A diastereoselective synthesis of pseudopeptidic hydantoins by an Ugi/cyclization/Ugi sequence

Article abstract of DOI:10.1016/j.tet.2012.01.073

A diastereoselective synthesis of helix-forming pseudopeptidic hydantoins by an Ugi 4CC/cyclization/reduction/Ugi 4CC sequence of reactions, giving mainly the l-adduct when benzoic acids were used, is described.

Full text of DOI:10.1016/j.tet.2012.01.073

Tetrahedron 68 (2012) 2621e2629
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journal homepage: www.elsevier.com/locate/tet
A diastereoselective synthesis of pseudopeptidic hydantoins by an Ugi/cyclization/
Ugi sequence
a
a
b
,
a,
*
*
~
ꢀ
María Sanudo , María García-Valverde , Stefano Marcaccini , Tomas Torroba
a Departamento de Química, Facultad de Ciencias, Universidad de Burgos, 09001 Burgos, Spain
Dipartamento di Chimica “Ugo Schiff”, Universita di Firenze, via della Lastruccia 13, I-50121 Sesto Fiorentino (FI), Italy
b
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective synthesis of helix-forming pseudopeptidic hydantoins by an Ugi 4CC/cyclization/
Received 19 December 2011
Received in revised form 23 January 2012
Accepted 25 January 2012
Available online 30 January 2012
reduction/Ugi 4CC sequence of reactions, giving mainly the
described.
L
-adduct when benzoic acids were used, is
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide
Ugi reaction
Pseudopeptidic
Hydantoin
Diastereoselective
1. Introduction
of Ugi/cyclization/Ugi reactions could easily give rise to peptide-
hydantoin chivmeras belonging to a new class of drug-like pepti-
domimetics. Not only the design demonstrated to be successful
but, as a bonus of the sequence, the second Ugi reaction showed
Hydantoins (imidazolidine-2,4-diones) constitute a very old
class of cyclic ureides of a
-amino acids,1 largely used as anticon-
vulsant drugs (i.e., phenytoin and its derivatives),2 also present in
a plethora of other commercial pharmaceutical products.3 Fur-
thermore, hydantoins are privileged scaffolds in the structure of
several new leads for current pharmacological developments such
as small-molecule inhibitors of cell division,4 a model for the dis-
covery of the PDE5 inhibitor tadalafil,5 nonsteroidal androgen re-
ceptor antagonists or agonists,6 and are present in some important
pharmacologically active naturally occurring hydantoin alkaloids7
or their synthetic precursors.8 The conformational rigidity of the
hydantoin scaffold in aminoacid derivatives9 and, very specially, in
peptidomimetics10 is crucial for their biological stability and ac-
tivity, often mimicking the appropriate conformation of the natural
polypeptide whose biological action is sought. Therefore the syn-
thesis of hydantoins is a very active research field,11 even if the
preparative methods for pseudopeptide hydantoins are still un-
common. We have previously developed some synthetic methods
for the preparation of pseudopeptidic benzodiazepines, diazepines,
diazocines, and triazinylalaninamides,12 as well as monocyclic
hydantoins,13 via Ugi four-component condensations followed by
cyclization reactions.14 We reasoned that a sequential combination
an unexpected diastereoselectivity, giving mainly the L-adduct
when benzoic acids were used. Diastereoselective Ugi reactions are
scarce,15 therefore in this paper we want to report our results in
the diastereoselective synthesis of pseudopeptidic hydantoins by
a sequence of Ugi/cyclization/reduction/Ugi reactions.
2. Results and discussion
We selected the readily available m- and p-nitrobenzaldehydes
as starting materials for the first Ugi reaction because the nitro
group could activate the carbonyl moiety and because the nitro
group could serve as a masked amino group for a further Ugi re-
action. Therefore, a mixture of nitrobenzaldehydes 1a,b (1 equiv)
and anilines 2aee (1 equiv) was stirred in methanol at room tem-
perature for 10 min, then isocyanides 3a,b (1 equiv) and tri-
chloroacetic acid 4 (1 equiv) were added consecutively to the imine
solution, and the mixture was stirred in methanol at room tem-
perature for one day until solid 5aef precipitated.16 Filtration and
recrystallization of the solid afforded 2-[N-aryl-N-(trichloroacetyl)
amino]-2-arylacetamide derivatives 5aef in fair yields (44e88%)
(Scheme 1), that were subsequently stirred in methanol with 1 M
sodium ethoxide (1 equiv) for 5 min, chilled, and the precipitate
filtered off to get 3-alkyl-1,5-diarylimidazolidin-2,4-dione
* Corresponding authors. Tel.: þ34 947 258088; fax: þ34 947 258831; e-mail
addresses: stefano.marcaccini@unifi.it (S. Marcaccini), ttorroba@ubu.es (T. Torroba).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.073

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
Scheme 1. Synthesis of hydantoin pseudopeptides 10aeu.
derivatives 6aef in fair yields (66e95%). Nitro groups in 6aef were
reduced to the amino derivatives 7aef by iron powder in acetic acid
at 60 ꢀC for 30 min. Aqueous work-up, extraction with chloroform,
and recrystallization gave 3-alkyl-1,5-diarylimidazolidin-2,4-dione
derivatives 7aef in fair yields (48e94%). Finally, a mixture of al-
dehydes 8aed (1 equiv) and hydantoin aniline 7aef (1 equiv) was
refluxed in methanol for 30 min, then isocyanides 3a,b (1 equiv)
and carboxylic acid 9aeg (1 equiv) were added consecutively to the
imine solution, and the mixture was refluxed in methanol until all
reagents dissolved, then the mixture was maintained at room
temperature for 1 day without stirring until solid 10aeu pre-
cipitated. Filtration and recrystallization of the solid afforded
hydantoin pseudopeptides 10aef, from 7a,b, and 10geu, from
7cef, in fair yields (44e88%) (Scheme 1). The recrystallized prod-
ucts 10aeu were characterized by the usual spectroscopic and
analytical techniques. DEPT experiments of selected examples
permitted to assign all NMR signals. Products 10aeu were obtained
in most cases as uneven mixtures of diastereoisomers, the relation
of them was calculated on the basis of NMR spectra in CDCl3 taken
from the reaction product previously to and after recrystallization,
to guarantee that no enrichment in the diastereomeric mixture
happened during recrystallization. The best diastereoselection was
achieved by using benzoic acids, suggesting that the planar aro-
matic nucleus had a strong influence on the mechanism. A plausible

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2623
Table 1
mechanism should consist on the attack of the isocyanide on the
protonated imine through a seven-centered transition state, sta-
bilized by stacking of the aromatic rings, by the opposite side
to the bulk hydantoin moiety with lk-selectivity (Scheme 2). When
there is no
stacking, the classic mechanism should apply,15f
H NMR signals for some hydantoins in the 6.4e5.0 ppm region
1H NMR (ppm) diast.1
d
1H NMR (ppm) diast.2
pep
10
d
d
6.05 (s, 1H, CH)
5.53 (d, J¼8.1 Hz, 0.92H, NH)
5.57 (d, J¼8.1 Hz, 0.08H, NH)
pep
5.11 (s, 1H, CH)
therefore losing most of the diastereoselectivity.
h
k
n
p
s
6.19 (s, 0.93H, CH),
6.13 (s, 0.07H, CH),
5.58 (d, J¼8.2 Hz, 0.07H, NH)
5.42 (d, J¼7.8 Hz, 0.93H, NH)
5.10 (s, 1H, CH)
6.11 (s, 0.93H, CH),
6.07 (s, 0.07H, CH),
5.55 (d, J¼8.1 Hz, 0.93H, NH)
5.71 (d, J¼8.5 Hz, 0.07H, NH)
5.09 (s, 0.93H, CH)
5.07 (s, 0.07H, CH)
6.05 (s, 1H, CH)
5.53 (d, J¼8.1 Hz, 0.92H, NH)
5.57 (d, J¼8.1 Hz, 0.08H, NH)
5.11 (s, 1H, CH)
6.28e6.20 (m, 1.96H, HArþ0.96H, CH)
5.59 (d, J¼7.9 Hz, 1H, NH)
5.28 (s, 1H, CH)
6.13 (s, 0.04H, CH),
6.18 (s, 0.86H, CH)
6.13 (s, 0.14H, CH)
5.50 (d, J¼8.3 Hz, 0.86H, NH)
5.66 (d, J¼8.1 Hz, 0.14H, NH)
5.15 (s, 1H, CH)
Scheme 2. A mechanism for hydantoin pseudopeptide 10k. Inset: X-ray diffraction
structure of 10k (only the S/S enantiomer).
