, J.
L. Curr. Top. Med. Chem. 2002, 2, 1011-1020 and references therein.
(3) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem. 2004,
47, 6311-6325 and references therein.
(4) Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A. Angew. Chem.,
Int. Ed. 2002, 41, 2290-2293.
(5) Wagner, G. K.; Kotschenreuther, D. A.; Zimmermann, W.; Laufer,
S. A. J. Org. Chem. 2003, 68, 4527-4530 and references therein.
(6) (a) Fullerton, T.; Sharma, A.; Prabhakar, U.; Tucci, M.; Boike, S.;
Davis, H.; Jorkasky, D.; Williams, W. Clin. Pharmacol. Ther. 2000, 67,
114; Abstract OI-B-4. (b) Adams, J. L.; Boehm, J. C.; Gallagher, T. F.;
Kassis, S.; Webb, E. F.; Hall, R.; Sorenson, M. E.; Garigipati, R. S.;
Griswold, D. E.; Lee, J. C. Bioorg. Med. Chem. Lett. 2001, 11, 2867-
2870.
(7) Wadsworth, S. A.; Cavender, D. E.; Beers, S. A.; Lalan, P.; Schafer,
P. H.; Malloy, E. A.; Wu, W.; Fahmy, B.; Olini, G. C.; Davis, J. E.;
Pellegrino-Gensey, J. L. J. Pharmacol. Exp. Ther. 1999, 291, 680-687.
(8) Fitzgerald, C. E.; Patel, S. B.; Becker, J. W.; Cameron, P. M.; Zaller,
D.; Pikounis, V. B.; O’Keefe, S. J.; Scapin, G. Nat. Struct. Biol. 2003, 10,
764-769.
(9) Biftu, T.; Feng, D.; Ponpipom, M.; Girotra, N.; Liang, G.-B.; Qian,
X.; Bugianesi, R.; Simeone, J.; Chang, L.; Gurnett, A.; Liberator, P.; Dulski,
P.; Leavitt, P. S.; Crumley, T.; Misura, A.; Murphy, T.; Rattray, S.; Samaras,
S.; Tamas, T.; Mathew, J.; Brown, C.; Thompson, D.; Schmatz, D.; Fisher,
M.; Wyvratt, M. Bioorg. Med. Chem. Lett. 2005, 15, 3296-3301.
(10) Plummer, C. W.; Finke, P. E.; Mills, S. G.; Wang, J.; Tong, X.;
Doss, G. A.; Fong, T. M.; Lao, J. Z.; Schaeffer, M.-T.; Chen, J.; Chen,
C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Van der Ploeg, L.
H. T. Bioorg. Med. Chem. Lett. 2005, 15, 1441-1446.
(11) Trillou, C. R.; Arnone, M.; Delgorge, C.; Gonalons, N.; Keane, P.;
Maffrand, J. P.; Soubrie´, P. Am. J. Physiol.: Regul., Integr. Comp. Physiol.
2003, 284, 345-353.
(12) Thompson, J. E.; Cubbon, R. M.; Cummings, R. T.; Wicker, L. S.;
Frankshun, R.; Cunningham, B. R.; Cameron, P. M.; Meinke, P. T.; Liverton,
N.; Weng, Y.; DeMartino, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 1219-
1223.
(13) Lettau, H. Z. Chem. 1970, 10, 462-462.
5304 J. Org. Chem., Vol. 71, No. 14, 2006

Aza-Heterocycles Containing an Imidazole Ring
Laufer et al.,4 and consequently the sequence resulted in the
formation of 4,5-diarylimidazol-2-ones bearing a wide range
of different substituents at N1.
SCHEME 1. Retrosynthetic Scheme Leading to Our
Targets 4,5-Fused Polycyclic Imidazoles 7 of Types I, II, and
III from Bicyclic Ketones 8I and Tricyclic Ketones 8IIa
A second general method also used that strategy, but the latter
step furnished imidazole-N-oxides components. The latter step
constitutes a limitation of the sequence because the expected
imidazole-N-oxides derivatives could not be synthesized under
acidic conditions. However, this reaction becomes effective
under neutral conditions with good yields when sophisticated
and expensive thiazinanes were used as partners of the reaction.
In an ultimate stage, N-oxides products were converted suc-
cessfully and efficaciously into corresponding imidazole-2-
thiones with carbocyclic 1,3-dithiones.3-5 These cyclic thiones,
which were required for the preparation of 2-alkylsulfanylimi-
dazoles as 1c, 1e, and 1f, could be obtained also directly when
R-oximoketones were reduced selectively into R-aminoketones
prior to the ring closure with potassium thiocyanate.14 More
recently, other variations using R-hydroxyketones protected at
the OH function9 or not,10 R-bromoketones9 and diketones9
leading, respectively, to 2-piperidinoimidazoles as 4 and 2-car-
boxamidoimidazoles as 5, were also developed. Finally, an
additional multicomponent route to 2,4,5-triarylimidazoles ki-
nase inhibitors was described in two steps by reaction of
R-hydroxyiminoketones, aldehydes, and ammonium acetate in
refluxing acetic acid followed by the Lewis acid induced
N-hydroxyimidazole N-O cleavage.12,15 Also, this approach was
demonstrated to be effective in one pot and two steps under
microwave assistance,16 showing evidence of the thermally
N-O linkage breaking. By using the photochemistry of 2-py-
ridone readily accessible from 2-alkyl-4,5-diarylimidazoles, the
oxidative cyclization of the latter into the pyridone-containing
tetracycle12 constitutes a valuable method to accede new
generation of products 6, which have new spectra of kinase
activities.