The lk-selectivity is in agreement with the structure observed by
single crystal X-ray diffraction of the main diastereoisomer of 10k
(Scheme 2). The relative configuration of the main diastereoisomer
for similar hydantoins 10d,h,n,p,s (obtained from aromatic acids
9b,f,g) was assigned as
(6.4e5.0 ppm region, Table 1).
Fig. 1. Crystal packing of 10k in a helix fashion (only the helix from the R/R enantiomer
is shown). (a) A view along the vertical axis. (b) An orthogonal view of the same helix
showing (in yellow dotted lines) the hydrogen bonds.
L
on the basis of 1H NMR spectra
3. Conclusion
The molecules pack helicoidally in the solid state, and the helix
structure is supported by two different hydrogen bonds, one of
them between the O1 of one molecule and the proton of an OH
group from an isopropanol solvent molecule, and the other one
between the oxygen of the same OH group and the proton from
a N4eH group of a nearby molecule, therefore forming enantio-
meric helixes, one of them (from the R/R enantiomer) is shown in
Fig. 1. In addition to the helix-forming behavior, these compounds
show a certain drug-conforming behavior, with positive drug-
likeness scores by the OSIRIS Property Explorer,17 for some of
these structures (such as 10d or 10h) although other characteristics
(such as c log P and therefore their suspected solubilities) should be
improved for satisfactory drug-scores. But because of the easy
manipulation of the final structures and the high diversity achieved
from very few simple starting materials, this method can be a useful
tool for the design of libraries of new drug-like compounds.
In summary, we have described a diastereoselective synthesis of
helix-forming pseudopeptidic hydantoins by an Ugi 4CC/cycliza-
tion/reduction/Ugi 4CC sequence of reactions, giving mainly the L-
adduct when benzoic acids were used. The reactions employ all
commercial or easily available starting materials, and are per-
formed under very simple experimental conditions and work-up,
without the use of column chromatography, which makes it use-
ful for new drug design.
4. Experimental section
4.1. General
Melting points are not corrected. Infrared spectra were registered
in potassium bromide tablets.1H and 13C NMR spectra were recorded

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2624
in DMSO-d6, CDCl3, CD3CN, or CD3OD, with instruments operating at
300 and 75 MHz, respectively, or at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per milllion with respect to re-
(EtOH/DMF). IR (KBr, cmꢁ1) 3272, 3069, 1651, 1606, 1557, 1375, 705.
1H NMR (400 MHz, CDCl3)
8.06e8.02 (m, 2H, HAr), 7.91e7.69 (m,
d
1H, HAr), 7.37e7.33 (m, 2H, HAr), 7.24e7.20 (m, 2H, HAr), 7.15e6.97
(m, 1H, HAr), 6.86e6.70 (m, 1H, HAr), 5.90 (s, 1H, CH), 5.63 (d,
J¼7.9 Hz, 1H, NH), 3.89e3.80 (m, 1H, CH cyclohexyl), 2.01e1.83 (m,
0
sidualsolventprotons,couplingconstants(Jxex )arereportedinhertz.
Low resolution mass spectra and HRMS were recorded in the positive
ion mode by electronic impact at 70 eV. All solvents were previously
dried according to standard procedures. Analytical TLC was per-
formed on silica gel 60 F254 plates. Flash column chromatography was
carried out on silica gel (0.040e0.063 mm).
2H, CH2),1.74e1.57 (m, 3H),1.42e1.27 (m, 2H),1.25e0.98 (m, 3H).13
C
NMR (100 MHz, CDCl3) d 166.3 (Cq),161.2 (Cq),147.9 (Cq) 140.3 (Cq),
137.8 (Cq),132.3 (CHAr),131.5 (CHAr),129.3 (CHAr),128.2 (CHAr),123.5
(CHAr), 92.6 (Cq), 68.8 (CH), 49.2 (CH), 32.8 (CH2), 32.7 (CH2), 25.3
(CH2), 24.8 (CH2), 24.7 (CH2). MS (EI) m/z (relative intensity) 501
(Mþþ4, 30), 499 (Mþþ2, 96), 497 (Mþ,100), 475 (40), 310 (50). HRMS
(EI) m/z calcd for C22H22Cl3N3O4 [Mþ] 497.0676, found 497.0683.
4.2. General procedure for the synthesis of hydantoins 10aeu
A solution of isocyanides 3a,b (2.5 mmol) in methanol (5 mL)
and trichloroacetic acid 4 (0.4 g, 2.5 mmol) were successively added
to a previously stirred (10 min, room temperature) mixture of
nitrophenylaldehydes 1a,b (2.5 mmol) and arylamines 2aee
(2.5 mmol) in methanol (30 mL) and the mixture was stirred at
room temperature for 24 h. Then the mixture was chilled, filtered,
and the precipitate was recrystallized from the appropriate solvent
to give 2-N-trichloroacetylaminoacetamides 5aef. Then a solution
of 1 M sodium ethoxide (2.8 mmol) was slowly added to a solution
of the corresponding 2-N-trichloroacetylaminoacetamides 5aef
(2.5 mmol) in methanol (15 mL). The mixture was stirred for 5 min,
chilled, and the precipitate was collected and recrystallized from the
appropriate solvent to obtain nitrophenylhydantoins 6aef. Then the
corresponding nitrophenylhydantoins 6aeg (2.5 mmol) were dis-
solved in acetic acid (20 ml) at 70 ꢀC, then the solution was warmed
to 50 ꢀC and iron powder (2 g) was added. When the reaction
temperature arose to 60 ꢀC, the mixture was stirred for additional
30 min. Then the mixture was cooled to ꢁ10 ꢀC and chloroform
(100 mL) and water (600 mL) was poured over it. The mixture was
filtered through a pad of Celite, and the organic and aqueous layers
were separated. The aqueous layer was extracted with chloroform.
The combined organic layers were washed with sodium hydro-
gencarbonate aqueous solution, dried with anhydrous sodium sul-
fate, and the solvent was eliminated under reduced pressure. The
residue was recrystallized from the appropriate solvent to get
aminophenylhydantoins 7aef. Then the corresponding amino-
phenylhydantoins 7aef (2.5 mmol) and aldehydes 8aed (2.5 mmol)
were dissolved in the minimum amount of methanol and the so-
lution was refluxed for 30 min. Then isocyanides 3a,b (2.5 mmol)
and acids 9aef (2.5 mmol) were added consecutively. The mixture
was refluxed until all reagents were dissolved and then refrigerated
slowly to room temperature without stirring until the precipitation
of a solid. The precipitate was filtered and recrystallized from the
appropriate solvent to give hydantoins 10aeu.
4.2.2. N-Cyclohexyl-2-[N-(p-methylphenyl)-N-(trichloroacetyl)
amino]-2-(p-nitrophenyl)acetamide 5b. White solid (0.82 g, 80%).
Mp 117e120 ꢀC (EtOH/DMF). IR (KBr, cmꢁ1): 3306, 3050,1651, 1604,
1519, 1345, 703. 1H NMR (200 MHz, DMSO-d6)
d
8.16 (d, J¼7.6 Hz,
1H, NH), 7.99 (d, J¼8.5 Hz, 2H, HAr), 7.77 (m, 1H, HAr), 7.37 (d,
J¼8.5 Hz, 2H, HAr), 7.08e6.71 (m, 3H, HAr), 6.05 (s, 1H, CH),
3.66e3.50 (m, 1H, CH cyclohexyl), 2.14 (s, 3H, CH3), 2.14e1.46 (m,
5H), 1.33e0.91 (m, 5H). 13C NMR (50 MHz, DMSO-d6)
d 166.4 (Cq),
159.4 (Cq), 146.8 (Cq) 141.5 (Cq), 137.9 (Cq), 134.5 (Cq), 132.4 (CHAr),
131.8 (CHAr), 127.8 (CHAr), 122.6 (CHAr), 92.8 (Cq), 67.0 (CH), 48.0
(CH), 31.9 (CH2), 25.0 (CH2), 24.4 (CH2), 24.2 (CH2), 20.4 (CH3). MS
(EI) m/z (relative intensity) 515 (Mþþ4, 8), 513 (Mþþ2, 24) 511 (Mþ,
30), 369 (50), 353 (100). HRMS (EI) m/z calcd for C23H24Cl3N3O4
[Mþ] 511.0832, found 511.0841.
4.2.3. N-Benzyl-2-[N-(4-methylphenyl)-N-(trichloroacetyl)amino]-2-
(m-nitrophenyl)acetamide 5c. White solid (0.80 g, 77%). Mp
151e154 ꢀC (i-PrOH). IR (KBr, cmꢁ1) 3276, 3030, 1733, 1673, 1528,
1350, 696. 1H NMR (200 MHz, DMSO-d6)
d
8.80 (t, J¼5.5 Hz, 1H, HAr),
8.64e6.61 (m, 13H, 12HArþNH), 6.16 (s, 1H, CH), 4.48e4.24 (m, 2H,
CH2 benz), 2.11 (s, 3H, CH3).13C NMR (50 MHz, DMSO-d6)
167.9 (Cq),
d
159.5 (Cq), 146.9 (Cq), 138.8 (Cq), 138.1 (Cq), 137.4 (CHAr), 135.7 (Cq),
134.5 (Cq), 132.6 (CHAr),129.3 (CHAr),128.1 (CHAr),127.9 (CHAr),127.0
(CHAr), 126.7 (CHAr), 125.3 (CHAr), 123.1 (CHAr), 92.9 (Cq), 67.1 (CH),
42.3 (CH2), 20.5 (CH3). MS (EI) m/z (relative intensity) 523 (Mþþ4,
15), 521 (Mþþ2, 45), 519 (Mþ, 47), 471 (30), 418 (50), 373 (100). HRMS
(EI) m/z calcd for C24H20Cl3N3O4 [Mþ] 519.0519, found 519.0510.
4.2.4. N-Benzyl-2-[N-(p-fluorophenyl)-N-(trichloroacetyl)amino]-2-
(m-nitrophenyl)acetamide 5d. White solid (0.90 g, 86%). Mp
91e93 ꢀC (EtOH). IR (KBr, cmꢁ1) 3293, 3030, 1680, 1600, 1537, 1504,
1348, 1215, 727. 1H NMR (400 MHz, CDCl3)
d 7.99e7.95 (m, 2H, HAr),
7.93 (br s, 1H, HAr), 7.41e7.39 (m, 1H, HAr), 7.31 (t, J¼7.9 Hz, 1H, NH),
7.25e7.14 (m, 5H, HAr), 6.95 (br s, 1H, HAr), 6.65e6.62 (m, 3H, HAr),
6.11 (s,1H, CH), 4.41 (d, J¼5.8 Hz, 2H, CH2 benz). 13C NMR (100 MHz,
X-ray diffraction: A single crystal of 10k was coated in high-
vacuum grease and mounted on a glass fiber. X-ray measure-
ments were made using a diffractometer with Mo K
a
radiation
CDCl3)
d
167.8 (Cq), 162.2 (d, 1J¼251.3 Hz, Cq), 161.1 (Cq), 147.7 (Cq),
ꢂ
(l
¼0.71073 A).18 Intensities were integrated19 from several series of
137.4 (Cq), 136.5 (CHAr), 135.3 (d, 3J¼8.1 Hz, CHAr), 134.7 (d,
3J¼8.1 Hz, CHAr), 134.6 (Cq), 132.8 (d, 4J¼3.4 Hz, Cq), 129.4 (CHAr),
128.6 (CHAr), 127.5 (CHAr), 127.4 (CHAr), 125.6 (CHAr), 123.9 (CHAr),
115.2 (d, 2J¼23.8 Hz, CHAr), 114.7 (d, 2J¼24.5 Hz, CHAr), 92.5 (Cq),
exposures, each exposure covering 0.3ꢀ in
u, and the total data set
being a hemisphere/sphere. Absorption corrections were applied,
based on multiple and symmetry-equivalent measurements.20 The
structure was solved by direct methods and refined by least squares
on weighted F2 values for all reflections.21 All non-hydrogen atoms
were assigned anisotropic displacement parameters and refined
without positional constraints. Hydrogen atoms H(100), were lo-
cated in the electron density difference map, assigned isotropic
displacement parameters and refined without positional con-
straints. All other hydrogen atoms were constrained to ideal ge-
ometries and refined with fixed isotropic displacement parameters.
Refinement proceeded smoothly to give the residuals. Complex
neutral-atom scattering factors were used.22
67.9 (CH), 43.7 (CH2). 19F NMR (100 MHz, CDCl3)
d
ꢁ110.7. MS (EI)
m/z (relative intensity) 527 (Mþþ4, 30), 525 (Mþþ2, 95), 523 (Mþ,
100), 512 (55), 367 (35), 284 (65), 247 (30). HRMS (EI) m/z calcd for
C23H17Cl3FN3O4 [Mþ] 523.0269, found 523.0258.
4.2.5. N-Benzyl-2-[N-(3-trifluoromethylphenyl)-N-(trichloroacetyl)
amine]-2-(m-nitrophenyl)acetamide 5e. White solid (0.50 g, 44%).
Mp 163e166 ꢀC (i-PrOH). IR (KBr, cmꢁ1), 3281, 3031, 1679, 1613,
1569, 1351, 711. 1H NMR (400 MHz, CDCl3)
d 8.33e7.87 (m, 3H, HAr),
7.43e7.18 (m, 9H, HAr), 6.96e6.78 (m, 1H, HAr), 6.41 (t, J¼5.1 Hz, 1H,
NH), 6.15 (s, 1H, CH), 4.51e4.39 (m, 2H, CH2 benz). 13C NMR
4.2.1. N-Cyclohexyl-2-[N-phenyl-N-(trichloroacetyl)amino]-2-(p-ni-
trophenyl)acetamide 5a. White solid (0.72 g, 72%). Mp 245e247 ꢀC
(100 MHz, CDCl3)
(Cq), 136.4 (CHAr), 134.4 (Cq), 130.1 (CHAr), 129.6 (CHAr), 128.7
d 167.5 (Cq),161.0 (Cq),147.9 (Cq),137.6 (Cq),137.3

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2625
(CHAr), 127.6 (CHAr), 127.5 (CHAr), 125.8 (CHAr), 125.6 (CHAr), 124.1
(CHAr), 92.4 (Cq), 67.6 (CH), 43.9 (CH2). MS (EI) m/z (relative in-
tensity) 577 (Mþþ4, 9), 575 (Mþþ2, 25), 573 (Mþ, 30), 373 (25), 287
(45), 231 (50), 97 (100). HRMS(EI) m/z calcd for C24H17Cl3F3N3O4
[Mþ] 573.0237, found 573.0248.
DMF). IR (KBr, cmꢁ1) 3003, 1782, 1698, 1537, 1372, 1179. 1H NMR
(200 MHz, CDCl3) 8.22e8.16 (m, 2H, HAr), 7.62e7.25 (m, 9H, HAr),
d
7.03e6.94 (m, 2H, HAr), 5.54 (s, 1H, CH), 4.81 (d, J¼14.3 Hz, 1H, CH2
benz), 4.72 (d, J¼14.3 Hz, 1H, CH2 benz). 13C NMR (50 MHz, CDCl3)
d
168.5 (Cq), 159.9 (d, 1J¼246.1 Hz, Cq), 154.2 (Cq), 148.7 (Cq), 135.3
(Cq), 134.8 (Cq), 132.7 (CHAr), 131.8 (d, 4J¼3.0 Hz, Cq), 130.5 (CHAr),
128.9 (CHAr), 128.8 (CHAr), 128.3 (CHAr), 124.3 (CHAr), 122.4 (d,
3J¼8.1 Hz, CHAr), 122.1 (CHAr), 116.3 (d, 2J¼22.8 Hz, CHAr), 63.5 (CH),
43.2 (CH2). MS (EI) m/z (relative intensity) 405 (Mþ, 11.6), 404 (42),
390 (33), 376 (100), 57 (89), 55 (48). HRMS (EI) m/z calcd for
C22H16FN3O4 [Mþ] 405.1125, found 405.1132.