a Key: Only cyclized products 7 of types I, II, and III, as possible
regioisomers, are represented.
transposition, which would produce the central six- and seven-
membered systems as fused imidazole compounds of types I
and II (Scheme 1), represents a novel and easy illustration of
this chemistry. In fact, as highlighted in the retrosynthetic
scheme, the selection of different alkyl, aralkyl, and aryl
substituents in spirohydantoin systems at the angular carbon as
in 9I and 9II, which are accessible from ketones 8I and 8II,
allows consideration of the stable N-acyliminium cation A. This
would act as an alkyl, aralkyl, and/or aryl scavenger after their
transposition according to pathways a and b in Scheme 1. Also,
the direct π-cyclization process leading to products 7 of type
III, with benzene as internal nucleophile, could constitute a
serious competing reaction. In the requisite intermediate A
generated from R-hydroxy lactams in acidic medium, cyclization
into imidazoles 7 (types I and II) and/or their regional isomers
not represented in the scheme may indeed originate from
intramolecular attack of either the electron-rich migrating
fragment or the less rich migrating one. At this stage, the
measurement of the impact of the nature of the migrating
fragment constitutes an important and interesting challenge for
the comprehension of the scope and limitation of this process.
In this sense, we present herein the preliminary results of our
finding on this combination of transposition/π-cationic cycliza-
tion and a mechanistic aspect of the transformation to access a
library of small molecules containing an imidazole nucleus fused
to simple and complex carbocycles and heterocycles.
Results and Discussion
Because the synthetic approaches toward these types of fused
imidazoles17 are few explored in the literature, allied with our
interest in the development of synthetic methodologies toward
original aza-heterocyclic systems containing an imidazole ring
fused to polycyclic skeletons with promising pharmaceutical
properties, we have continued to explore synthetic opportunities
on the basis of our recent reports using N-acyliminium cycliza-
tion in tandem with Grignard reaction,18 Pummerer cyclization,19
N-acyliminium ion isomerization,20 and N-acyliminium ion
isomerization/double alkyl transposition.21
To the best of our knowledge, the application of this
π-cationic cyclization in association with alkyl, aralkyl, and aryl
(14) Interestingly, the concomitant reduction of the ketone adjacent to
the oxime has been rendered marginal when the reduction process was
performed with Pd-catalyzed hydrogenolysis under acid conditions. For this
end, see: Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht,
W. J. Med. Chem. 2003, 46, 3230-3244.
(15) Laufer, S. A.; Striegel, H.-G.; Wagner, G. K. J. Med. Chem. 2002,
45, 4695-4705.
(16) Sparks, R. B.; Combs, A. P. Org. Lett. 2004, 6, 2473-2475.
(17) Photochemically driven oxidative cyclization of 4,5-diphenylimi-
dazole and other similar compounds has also been reported. For this purpose,
see: Purushothaman, E.; Pillai, V. N. R. Indian J. Chem., Sect. B 1989,
28, 290-293.
(18) (a) Da¨ıch, A.; Marchal´ın, Sˇ.; Pigeon, P.; Decroix, B. Tetrahedron
Lett. 1998, 39, 9187-9190. (b) Chihab-Eddine, A.; Da¨ıch, A.; Jilale, A.;
Decroix, B. Tetrahedron Lett. 2001, 42, 573-576. (c) Chihab-Eddine, A.;
Da¨ıch, A.; Jilale, A.; Decroix, B. Heterocycles 2002, 58, 449-456.
(19) Hucher, N.; Decroix, B.; Da¨ıch, A. Org. Lett. 2000, 2, 1201-1204.
For our study, spirohydantoins 9 as starting materials were
synthesized (Scheme 2). For this purpose, we have chosen the
use of the well-established Bucherer-Berg reaction22 for the
following reasons: (1) the reaction uses cheap reagents as well
(20) (a) Hucher, N.; Decroix, B.; Da¨ıch, A. J. Org. Chem. 2001, 66,
4695-4703. (b) Cul, A.; Chihab-Eddine, A.; Pesquet, A.; Marchal´ın,
Sˇ.; Da¨ıch, A. J. Heterocycl. Chem. 2003, 40, 499-505. (c) Fogain-Ninkam,
A.; Da¨ıch, A.; Decroix, B.; Netchita¨ılo, P. Eur. J. Org. Chem. 2003, 4273-
4278. (d) Hucher, N.; Pesquet, A.; Netchita¨ılo, P.; Da¨ıch, A. Eur. J. Org.
Chem. 2005, 2758-2770.
(21) Pesquet, A.; Da¨ıch, A.; Decroix, B.; Van Hijfte, L. Org. Biomol.
Chem. 2005, 3, 3937-3947.