4.2.6. N-Benzyl-2-[N-(m-fluorophenyl)-N-(trichloroacetyl)amino]-2-
(m-nitrophenyl)acetamide 5f. White solid (0.92 g, 88%). Mp
168e170 ꢀC (EtOH). IR (KBr, cmꢁ1): 3265, 3071, 1693, 1607, 1594,
1191, 714. 1H NMR (400 MHz, CDCl3)
d
8.06 (d, J¼8.2 Hz, 1H, HAr),
8.02 (br s, 1H, HAr), 7.70 (br s, 1H, HAr), 7.46 (d, J¼7.4 Hz, 1H, HAr),
7.34 (t, J¼7.9 Hz, 1H, HAr), 7.28e7.18 (m, 5H, HAr), 7.04e6.68 (m, 2H,
HAr), 6.52 (br s, 1H, HAr), 6.36 (t, J¼5.7 Hz, 1H, NH), 6.05 (s, 1H, CH),
4.2.11. 3-Benzyl-5-(m-nitrophenyl)-1-(m-trifluoromethylphenyl)imi-
dazolidin-2,4-dione 6e. White solid (0.64 g, 95%). Mp 170e172 ꢀC (i-
PrOH/DMF). IR (KBr, cmꢁ1) 3011, 1775, 1724, 1532, 1354. 1H NMR
4.46 (d, J¼5.7 Hz, 2H, CH2 benz). 13C NMR (100 MHz, CDCl3)
d 167.4
(Cq), 161.6 (d, 1J¼249.2 Hz, Cq), 161.0 (Cq), 147.8 (Cq), 138.7 (d,
3J¼9.8 Hz, Cq), 137.3 (Cq), 136.4 (CHAr), 134.5 (Cq), 129.5 (CHAr),
128.7 (CHAr), 128.5 (d, 4J¼3.0 Hz, CHAr), 127.6 (CHAr), 127.5 (CHAr),
125.6 (CHAr), 124.1 (CHAr), 120.0 (CHAr), 116.4 (d, 2J¼20.7 Hz, CHAr),
92.4 (Cq), 68.3 (CH), 43.9 (CH2). MS (EI) m/z (relative intensity) 527
(Mþþ4, 27), 525 (Mþþ2, 85), 523 (Mþ, 90), 404 (54), 314 (65), 257
(49), 205 (45), 117 (81), 91 (100). HRMS (EI) m/z calcd for
C23H17Cl3FN3O4 [Mþ] 523.0269, found 523.0258.
(400 MHz, CDCl3)
d 8.20e8.18 (m, 2H, HAr), 7.90 (s, 1H, HAr),
7.62e7.29 (m, 10H, HAr), 5.60 (s, 1H, CH), 4.81 (d, J¼14.4 Hz, 1H, CH2
benz), 4.75 (d, J¼14.4 Hz, 1H, CH2 benz). 13C NMR (50 MHz, CDCl3)
d
168.1 (Cq), 154.0 (Cq), 148.7 (Cq), 136.4 (Cq), 135.0 (Cq), 134.3 (Cq),
132.5 (CHAr), 131.8 (q, 2J¼32.8 Hz, Cq), 130.6 (CHAr), 129.9 (CHAr),
128.9 (CHAr), 128.7 (CHAr), 128.4 (CHAr), 124.4 (CHAr), 123.4 (q,
1J¼272.6 Hz, Cq), 122.6 (CHAr), 121.8 (CHAr), 121.7(q, 3J¼3.7 Hz
,CHAr), 116.8 (q, 3J¼3.9 Hz, CHAr), 62.9 (CH), 43.3 (CH2). 19F NMR
4.2.7. 3-Cyclohexyl-5-(p-nitrophenyl)-1-phenylimidazolidin-2,4-
dione 6a. White solid (0.38 g, 66%). Mp 245e247 ꢀC (EtOH/DMF). IR
(KBr, cmꢁ1) 3044, 1771, 1713, 1519, 1348. 1H NMR(200 MHz, DMSO-
(400 MHz, CDCl3)
d
ꢁ63.2. MS (EI) m/z (relative intensity) 456
(Mþþ1, 100), 455 (Mþ, 34), 425 (82), 406 (54). HRMS (EI) m/z calcd
for C23H16F3N3O4 [Mþ] 455.1093, found 455.1088.
d6)
d
8.19 (d, J¼8.3 Hz, 2H, HAr), 7.66 (d, J¼8.1 Hz, 2H, HAr), 7.51 (d,
J¼8.3 Hz, 2H, HAr), 7.32e7.16 (m, 3H, HAr), 6.19 (s, 1H, CH),
4.2.12. 3-Benzyl-5-(m-nitrophenyl)-1-(m-fluorophenyl)imidazolidin-
2,4-dione 6f. White solid (0.50 g, 82%). Mp 142e143 ꢀC (EtOH). IR
(KBr, cmꢁ1) 3033, 1775, 1714, 1532, 1367. 1H NMR (400 MHz, CDCl3)
3.96e3.83 (m, 1H, CH cyclohexyl), 2.13e1.01 (m, 10H). 13C NMR
(50 MHz, DMSO-d6)
d 168.9 (Cq), 153.8 (Cq), 147.6 (Cq), 141.0 (Cq),
136.0 (Cq), 128.8 (CHAr), 128.6 (CHAr), 127.6 (CHAr), 126.0 (CHAr),
124.6 (CHAr), 123.9 (CHAr), 123.5 (CHAr), 120.8 (CHAr), 61.9 (CH), 51.4
(CH), 28.8 (CH2), 25.2 (CH2), 24.7 (CH2). MS (EI) m/z (relative in-
tensity) 380 (Mþþ1, 14), 379 (Mþ, 95), 298 (100), 226 (45). HRMS
(EI) m/z calcd for C21H21N3O4 [Mþ] 379.1532, found 379.1541.
d 8.10e8.08 (m, 2H, HAr), 7.52e7.43 (m, 2H, HAr), 7.32e7.09 (m, 7H,
HAr), 6.98e6.96 (m, 1H, HAr), 6.73e6.68 (m, 1H, HAr), 5.44 (s, 1H,
CH), 4.70 (d, J¼14.4 Hz, 1H, CH2 benz), 4.63 (d, J¼14.3 Hz, 1H, CH2
benz). 13C NMR (100 MHz, CDCl3)
d 168.2 (Cq), 162.9 (d,
1J¼246.6 Hz, Cq), 153.9 (Cq), 148.7 (Cq), 137.3 (d, 3J¼10.5 Hz, Cq),
135.1 (Cq), 134.5 (Cq), 132.4 (CHAr), 130.6 (CHAr), 130.5 (CHAr), 128.8
(CHAr), 128.7 (CHAr), 128.3 (CHAr), 124.3 (CHAr), 121.8 (CHAr), 114.9
4.2.8. 3-Cyclohexyl-5-(p-nitrophenyl)-1-(p-methylphenyl)imidazoli-
din-2,4-dione 6b. White solid (0.56 g, 95%). Mp 182e184 ꢀC (EtOH/
DMF). IR (KBr, cmꢁ1) 3007,1774,1711,1517,1345. 1H NMR (200 MHz,
4
2
2
(d, J¼3.0 Hz, CHAr), 11.9 (d, J¼21.1 Hz, CHAr), 107.6 (d, J¼26.8 Hz,
CHAr), 63.0 (CH), 43.2 (CH2). MS (EI) m/z (relative intensity) 405
(Mþ, 8.9), 404 (30), 390 (20), 376 (100), 138 (72), 91 (71). HRMS (EI)
m/z calcd for C22H16FN3O4 [Mþ] 405.1125, found 405.1127.
DMSO-d6)
d
8.17 (d, J¼8.4 Hz, 2H, HAr), 7.63 (d, J¼8.4 Hz, 2H, HAr),
7.37 (d, J¼8.0 Hz, 2H, HAr), 7.08 (d, J¼8.0 Hz, 2H, HAr), 6.14 (s, 1H,
CH), 3.92e3.81 (m, 1H, CH cyclohexyl), 2.17 (s, 3H, CH3), 2.11e1.13
(m, 10H). 13C NMR (50 MHz, DMSO-d6)
d
169.1 (Cq), 153.8 (Cq), 147.6
4.2.13. 3-Cyclohexyl-5-(p-aminophenyl)-1-phenylimidazolidin-2,4-
dione 7a. White solid (0.22 g, 53%). Mp 215e216 ꢀC (EtOH). IR (KBr,
cmꢁ1): 3456, 3374, 3059, 3044, 1767, 1706. 1H NMR (200 MHz,
(Cq), 141.2 (Cq), 133.9 (Cq), 133.4 (Cq), 129.3 (CHAr), 129.1 (CHAr),
128.6 (CHAr), 127.6 (CHAr), 124.9 (Cq), 123.9 (CHAr), 123.5 (CHAr),
121.0 (CHAr), 62.0 (CH), 51.3 (CH), 28.8 (CH2), 28.7 (CH2), 25.2 (CH2),
24.7 (CH2), 20.2 (CH3). MS (EI) m/z (relative intensity) 393 (Mþ, 90),
338 (95), 359 (52), 352 (49), 288 (100), 198 (61). HRMS (EI) m/z
calcd for C22H23N3O4 [Mþ] 393.1689, found 393.1700.
DMSO-d6)
CH), 5.18 (br s, 2H, NH2), 3.91e3.84 (m, 1H, CH cyclohexyl),
2.14e1.06 (m, 10H). 13C NMR (50 MHz, DMSO-d6)
170.9 (Cq), 153.9
d 7.48e6.93 (m, 7H, HAr), 6.49 (m, 2H, HAr), 5.67 (br s, 1H,
d
(Cq), 149.0 (Cq), 136.4 (Cq), 128.5 (CHAr), 127.9 (CHAr), 124.1 (CHAr),
121.1 (CHAr), 120.4 (Cq), 113.9 (CHAr), 62.5 (CH), 50.9 (CH), 28.9
(CH2), 28.8 (CH2), 25.3 (CH2), 24.8 (CH2). MS (EI) m/z (relative in-
tensity) 350 (Mþ1, 100), 349 (Mþ, 73), 267 (25), 195 (91), 196 (28).
HRMS (EI) m/z calcd for C21H23N3O2 [Mþ] 349.1790, found 349.1792.
4.2.9. 3-Benzyl-5-(m-nitrophenyl)-1-(p-methylphenyl)imidazolidin-
2,4-dione 6c. White solid (0.44 g, 75%). Mp 162e163 ꢀC (EtOH/
DMF). IR (KBr, cmꢁ1) 3007, 1772, 1715, 1525, 1351. 1H NMR (40 MHz,
CDCl3)
d 8.09e8.04 (m, 2H, HAr), 7.50e7.49 (m, 1H, HAr), 7.40 (t,
J¼7.9 Hz, 1H, HAr), 7.35e7.33 (m, 2H, HAr), 7.24e7.16 (m, 5H, HAr),
6.99e6.97 (m, 2H, HAr), 5.46 (s, 1H, CH), 4.71 (d, J¼14.4 Hz, 1H, CH2
benz), 4.63 (d, J¼14.4 Hz, 1H, CH2 benz), 2.15 (s, 3H, CH3). 13C NMR
4.2.14. 3-Cyclohexyl-5-(p-aminophenyl)-1-(p-methylphenyl)imida-
zolidin-2,4-dione 7b. White solid (0.30 g, 69%). Mp 182e183 ꢀC
(EtOH). IR (KBr, cmꢁ1): 3444, 3368, 3037, 1700, 1624. 1H NMR
(100 MHz, CDCl3)
d
168.7 (Cq),154.1 (Cq),148.5 (Cq),135.4 (Cq),135.1
(400 MHz, CDCl3) d 7.33e7.30 (m, 2H, HAr), 7.08e7.02 (m, 4H, HAr),
(Cq), 135.0 (Cq), 133.0 (Cq), 132.7 (CHAr), 130.2 (CHAr), 129.8 (CHAr),
128.7 (CHAr), 128.6 (CHAr), 128.1 (CHAr), 124.0 (CHAr), 122.0 (CHAr),
120.4 (CHAr), 63.2 (CH), 43.0 (CH2), 20.7 (CH3). MS (EI) m/z (relative
intensity) 402 (Mþþ1, 21), 401 (Mþ, 99), 240 (64),132 (38), 91 (100).
HRMS (EI) m/z calcd for C23H19N3O4 [Mþ] 401.1375, found 401.1364.
6.62e6.59 (m, 2H, HAr), 5.20 (s, 1H, CH), 4.05e3.97 (m, 1H, CH
cyclohexyl), 3.69 (br s, 2H, NH2), 2.25 (s, 3H, CH3), 2.23e2.10 (m,
2H), 1.85e1.59 (m, 5H), 1.39e1.16 (m, 3H). 13C NMR (100 MHz,
CDCl3)
d 170.8 (Cq), 154.6 (Cq), 147.0 (Cq), 134.2 (Cq), 134.0 (Cq),
129.5 (CHAr),127.9 (CHAr),122.9 (Cq),120.7 (CHAr),115.5 (CHAr), 63.5
(CH), 51.9 (CH), 29.4 (CH2), 29.2 (CH2), 25.8 (CH2), 25.7 (CH2), 25.0
(CH2), 20.8 (CH3). MS (EI) m/z (relative intensity) 364 (Mþþ1, 10),
363 (Mþ, 45), 362 (41), 281 (31), 245 (38), 211 (33), 210 (52), 209
4.2.10. 3-Benzyl-5-(m-nitrophenyl)-1-(p-fluorophenyl)imidazolidin-
2,4-dione 6d. White solid (0.56 g, 92%). Mp 169e170 ꢀC (EtOH/

~
M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2626
(81), 147 (45), 106 (100). HRMS (EI) m/z calcd for C22H25N3O2 [Mþ]
363.1947, found 363.1755.
6.75e6.64 (m, 2H, HAr), 5.98 (s, diast.2, 0.34H, CH), 5.94 (s, diast.1,
0.66H, CH), 5.41e5.34 (m,1H, NH), 5.31 (s,1H, diast.2, 0.34H, CH), 5.28
(s, diast.1, 0.66H, CH), 4.39e4.20 (m, 2H, CH2), 4.09e3.91 (m,1H, CH),
3.85e3.66 (m, 1H, CH), 2.25 (s, diast.1, 2H, CH3), 2.15 (s, diast.2, 1H,
4.2.15. 3-Benzyl-5-(m-aminophenyl)-1-(p-methylphenyl)imidazoli-
din-2,4-dione 7c. White solid (0.42 g, 94%). Mp 152e154 ꢀC (EtOH).