J. Org. Chem, Vol. 71, No. 14, 2006 5305

Pesquet et al.
SCHEME 2. Scheme Leading to Starting Spirohydantoins
SCHEME 3. Scheme Leading to N1,N3- and N3-Alkylated
9Ia-f and 9IIg,ha
Spirohydantoins 10a-h and 11a-ga
a Key: N1-Benzylation reaction was not observed in this case.
poor yields of 12% and 21%, respectively. It is noteworthy that,
although a variety of reaction times, solvent ratios, and
temperatures were explored, the formation of spiro-hydantoins
9If and 9IIh was not accompanied by the increase of the yield.
This is probably due to the relatively low electrophilicity of
ketones as well as their low solubility in the solvents of the
reaction (EtOH-H2O). The structure of spirohydantoins 9 was
1
secured by their H and 13C NMR spectra, including DEPT
programs and elemental analyses. The 1H NMR spectra showed
two NH singlets exchangeable with D2O. More interestingly,
the 13C NMR spectra revealed the presence of two quaternary
carbons corresponding to C2dO and C4dO hydantoin functions
at δ ) 156.5-156.9 ppm and δ ) 173.6-178.6 ppm,
respectively. The spectra revealed also a ‘‘spiro-carbon” C4 at
δ ) 60.8-71.9 ppm. These values are comparable to that
reported in the literature for related spirohydantoins.22,23
Next, we treated the spirohydantoins 9 with base and halides
in different exploratory experimental N-alkylation conditions.
From these results, its seems that the alkylation process under
solid-liquid-phase transport catalysis (PTC) conditions con-
stitutes the best method to accomplish this sequence because
they furnish two separable products in accordance with our
prediction. The monoalkylation reaction of hydantoin 9 at N3
exclusively could also be achieved in acceptable yield by using
KOH as a base and polar protic (EtOH) or polar nonprotic
(DMSO) as solvent according to the reported protocols.26 The
monoalkylation process of hydantoin was also reported in the
literature by using the Mitsunobu synthesis.27
a Key: For comparisons, see the following references: (a) ref 23; (b)
ref 39; and (c) ref 22b.
as soft conditions, (2) the reaction was accomplished in one
step starting from the appropriate ketones, and finally (3) the
reaction is easy to use and is compatible with a large-scale
production. Under these conditions (i.e., 1.5 equiv of KCN, 10
equiv of (NH4)2CO3, EtOH-H2O (1:1), 55-60 °C), good to
excellent yields (63-98%)23 were obtained after 24 h to 3 weeks
of reaction with ketones 8Ia-e and 8IIg. A substrate in pyr-
role series as 8If24 and 8IIh25 underwent spirocyclization in very
So, as depicted in Scheme 3, the N1,N3-dialkylated and
N3-alkylated spirohydantoins 10a-h and 11a-g were ob-
tained by condensation of benzyl bromide with spirohydantoins
9a-h under PTC using anhydrous potassium carbonate as base
and a mixture of potassium iodide and crown ether 18-C-6 as
(22) (a) Bucherer, H. T.; Brandt, W. J. Prakt. Chem. 1934, 5, 129-150.
(b) Henze, H. H.; Speer, R. J. J. Am. Chem. Soc. 1942, 64, 522-523. (c)
Edward, J. T.; Jitrangsri, C. Can. J. Chem. 1975, 53, 3339-3350.
(23) In general, our yields are better than those reported in the literature
except for the spirohydantoin 9Ic. For that, see: Sarges, R.; Schnur, R. C.;
Belletire, J. L.; Peterson, M. J. J. Med. Chem. 1988, 31, 230-243.
(24) Santaniello, E.; Farachi, C.; Ponti, F. Synthesis 1979, 617-618.
(25) Mazzola, V. J.; Bernady, K. F.; Franck, R. W. J. Org. Chem. 1967,
32, 486-489.
(26) (a) Kohn, H.; Liao, Z.-K. J. Org. Chem. 1982, 47, 2787-2789. (b)
Liao, Z.-K.; Kohn, H. J. Org. Chem. 1984, 49, 3812-3819. (c) Liao, Z.-
K.; Kohn, H. J. Org. Chem. 1984, 49, 4745-4751. (d) Ware, E. Chem.
ReV. 1950, 46, 403-470. (e) Lopez, C. A.; Trigo, G. G. AdV. Heterocycl.
Chem. 1985, 38, 177-228.
(27) Mitsunobu, O. Synthesis 1981, 1-28.
5306 J. Org. Chem., Vol. 71, No. 14, 2006

Aza-Heterocycles Containing an Imidazole Ring
SCHEME 4. Scheme Leading to r-Hydroxyspirolactams
12a-h and 13a-ga
the case of component 12c, only traces of the second isomer
were observed.
With the same protocol as above, the reduction of N3-ben-
zylated spirohydantoin 11a, as a representative model of
monoalkylated spirohydantoins class, occurred and led to the
expected R-hydroxyspirolactam 13a as a minor and inseparable
reduced isomer. This was accompanied, particularly, with the
opened ureine-alcohol and other products difficult to identify.
The use of this protocol at ambient temperature led also to
starting material unchanged due to its insolubility in ethanol
11a. To perform this sequence, our attention was directed to
other reductant agents. Earlier studies have shown that N3-alkyl-
and N3-aralkylhydantoins substituted at C3 could be reduced
selectively into corresponding 4-hydroxyimidazolidin-2-ones
with LiAlH4 in anhydrous THF or diethyl ether at room
temperature.26b,c,29b,31 The reaction under slightly more vigorous
conditions (reflux of THF or diethyl ether) gave the expected
products accompanied by imidazolidin-2-ones,32 imidazoles,33
and/or imidazolidines.32,33 In light of these findings, we decided
to adopt this protocol for the above spirohydantoins. At the
outset, spirohydantoin 11a was engaged in this reaction.
Surprisingly, this yielded cleanly R-hydroxyspirolactam 13a as
a >9.5:0.5 mixture of two diastereomers in 74% yield after
treatment of 11a with 3 equiv of LiAlH4 in dry THF at -5 to
0 °C for 1 h, and then 12 h at ambient temperature. Recrystal-
lization of the crude product from dry ethanol led to 13a in
pure form.
The results with a variety of N3-benzylspirohydantoins 11b-g
are presented in Scheme 4 and showed the effectiveness in all
cases of the experimental procedure that was characterized, in
addition, by operational simplicity. Because byproducts as
spiroimidazolidin-2-ones32 and/or spiroimidazolidines32,33 are
formed according to the reports of the above authors26,29 and
others32,33 for “nonspiranic” hydantoins, isolation of the expected
products 13b-g entailed simply diluting the reaction mixture
with EtOH-5% HCl solution followed by filtration on a short
column of Celite, concentration, water dilution, organic separa-
tion, solvent evaporation, and finally recrystallization of the
crude products. In some cases, prior removal of the organic
solvent facilitated this process. The crude products isolated in
this fashion precipitate out of the solution and were generally
of high purity as judged by NMR spectral data and elemental
analyses (products 13a-d and 13g). From the results sum-
marized in Scheme 4, it is apparent that high to excellent yields
of R-hydroxyspirolactams 13 are generally obtained except in
the case of products 13a and 13d, for which yields are of 74%
and 71%, respectively. Interestingly, adducts 13a, 13b, 13d, and
13g were obtained as a single isomer. Component 13g was
isolated in ethoxy form, which resulted from the etherification
of its R-hydroxyspirolactam congener with ethanol in acidic
medium via the intermediacy of N-acyliminium cation.30 In
addition, if R-hydroxyspirolactam 13c was isolated as a mixture
of two isomers with, however, only trace amounts of the minor
one, R-hydroxyspirolactams 13e and 13f were obtained in 9.5:
0.5 and 5.5:4.5 ratios and as inseparable mixtures.
a Key: (a) Yields of the crude product. (b) The products were obtained
as two inseparable isomers. (c) The product is not isolated in pure form.
(d) This hydroxyspirohydantoin was isolated in ethoxy form. (e) No
reduction was conducted in this case.
catalysts.28 Under these conditions, compounds 10a-h and
11a-g as crystalline solids were obtained after refluxing in dry
toluene for 24 h, followed by chromatography separation on a
silica gel column in yields ranging from 13% to 39% for 10a-h
and 25% to 57% for 11a-g, respectively. From these results,
it is clear that the N1,N3-dialkylated spirohydantoins are the
major products except for spirohydrantoins 10b and 10e. Also,
from 9h as a starting spirohydrantoin, only the dialkylated
product 10h was isolated as the sole reaction product with,
however, a modest yield (39%).
The alkylated spirohydantoins 10 and 11 were then submitted
separately to the reduction reaction, for the isolation of the
corresponding R-hydroxyspirolactams as N-acyliminium cations
precursors (Scheme 4). According to Hough et al. reports on
hydantoins,29 inspired from the Speckamp work on N-alkylated
succinimides,30 the reduction of N1,N3-dialkylated spirohydan-
toins 10a-h was carried out with a large excess of NaBH4 (6
equiv) in dry ethanol at reflux for 1.5-24 h (the reaction was
monitored by TLC using a silica gel column and CH2Cl2 as
eluent). The resulting R-hydroxyspirolactams 12a-h were
isolated in pure form after classical workup followed by
recrystallization from suitable solvent in excellent yields
(86-99%), although mixtures of isomers were often obtained.
In fact, 4-hydroxy-N1,N3-dibenzylspirohydantoins 12b, 12e, and
12g were isolated in yields of 91%, 97%, and 96%, respectively,
as the sole reaction products. On the contrary, 4-hydroxyspiro-
hydantoin derivatives 12a, 12d, 12f, and 12h were obtained in
9:1, 5.5:4.5, 9.5:0.5, and 7:3 mixtures of two isomers inseparable
in yields of 92%, 99%, 99%, and 86%, respectively. Finally, in
One final aspect that deserves comment concerns the structure
determination of R-hydroxyspirolactams 12a-h and 13a-g.
(28) (a) Hucher, N.; Da¨ıch, A.; Decroix, B. J. Heterocycl. Chem. 1998,
35, 1477-1548. (b) Chihab-Eddine, A.; Da¨ıch, A.; Jilale, A.; Decroix, B.