IR (KBr, cmꢁ1): 3471, 3377, 3029, 1715, 1698. 1H NMR (200 MHz,
CH3), 1.94e0.90 (m, 20H). 13C NMR (50 MHz, CDCl3)
d 169.3 (Cq),
168.2 (Cq, diast.2), 168.1 (Cq, diast.1), 167.6 (Cq), 156.5 (Cq), 154.3
(Cq), 138.8 (Cq, diast.1), 138.6 (Cq, diast.2), 138.5 (Cq, diast.2), 138.4
CDCl3) d 7.47e7.05 (m, 10H, HAr), 6.68e6.56 (m, 3H, HAr), 5.30 (s, 1H,
CH), 4.81 (d, J¼14.4 Hz, 1H, CH2 benz), 4.71 (d, J¼14.4 Hz, 1H, CH2
(Cq, diast.1),136.3 (Cq),134.0 (CHAr),131.3 (CHAr, diast.2),131.2 (CHAr,
benz), 3.12 (br s, 2H, NH2), 2.26 (s, 3H, CH3). 13C NMR (50 MHz,
diast.1), 130.5 (Cq), 130.2 (CHAr), 130.1 (Cq), 129.2 (CHAr), 129.1
(CHAr), 129.0 (CHAr), 127.4 (CHAr), 126.2 (Cq), 124.7 (CHAr, diast.1),
124.6 (CHAr, diast.2), 120.2 (CHAr), 116.0 (CHAr), 66.8 (CH2), 64.9 (CH,
diast.1), 64.6 (CH, diast.2), 62.9 (CH), 52.2 (CH), 48.9 (CH), 32.7 (CH2),
29.3 (CH2), 29.1 (CH2), 25.8 (CH2), 25.4 (CH2), 24.9 (CH2), 24.8 (CH2),
24.7 (CH2), 21.1 (CH3, diast.1), 21.0 (CH3, diast.2).
CDCl3)
d 169.9 (Cq), 147.0 (Cq), 135.8 (Cq), 134.3 (Cq), 134.1 (Cq),
130.2 (CHAr), 129.6 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.0 (CHAr),
120.2 (CHAr), 116.8 (CHAr), 115.9 (CHAr), 113.1 (CHAr), 64.4 (CH), 42.8
(CH2), 20.7 (CH3). MS (EI) m/z (relative intensity) 372 (Mþþ1, 6.3),
371 (Mþ, 0.8), 137 (11), 69 (31), 83 (29), 55 (61), 57 (100). HRMS (EI)
m/z calcd for C23H21N3O2 [Mþ] 371.1634, found 371.1632.
4.2.20. N-Benzyl 2-[N-(p-chlorophenoxyacetyl)-N-[4-(3-cyclohexyl-
2,4-dioxo-1-phenylimidazolidin-5-yl)phenylamino]-2-(p-tolyl)acet-
amide 10b. White solid (0.41 g, 54%, EtOH/DMF). IR (KBr, cmꢁ1):
3265, 3066, 1770, 1710, 1667, 1599. 1H NMR (200 MHz, CDCl3)
4.2.16. 3-Benzyl-5-(m-aminophenyl)-1-(p-fluorophenyl)imidazoli-
din-2,4-dione 7d. White solid (0.35 g, 77%). Mp 61e64 ꢀC (cyclo-
hexane). IR (KBr, cmꢁ1): 3462, 3371, 3032, 1772, 1711. 1H NMR
(400 MHz, CDCl3)
d
7.45e7.40 (m, 4H, HAr), 7.35e7.29 (m, 3H, HAr),
d 7.38e7.11 (m, 15H, HAr), 6.84e6.62 (m, 7H, HAr), 6.13e6.04 (m, 1H,
7.12e7.08 (m, 1H, HAr), 6.97e6.93 (m, 2H, HAr), 6.63e6.59 (m, 2H,
HAr), 6.52 (t, J¼2.0 Hz, 1H, HAr), 5.26 (s, 1H, CH), 4.80 (d, J¼14.4 Hz,
1H, CH2 benz), 4.72 (d, J¼14.4 Hz,1H, CH2 benz), 3.69 (br s, 2H, NH2).
CH), 6.02 (s, diast.1, 0.5H, NH), 5.99 (s, diast.2, 0.5H, NH), 5.31 (s,
diast.1, 0.5H, CH), 5.28 (s, diast.2, 0.5H, CH), 4.52e4.38 (m, 2H, CH2),
4.40e4.18 (m, 2H, CH2), 4.08e3.92 (m, 1H, CH cyclohexyl), 2.23 (s,
13C NMR (100 MHz, CDCl3)
d
169.6 (Cq), 159.4 (d, 1J¼244.8 Hz, Cq),
diast.2, 1.5H, CH3), 2.14 (s, diast.2, 1.5H, CH3), 2.10e1.14 (m,10H). 13
C
154.4 (Cq), 147.3 (Cq), 135.6 (Cq), 133.6 (Cq), 132.5 (d, 4J¼2.6 Hz, Cq),
130.2 (CHAr), 128.7 (CHAr), 128.0 (CHAr), 122.0 (CHAr), 121.9 (d,
3J¼8.0 Hz, CHAr), 116.5 (CHAr), 115.8 (CHAr), 115.7 (d, 2J¼22.5 Hz,
NMR (50 MHz, CDCl3) d 167.0 (Cq), 167.4 (Cq), 156.2 (Cq), 154.0 (Cq),
138.4 (Cq), 138.3 (Cq, diast.1), 138.2 (Cq, diast.2), 137.4 (Cq), 135.9
(Cq), 133.8 (Cq), 130.9 (Cq, diast.1), 130.8 (Cq, diast.2), 129.9 (CHAr),
129.8 (CHAr), 128.9 (CHAr), 128.7 (CHAr), 128.2 (CHAr), 127.2 (CHAr),
127.1(CHAr), 127.0 (CHAr), 125.9 (Cq), 124.4 (Cq, diast.1), 124.3 (Cq,
diast.2),119.9 (CHAr),115.7 (CHAr), 66.6 (CH2), 64.9 (CH, diast.1), 64.6
(CH, diast.2), 62.7 (CH), 52.0 (CH), 43.5 (CH2), 29.1(CH2), 29.0 (CH2),
25.6 (CH2), 24.8 (CH2), 20.9 (CH3, diast.1), 20.8 (CH3, diast.2).
CHAr), 64.6 (CH), 42.8 (CH2). 19F NMR (400 MHz, CDCl3)
d
ꢁ117.8. MS
(EI) m/z (relative intensity) 376 (Mþ.þ1,100), 375 (Mþ, 24), 356 (12).
HRMS (EI) m/z calcd for C22H18FN3O2 [Mþ] 375.1383, found 375.1374.