J. Heterocycl. Chem. 2000, 37, 1543-1548.
(29) Hough, T. L. J. Heterocycl. Chem. 1989, 26, 1523-1525. See
also: Cortes, S.; Kohn, H. J. Org. Chem. 1983, 48, 2246-2254.
(30) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-
3856.
(31) Marquez, V. E.; Twanmoh, L.; Wood, H. B.; Driscoll, J. S. J. Org.
Chem. 1972, 37, 2558-2561.
(32) (a) Marshall, F. J. J. Am. Chem. Soc. 1956, 78, 3696-3697. (b) De
la Costa, E.; Ballestros, P.; Trigo, G. G. Heterocycles 1981, 16, 1647-
1650.
(33) Wilk, I. J.; Close, W. J. Org. Chem. 1950, 15, 1020-1022.
J. Org. Chem, Vol. 71, No. 14, 2006 5307

Pesquet et al.
Thus, the assignment of these structures was made on the basis
of their IR and NMR spectra (1H,13C experiments including
NOE difference and DEPT programs, respectively). In the case
of solids, their elemental analyses were also performed. So, the
1H NMR spectra of 12a-h (CDCl3) and 13a-g (DMSO-d6)
showed the methylene group of the -N-CH2- functionalities
as an AB system due to the diastereotopic effect with a coupling
constant of J ) 15-17 Hz for 12a-h and 13a-g characteristic
of gem protons. Also, the newly created angular proton CH in
12a-h appears as a doublet at δ ) 4.47-4.89 ppm with a
coupling constant of J ) 7-11 Hz characteristic of a geminate
coupling between CH and OH in the secondary “alcohol”
function,34 except for R-hydroxyspirolactam 12f in which no
coupling of CH(OH) was observed. Interestingly, the same
angular protons in 13a-g appear as a singlet in the majority of
the cases at δ ) 4.31-4.70 ppm except for 13c. In this case,
CH appears as a doublet at δ ) 4.71 ppm with J ) 10 Hz
comparable to that observed for its homologues 12a-h. In
addition, the 1H NMR spectral data of 13a-g showed an N-H
signal as a broad singlet at δ ) 4.69-7.10 ppm, which is
exchangeable with D2O. Likewise, the key feature in the 13C
NMR spectra of 4-hydroxyspirohydantoins 12a-h and 13a-g
was the appearance of an additional tertiary carbon (CH(OH))
at δ ) 82.4-86.6 ppm for 12a-h and at δ ) 84.4-85.8 ppm
for 13a-g, while, in comparison to their spirohydantoins
examples for this intramolecular amidoalkylation transformation
(Scheme 5). Thus, treatment of the N-acyliminium precursor
12a with neat TFA,36a formic acid,26b,37 catalytic amounts of
PTSA,26a,35a-c or TFAA alone26c or in the presence of Lewis
acid as SnCl426b failed or furnished a mixture of some products
accompanied in all cases by the unreacted starting material. The
best formulation to accomplish this reaction totally seems to
be a mixture of TFAA/TFA in precise proportion (1/1) as
mentioned in a few cases earlier.26a,b In these acidic conditions
(i.e., TFAA/TFA (1/1) with a slight excess (1.3 equiv) of each
reactant relative to substrate, CH2Cl2, reflux, 24 h), the cyclized
product, identified as 1,3-dibenzyl-4,5-dihydrobenzo[e]benz-
imidazol-2-one (14a), was isolated as a crystalline material in
97% yield. From this result, its seems that the reaction did not
occur by direct attack of the N-acyliminium intermediate Ia
(Scheme 5) with the π-aromatic system by N3 to furnish the
spiro-fused imidazolone product of type III (Scheme 1), but
by a tandem transposition/cationic cyclization process in a one-
pot procedure. To determine the nature of the fragment, which
transposed during the process, the examination of the “pseudoun-
symmetrically” ω-carbinollactam 13a was necessary. So, 13a
under the same protocol as above led to 1-benzyl-4,5-dihy-
drobenzo[e]benzimidazol-2(3H)-one (15a) in 92% yield after
recrystallization of the crude product from dry ethanol. The
phenyl migrating group during the reaction as well as the
structures of the cyclized products 14a and 15a were determined
from a consideration of the published results in related bicyclic
imidazolones.35 Confirmation was obtained from NOE experi-
ments that involved irradiation of the methylene protons of the
benzyl group and aromatic proton H9 of the monobenzylated
cyclized product 15a (see Scheme 5). In this case, the resulting
NMR spectra exhibited a significant NOE enhancement, indicat-
ing that the H9 and the methylene protons are spatially proximate
and consequently the migrating group is on the same side of
the benzyl group. Finally, because of the potential concurrent
NOE effects in the same spectral region of the two benzylic
protons, the NOE experiments were not done on the product
14a.
congeners 10a-h and 11a-g, one quaternary carbon (δCdO
)
170.9-175.9 ppm for 10a-h and δCdO ) 172.0-176.4 ppm
for 11a-g) disappears in the aromatic region. These facts are
the consequence of the regioselective reduction of one of the
carbonyl functions under the conditions discussed above. Im-
portantly, from an examination of the above results, it is apparent
that the stereochemical outcome of the reduction reaction is
independent of the substitution at nitrogen(s) atom(s) as well
as the “spiro” fragment attached at the C4 position of the
hydantoin nucleus. Interestingly, these facts were of no conse-
quence to the overall synthetic strategy because the hydroxy-
spirolactams furnished under acidic influence a planar N-
acyliminium species as intermediates of the cyclization reaction.