4.2.17. 3-Benzyl-5-(m-aminophenyl)-1-(m-trifluoromethylphenyl)
imidazolidin-2,4-dione 7e. White solid (0.44 g, 87%). Mp
146e147 ꢀC (EtOH). IR (KBr, cmꢁ1): 3490, 3401, 3013, 1716, 1698. 1H
4.2.21. N-Cyclohexyl 2-[N-(p-chlorophenoxyacetyl)-N-[4-(3-
cyclohexyl-2,4-dioxo-1-p-tolyl-imidazolidin-5-yl)phenylamino]-2-
phenylacetamide 10c. White solid (0.51 g, 69%, EtOH/DMF). IR (KBr,
cmꢁ1): 3263, 3062, 1772, 1711, 1681. 1H NMR (200 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d 7.93 (s, 1H, HAr), 7.36e7.14 (m, 8H, HAr),
6.97 (t, J¼7.8 Hz, 1H, HAr), 6.52e6.41 (m, 3H, HAr), 5.18 (s, 1H, CH),
4.69 (d, J¼14.5 Hz, 1H, CH2 benz), 4.61 (d, J¼14.5 Hz, 1H, CH2 benz),
3.45 (br s, 2H, NH2). 13C NMR (100 MHz, CDCl3)
d
169.3 (Cq), 154.3
d
7.26e6.96 (m, 15H, HAr), 6.66 (d, J¼8.9 Hz, 2H, HAr), 5.98 (s, 1H,
(Cq), 147.4 (Cq), 137.0 (Cq), 135.4 (Cq), 133.2 (Cq), 131.3 (q,
2J¼32.5 Hz, Cq), 130.3 (CHAr), 129.4 (CHAr), 128.7 (CHAr), 128.6
(CHAr), 128.1 (CHAr), 123.6 (q, 1J¼272.6 Hz, Cq), 122.2 (CHAr), 120.8
(q, 3J¼3.8 Hz, CHAr), 116.5 (q, 3J¼4.0 Hz, CHAr), 116.2 (CHAr), 115.9
(CHAr), 112.5 (CHAr), 64.0 (CH), 42.8 (CH2). 19F NMR (400 MHz,
CH), 5.48 (d, J¼6.8 Hz, diast.1, 0.5H, NH), 5.45 (d, J¼6.8 Hz, diast.2,
0.5H, NH), 5.25 (s, diast.1, 0.5H, CH), 5.23 (s, diast.2, 0.5H, CH),
4.38e4.20 (m, 2H, CH2), 4.05e3.90 (m, 1H, CH cyclohexyl),
3.84e3.67 (m, 1H, CH Cyclohexyl), 3.30 (s, diast.1, 1.5H, CH3), 3.29 (s,
diast.2, 1.5H, CH3), 2.30e0.97 (m, 20H). 13C NMR (50 MHz, CDCl3)
CDCl3)
d
ꢁ63.0. MS (EI) m/z (relative intensity) 425 (Mþ, 21), 278
d 169.5 (Cq, diast.1), 169.4 (Cq, diast.2), 168.0 (Cq), 167.7 (Cq), 156.5
(44), 84 (77), 59 (81), 57 (100), 55 (62). HRMS (EI) m/z calcd for
(Cq), 154.3 (Cq), 138.5 (Cq), 134.5 (Cq, diast.1), 134.4 (Cq, diast.2),
134.2 (Cq, diast.2), 134.1 (Cq, diast.1), 133.6 (Cq, diast.1), 133.5 (Cq),
133.4 (Cq, diast.2), 130.2 (CHAr), 130.1 (CHAr), 129.5 (CHAr), 129.4
(CHAr), 129.1 (CHAr), 128.5 (Cq, diast.1), 128.4 (Cq, diast.2), 128.3
(CHAr), 127.5 (CHAr), 126.2 (Cq), 120.7 (CHAr), 120.4 (CHAr), 116.0
(CHAr), 66.8 (CH), 65.1 (CH, diast.1), 65.0 (CH, diast.2), 63.2 (CH,
diast.2), 63.0 (CH, diast.1), 52.1 (CH), 48.9 (CH), 32.6 (CH2), 29.3
(CH2), 29.1 (CH2), 29.0 (CH2) 25.7 (CH2), 25.3 (CH2), 24.9 (CH2), 24.7
(CH2), 24.6 (CH2), 20.7 (CH3).
C23H18F3N3O2 [Mþ] 425.1351, found 425.1356.
4.2.18. 3-Benzyl-5-(m-aminophenyl)-1-(m-fluorophenyl)imidazoli-
din-2,4-dione 7f. White solid (0.29 g, 64%). Mp 118e120 ꢀC (EtOH).
IR (KBr, cmꢁ1): 3453, 3419, 1762, 1703. 1H NMR (400 MHz, CDCl3)
d
7.36e6.97 (m, 9H, HAr), 6.66e6.42 (m, 4H, HAr), 5.13 (s,1H, CH), 4.67
(d, J¼14.5 Hz, 1H, CH2 benz), 4.59 (d, J¼14.5 Hz, 1H, CH2 benz), 3.57
(br s, 2H, NH2). 13C NMR (100 MHz, CDCl3)
169.3 (Cq), 162.7 (d,
d
1J¼245.2 Hz, Cq), 154.3 (Cq), 147.3 (Cq), 138.0 (d, 3J¼10.7 Hz, Cq),
135.5 (Cq), 133.4 (Cq), 130.6 (CHAr), 130.4 (d, J¼9.3 Hz, CHAr), 128.6
(CHAr), 128.5 (CHAr), 128.0 (CHAr), 116.5 (CHAr), 116.2 (CHAr), 115.1 (d,
4J¼2.9 Hz, CHAr), 112.9 (CHAr), 111.1 (d, 2J¼21.1 Hz, CHAr), 107.2 (d,
2J¼26.9 Hz, CHAr), 64.1 (CH), 42.7 (CH2). MS (EI) m/z (relative in-
tensity) 376 (Mþþ1, 44), 375 (Mþ, 100), 214 (49), 213 (53), 91 (44) .
HRMS (EI) m/z calcd for C22H18FN3O2 [Mþ] 375.1383, found 375.1381.
4.2.22. N-Cyclohexyl 2-[N-(p-chlorobenzoyl)-N-[4-(3-cyclohexyl-2,4-
dioxo-1-p-tolyl-imidazolidin-5-yl)phenylamino]-2-phenylacetamide
10d. White solid (0.56 g, 79%, EtOH/DMF). IR (KBr, cmꢁ1): 3276,
3086, 1771, 1713, 1651. 1H NMR (400 MHz, CDCl3)
d 7.25e6.93 (m,
17H, HAr), 6.05 (s, 1H, CH), 5.57 (d, J¼8.1 Hz, diast.2, 0.08H, NH), 5.53
(d, J¼8.1 Hz, diast.1, 0.92H, NH), 5.11 (s, 1H, CH), 3.99e3.91 (m, 1H,
CH cyclohexyl), 3.86e3.77 (m, 1H, CH cyclohexyl), 2.30 (s, 3H, CH3),
2.17e1.81 (m, 6H), 1.72e1.54 (m, 5H), 1.36e0.95 (m, 9H). 13C NMR
4.2.19. N-Cyclohexyl 2-[N-(p-chlorophenoxyacetyl)-N-[4-(3-
cyclohexyl-2,4-dioxo-1-phenylimidazolidin-5-yl)phenylamino]-2-(p-
tolyl)acetamide 10a. White solid (0.34 g, 45%, EtOH/DMF). IR (KBr,
cmꢁ1): 3267, 3081, 1772, 1715, 1680, 1645, 1504, 1491, 1410. 1H NMR
(100 MHz, CDCl3)
d 169.7 (Cq), 169.5 (Cq), 168.1 (Cq), 154.3 (Cq),
141.8 (Cq), 135.5 (Cq), 134.5 (Cq), 134.4 (Cq), 134.0 (Cq), 133.5 (Cq),
132.7 (Cq), 131.0 (CHAr), 130.1 (CHAr), 130.0 (CHAr), 129.5 (CHAr),
128.6 (CHAr), 127.8 (CHAr), 127.1 (CHAr), 120.5 (CHAr), 66.6 (CH), 63.2
(200 MHz, CDCl3) d 7.39e7.08 (m, 11H, HAr), 6.90e6.79 (m, 4H, HAr),

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2627
(CH), 52.0 (CH), 48.9 (CH), 32.8 (CH2), 29.3 (CH2), 29.0 (CH2), 25.8
(CH2), 25.4 (CH2), 24.9 (CH2), 24.8 (CH2), 24.7 (CH2), 20.8 (CH3).
1.93e1.50 (m, 5H), 1.34e0.91 (m, 5H). 13C NMR (100 MHz, CDCl3)
169.9 (Cq), 168.8 (Cq), 168.2 (Cq), 154.0 (Cq), 141.1 (Cq), 135.7 (Cq),
d
135.3 (Cq), 134.5 (Cq), 134.1 (Cq), 133.5 (Cq), 132.8 (Cq), 132.0 (Cq),
130.6 (CHAr), 129.8 (CHAr), 129.6 (CHAr), 129.4 (CHAr), 129.1 (CHAr),
128.8 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.5 (CHAr), 128.1 (CHAr),
127.8 (CHAr), 125.9 (CHAr), 120.1 (CHAr), 65.2 (CH), 63.2 (CH), 48.9
(CH), 42.9 (CH2), 32.8 (CH2), 32.9 (CH2), 25.5 (CH2), 24.8 (CH2), 24.7
(CH2), 20.8 (CH).