Because of the small body of literature on hydroxycycla-
nespirolactams regarding the reactivity of these functionalities
in acidic medium35 allied with the fact that only N3-aralkyl-
(alkenyl and acetylenic)-4-hydroxyimidazolidin-2-ones26a-c,36
and 4-alkenyl-4-hydroxyimidazolidin-2-ones37 were explored in
intramolecular N-carbamoyliminium ion cyclization reactions,
the behavior of ω-carbinollactams of types 12 and 13 bearing
two nucleophiles was examined under acid influence. The
hydantoins in substrates 12 and 13 differed in the nature of the
cycle as “spiro” group attached at the C5 position, and minor
variation also existed at the N1 position (R1 = Bn for 12 and
R1 = H for 13).
Having established the facility and capacity of “symmetrical”
and “unsymmetrical” hydroxylactams 12a and 13a to provide
a tandem aryl transposition/π-cationic cyclization in forming
interesting fused N-heterocyclic systems, we envisioned whether
this process might be extended for the preparation of other six-
membered rings, corresponding seven-membered rings bearing
a heteroatom or not, and other aromatic nuclei fused to
imidazolone. Thus, attempts under our cyclization protocol as
delineated in Scheme 5 from hydroxylactams as 12b-e and
13b-e proved successful in all cases, and in each case only
one product was obtained with excellent yields ranging from
86% to 98% except for product 14b. In the latter case, the 1,3-
dibenzyl-4,9-dihydrobenzo[f]benzimidazol-2-one (14b) (38%)
was accompanied by the corresponding oxidized component,
1,3-dibenzylbenzo[f]benzimidazol-2-one (18), in 58% yield and
was easily separated by chromatography on a silica gel col-
umn using a mixture of cyclohexane/AcOEt in a 3/2 ratio as
eluent. Also, in the case of substrate 13d, no reaction occurred;
only trace amounts of starting material were recovered. From
these results, products 14a,c,e and 15a,c,e showed an aryl
migrating group, while products 14b,d and 15b evidenced the
migration of the benzyl group instead of the phenylethyl one
for 14d. Importantly, in all cases, the reaction seems to be
regiospecific because during the cyclization process only the
At the outset of our investigations, the 4-hydroxyimidazolidin-
2-ones 12a (R1 = Bn) and 13a (R1 = H) were chosen as test
(34) Comparable coupling constant values are traditionally observed in
the R-hydroxylactams products. This phenomenon is breakable when adding
D2O. See refs 18-21 for examples.
(35) To our knowledge, only a few reports in this area are published.
See: (a) Rubido, J.; Pedregal, C.; Espada, M. Synthesis 1985, 307-309.
(b) Salazar, L.; Rubido, J.; Espada, M.; Pedregal, C.; Trigo, G. J. Heterocycl.
Chem. 1986, 23, 481-485. (c) Pedregal, C.; Espada, M.; Salazar, L. J.
Heterocycl. Chem. 1986, 23, 487-489.
(36) (a) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. Synthesis 1983,
585-587. (b) Hamersma, J. A. M.; Nossin, P. M. M.; Speckamp, W. N.
Tetrahedron 1985, 41, 1999-2005.
(37) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1985, 50, 1884-1888.
5308 J. Org. Chem., Vol. 71, No. 14, 2006

Aza-Heterocycles Containing an Imidazole Ring
SCHEME 5. Synthetic Pathway Leading to 4,5-Fused Imidazolidin-2-ones 14 and 15a
a Key: (a) This product was accompanied by the oxidized cyclic component 18 in 58% yield. (b) No tandem transposition/cyclization was observed in
this case.
SCHEME 6. Synthetic Transformations of Hydroxy Lactam
12b to 1,3-Dibenzyl-4,9-dihydrobenzo[f]benzimidazol-2-one
(14b) and 1,3-Dibenzylbenzo[f]benzimidazol-2-one (18)
of this oxidation reaction, which did not need any activator,
and due to the good acidity of the methylene protons in the
4,9-dihydrobenzo[f]benzimidazol-2-one core of 14b, product 18
was also obtained directly from hydroxyspirolactam 12b in 78%
yield after chromatography purification followed by recrystal-
lization from ethanol/diethyl ether. Also, in this case, we have
used the same general protocol established above, but 30 h at
refluxing CH2Cl2 was necessary for complete reaction (moni-
tored by TLC using cyclohexane/AcOEt (3/2) as eluting
solvents).
To establish the generality and versatility of this tandem
cyclization process, we decided to study the effect of hetero-
cyclic, tricyclic, and triheterocyclic nuclei as tetrahydroindole,
fluorene, and pyrrolo[1,2-a]indole. At the same time, our interest
was also to measure the impact of the steric and electronic
effects on the transposition-cyclization step.
Thus, the hydroxy lactams 12f and 13f in the tetrahydroindole
series were treated with TFAA/TFA (1/1) according to the
established protocol given above. The examination of the TLC
of the reaction mixture indicated the presence of only one
product (Scheme 7), which, after a classical workup, was
identified as 14f and 15f, respectively, resulting from the
successive formation of N-acyliminiun cation intermediate Af
(Scheme 1), the transposition of the pyrrole ring, and deproto-
nation. This process occurs cleanly and affords the 4,5-fused
imidazol-2-ones 14f and 15f in 99% and 81% yields, respec-
transposition of the electronically rich group was taken into
consideration.
Taking into account that product 14b is unstable under the
conditions of the reaction, an additional study on the transposi-
tion/N-amidoalkylation of 12b was envisaged. So, as highlighted
in Scheme 6, exposure of the isolated product 14b to the well-
established protocol gave after 12 h of the reaction exclusively
the oxidized product 18 in quantitative yield. No additional
purification of the product was needed. Because of the facility
J. Org. Chem, Vol. 71, No. 14, 2006 5309

Pesquet et al.
SCHEME 7. Synthetic Transformation of
Hydroxyspirolactams 12f-h and 13f,g into Azatricyclic and
Azatetracyclic Systems Containing an Imidazol-2-one
Nucleusa
in these cases, no preference between the migrating groups could
be done. In fact, in 14g and 15g only one phenyl migrating
group exists, while in 14h the presence of the benzyl group
attached at N1 and N3 rendered the choice of the migrating group
inoperative. These suggestions were based on published results35
and on our own studies using 1H NMR consideration as detailed
above. As a consequence, the second pathway b consisting of
the formation of the polyheterocyclic systems 16a-f and 17a-f
was definitely excluded.
1
Several key features in the H and 13C NMR spectra of the
cyclized compounds 14a-h and 15a-g were diagnostic of
structure. For instance, in the 1H NMR spectra of 1,3-
dibenzylimidazolidin-2-ones 14a-h, the methylene protons of
the -N-CH2- functionalities, which were an AB system in
hydroxylactams congeners 12a-h, appeared as a distinct singlet
between δ ) 4.81 and 5.70 ppm due to the absence of the
diastereotopic effect. The spectra showed also the disappearance
of two peak signals corresponding to the angular proton at C4
and OH (CH(OH) coupling) in 12a-h. For 3-benzylimidazo-
lidin-2-ones 15a-g, the 1H NMR spectra revealed the presence
of a distinct N-H absorption at δ ) 9.76-10.68 ppm for 15a-f
and in the aromatic region between δ ) 7.28 and 7.72 ppm for
product 15g, which disappeared after D2O exchange. They
revealed also the presence of a singlet corresponding to the
methylene protons of the benzyl group. Of particular note, this
one appeared at δ ) 4.48 and 5.66 ppm and was in general
upfield as compared to those in the structures of 14a-h. A small
shielding of ∆δ ) 0.10-0.18 ppm between products 14 and
15 was observed in all cases except for 14e and 15e in which
it was ∆δ ) 0.50 ppm.
Carbon-13 NMR data proved to be of particular value in the
assignment of the structure of 1,3-dibenzylimidazolidin-2-ones
14a-h and 3-benzylimidazolidin-2-ones 15a-g. The most
distinguishing feature in the 13C NMR spectra was the regular
appearance of one downfield signal between δ ) 153.3 and
156.0 ppm for 14a-h and δ ) 153.9 and 156.2 ppm for
15a-g, which have been attributed to the carbon C2.38 Variation
of the “substituents” at C4 and C5 positions on the imidazolidin-
2-one ring led to only small changes in the chemical shifts values
for this resonance. Yet we noted in this data set for the same
carbon C2 a consistent upfield shift of ∆δ ) 0.90-1.20 ppm in
comparison between 14a-e and 15a-e, while when we are
considering products 14f-h and 15f,g, importantly, a small
downfield signal of ∆δ ) 0.50-0.80 ppm was observed. This
is due probably, in the latter cases, to the presence of
diheterocyclic, tricyclic, and triheterocyclic fused imidazolidin-
2-one as constraint systems.
a Key: This hydroxyspirolactam 13g was isolated in ethoxy form.
tively. Although the pyrrole nucleus is present instead of the
phenyl one (in the N-acyliminium cations precursors 12a,c,e
and 13a,c,e), there is no discernible preference between the
phenyl and pyrrole groups. Furthermore, the pyrrole ring seems
to be stable in the TFAA-TFA combination without notable
affection of the transformation yields.
Similarly as above, hydroxyspirolactams in fluorene series
12g and 13g led to the cyclized products 14g and 15g. In this
reaction, the starting N-acyliminium ion precursor 13g was in
the ethoxy form (hydroxy- and ethoxylactams generate the same
N-acyliminium species in acidic medium). If the “symmetri-
cally” imidazol-2-one product 14g was isolated in an excellent
yield of 99%, the “unsymmetrically” imidazol-2-one 15g was
isolated in a decreased yield of 67%. This effect has also been
observed as above for the “pseudounsymmetrically” imidazol-
2-one 15f (81%) as compared to its “pseudosymmetrically”
homologue 14f (99%). Furthermore, the change of the steric
effect by considering hydroxyspirolactam in pyrrolo[1,2-a]indole
series did not affect the course of the reaction because the
treatment of 12h led to the cyclized product 14h in a very good
yield of 96%.
The synthetic pathway leading to the cyclized products 14a-f
and 15a-f occurred through a cascade process and commences
with the formation of N-acyliminium species Aa-f in acid
conditions. At this stage, two pathways a and b were possible
(Scheme 8). The first pathway a consists of the heterolytic
cleavage of the linkage Aryl-Cspiranic (n ) 0). The transposition
of the resulting electronically rich group (phenyl or pyrrole ring
in the case of 14a,c,e,f and 15a,c,e,f) to form the cyclic
N-acyliminium cations Ba-f was followed in an ultimate step
by its spontaneous deprotonation, affording the polyheterocyclic
targets 14a-f and 15a-f. Also, when the n value differs from
0, only the rich group migrates preferentially (benzyl group in
the case of 14b,d and 15b). Finally, the formation of the
products 14g,h and 15g seems to pursue the same facts because,
In summary, N1,N3-dibenzyl- and N3-benzylspirohydantoins
10a-h and 11a-g, obtained easily in good yields by the
N-alkylation process under PTC conditions in one step from
corresponding spirohydantoins 9Ia-f and 9IIg,h, have been
shown to undergo NaBH4 reduction (EtOH, reflux, 1.5-24 h)
and LiAlH4 reduction (THF, rt, 12 h) to give, respectively,
N1,N3-dibenzyl-4-hydroxy-5-spiroimidazolidin-2-ones (12a-h)
and N3-benzyl-4-hydroxy-5-spiroimidazolidin-2-ones (13a-g)
in good to excellent yields. It is noteworthy that the use of
LiAlH4 or NaBH4 for reduction of spirohydantoins 10a-h or
(38) (a) Fujiwara, H.; Bose, A. K.; Manhas, M. S.; Van der Veen, J. M.
J. Chem. Soc., Perkin Trans. 2 1980, 11, 1573-1577. (b) Poupaert, J. H.;
Claesen, M.; Degelaen, J.; Dumont, P.; Toppet, S. Bull. Soc. Chim. Belg.
1977, 86, 465-472.
(39) Goodson, L. H.; Honigberg, I. L.; Lehman, J. J.; Burton, W. H. J.
Org. Chem. 1960, 25, 1920-1924.
5310 J. Org. Chem., Vol. 71, No. 14, 2006

Aza-Heterocycles Containing an Imidazole Ring
SCHEME 8. Mechanism of the Formation of Systems Containing an Imidazol-2-one Nucleus
11a-g was not effective because the reaction failed in some
cases or gave a mixture of inseparable products containing the
starting material. The same observations were made also when
the reduction reaction was conducted at refluxing THF or diethyl
ether in the case of spirohydantoins 10a-h and when a
cosolvent such as THF or diethyl ether was present in the cases
of spirohydantoins 11a-g.
Finally, we anticipate that the novel transformations devel-
oped in this project, particularly the access to the substituted
imidazolidin-2-ones of type 15, will find further applications
in synthesis using either the secondary amide chemistry directly
or the sulfur chemistry via corresponding thioamides and their
functionalization. Our products of type 15 are particularly
adapted for these transformations as outlined in the Introduction.
These systems are currently under investigation in our laboratory
and will be reported soon.
The cyclization of the latter cyclic N-acyliminium precursors
of general structures 12 and 13 with TFAA-TFA combination
in precise proportion (1/1) provides a versatile short synthesis
of two categories of 4,5-fused tricyclic and tetracyclic imida-
zolidin-2-ones 14 and 15 under mild conditions and via an
interesting tandem transposition/π-cationic cyclization. The key
step of this transformation is based on the formation of the cyclic
N-acyliminium intermediates A, from which a transposition of
the electronically rich group resulted in the ring expansion
leading to a stable cyclic cation, which loses one proton
spontaneously to give the title products 14 and 15. Importantly,
whatever the presence of serious competing reactions as shown
in Schemes 1 and 8, the reaction seems to be clean and
regiospecific. Furthermore, this tandem process seems to be
general to cyclic N-acyliminium ions derived from spirobicyclic
and spirotricyclic systems, compatible with a nonprotected
nitrogen atom, and furnished the desirable products in good to
excellent yields.
Acknowledgment. We are grateful to Johnson & Johnson,
Pharmaceutical R&D, Division of Janssen-Cilag, for support
of this research. We thank also the Region of “Haute Nor-
mandie” for a Regional-Industrial Graduate Fellowship (BRI/
2000-2003), attributed to A.P. We also are grateful for many
helpful comments from and discussions with Professor Bernard
Decroix (University of Le Havre) throughout the course of this
work.
Supporting Information Available: Spectroscopic data of all
1
compounds including H NMR, 13C NMR (DEPT program), and
IR spectra and complete experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060616S
J. Org. Chem, Vol. 71, No. 14, 2006 5311