4.2.23. N-Cyclohexyl 2-[N-(2-chloroacetyl)-N-[4-(3-cyclohexyl-2,4-
dioxo-1-p-tolyl-imidazolidin-5-yl)phenylamino]-2-(p-tolyl)acet-
amide 10e. White solid (0.27 g, 40%, EtOH). IR (KBr, cmꢁ1): 3269,
3034, 1773, 1714, 1677, 1647. 1H NMR (400 MHz, CDCl3)
d 7.20e7.00
(m, 7H, HAr), 6.80e6.68 (m, 5H, HAr), 5.85 (s, diast.2, 0.40H, CH), 5.82
(s, diast.1, 0.60H, CH), 5.39 (d, J¼8.1 Hz, diast.2, 0.40H, NH), 5.39 (d,
J¼8.1 Hz, diast.1, 0.60H, NH), 5.21 (s, diast.2, 0. 40H, CH), 5.18 (s,
diast.1, 0.60H, CH), 3.97e3.89 (m, 1H, CH cyclohexyl), 3.77e3.65 (m,
3H, CH cyclohexylþCH2), 2.25 (s, diast.2, 1.20H, CH3), 2.24 (s, diast.1,
1.80H, CH3), 2.18 (s, 3H, CH3),1.86e1.46 (m,11H),1.30e0.87 (m, 9H).
4.2.27. N-Cyclohexyl 2-[N-(p-nitrophenylacetyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(p-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-fluo-
rophenyl)acetamide 10i. White solid (0.46 g, 60%, DMF). IR (KBr,
cmꢁ1): 3344, 1771, 1708, 1679, 1647. 1H NMR (400 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d
169.7 (Cq), 168.4 (Cq, diast.2),168.4 (Cq,
d 8.03e8.00 (m, 2H, HAr), 7.78e7.64 (m, 1H, HAr), 7.40e6.61 (m, 17H,
diast.1), 166.7 (Cq, diast.2), 166.6 (Cq, diast.1), 154.6 (Cq), 139.5 (Cq),
138.7 (Cq), 134.8 (Cq), 134.4 (Cq), 133.9 (Cq), 131.5 (Cq), 130.8 (Cq),
130.4 (CHAr, diast.1), 130.3 (CHAr, diast.2), 129.9 (CHAr, diast.1), 129.8
(CHAr, diast.2), 129.3 (CHAr, diast.1), 129.3 (CHAr, diast.2), 127.7 (CHAr),
120.7 (CHAr, diast.1), 120.6 (CHAr, diast.2), 65.6 (CH), 63.4 (CH,
diast.2), 63.3 (CH, diast.1), 52.4 (CH), 49.1 (CH), 42.9 (CH2), 33.0
(CH2), 33.0 (CH2), 29.5 (CH2), 29.4 (CH2), 26.0 (CH2), 26.0 (CH2), 25.6
(CH2), 25.2 (CH2), 25.0 (CH2), 24.9 (CH2), 21.3 (CH3), 21.1 (CH3).
HAr), 6.41 (s, diast.1, 0.59H, HAr), 6.37 (s, diast.2, 0.41H, HAr), 6.07 (s,
diast.1, 0.59H, CH), 5.96 (s, diast.2, 0.41, CH), 5.61 (s, diast.1, 0.59H,
NH), 5.43 (s, diast.2, 0.41H, NH), 5.37 (s, diast.2, 0.41H, CH), 5.13 (s,
diast.1, 0.59H, CH), 4.74 (s, diast.2, 0.82H, CH2), 4.70 (s, diast.1, 1.18H,
CH2), 3.77e3.73 (m, 1H, CH cyclohexyl), 3.40e3.32 (m, 2H, CH2),
1.90e0.92 (m, 10H). 13C NMR (100 MHz, CDCl3)
d 169.9 (Cq), 168.6
(Cq), 168.0 (Cq), 162.4 (d, 1J¼249.9 Hz, Cq), 159.4 (d, 1J¼249.0 Hz,
Cq), 154.0 (Cq), 146.7 (Cq), 142.2 (Cq), 139.8 (Cq), 135.3 (Cq), 132.2
(CHAr), 131.9 (CHAr), 130.0 (CHAr), 129.6 (CHAr), 128.7 (CHAr), 128.2
(CHAr), 125.8 (CHAr), 123.4 (CHAr), 123.1 (Cq), 121.3 (CHAr), 115.8 (d,
2J¼23.8 Hz, CHAr), 115.3 (d, 2J¼21.5 Hz, CHAr), 63.9 (CH, diast.1), 63.7
(CH, diast.2), 63.4 (CH, diast.1), 63.2 (CH, diast.2), 48.9 (CH), 42.9
(CH2), 41.4 (CH2), 32.6 (CH2), 25.3 (CH2), 24.7 (CH2), 24.6 (CH2).
4.2.24. N-Cyclohexyl 2-[N-(3-phenylpropargyl)-N-[4-(3-cyclohexyl-2,4-
dioxo-1-p-tolyl-imidazolidin-5-yl)phenylamino]-2-phenylacetamide
10f. White solid (0.30 g, 42%, EtOH). IR (KBr, cmꢁ1): 3269, 3061, 1771,
1713, 1648, 1605. 1H NMR (200 MHz, CDCl3)
d 7.34e6.91 (m, 18H, HAr),
6.01 (br s, 1H, CH), 5.75e5.71 (m, 1H, NH), 5.26 (s, diast.1, 0.65H, CH),
5.24 (s, diast.2, 0.35H, CH), 4.06e3.90 (m, 1H, CH cyclohexyl),
3.87e3.71 (m, 1H, CH cyclohexyl), 2.27 (s, diast.1, 1.95H, CH3), 2.15 (s,
diast.2, 1.05H, CH3), 2.30e0.93 (m, 20H). 13C NMR (50 MHz, CDCl3)
4.2.28. N-Cyclohexyl 2-[N-(3-phenylpropargyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(p-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-fluo-
rophenyl)acetamide 10j. White solid (0.49 g, 67%, EtOH/H2O). IR
(KBr, cmꢁ1): 3212, 3068, 2211, 1777, 1716, 1639, 1601. 1H NMR
d
169.6 (Cq, diast.1), 169.56 (Cq, diast.2), 167.8 (Cq), 154.7 (Cq, diast.2),
154.5 (Cq, diast.1), 140.5 (Cq), 134.4 (Cq), 134.3 (Cq), 133.9 (Cq), 133.8
(Cq), 132.7 (CHAr), 131.9 (CHAr),130.2 (CHAr), 130.1 (CHAr), 129.5 (CHAr),
128.6 (CHAr), 128.5 (CHAr), 128.4 (CHAr), 126.9 (CHAr), 126.8 (CHAr),
120.7 (CHAr), 120.3 (CHAr), 119.9 (Cq), 92.5 (Cq), 82.4 (Cq), 64.9 (CH,
diast.2), 64.8 (CH, diast.1), 63.6 (CH, diast.1), 63.4 (CH, diast.2), 52.1
(CH), 48.8 (CH), 32.7 (CH2), 32.7 (CH2), 29.3 (CH2), 29.1 (CH2), 25.8
(CH2), 25.4 (CH2), 25.0 (CH2), 24.8 (CH2), 24.7 (CH2), 20.8 (CH3).
(400 MHz, CDCl3) d 7.37e7.10 (m, 13H, HAr), 7.00e6.93 (m, 4H, HAr),
6.86e6.64 (m, 5H, HAr), 6.09 (s, diast.2, 0.37H, CH), 6.03 (s, diast.1,
0.63H, CH), 5.79 (d, J¼8.0 Hz, diast.1, 0.63H, NH), 7.75 (d, J¼7.6 Hz,
diast.2, 0.37H, NH), 5.35 (s, diast.2, 0.37H, CH), 5.29 (s, diast.1, 0.63H,
CH), 4.73e4.53 (m, 2H, CH2), 3.82e3.73 (m, 1H, CH Cyclohexyl),
1.93e1.79 (m, 2H), 1.69e1.55 (m, 3H), 1.36e0.96 (m, 5H). 13C NMR
(100 MHz, CDCl3)
d 169.2 (Cq, diast.1), 169.1 (Cq, diast.2), 168.0 (Cq,
diast.1),167.9 (Cq, diast.2),162.8 (d, 1J¼248.6, Cq, diast.2, CF),162.7 (d,
1J¼249.1, Cq, diast.1, CF), 159.7 (d, J¼245.4, Cq, diast.1, CF), 159.6 (d,
J¼245.4, Cq, diast.2, CF), 155.0 (Cq, diast.1), 154.9 (Cq, diast.2), 154.5
(Cq, diast.2), 154.4 (Cq, diast.1), 140.5 (Cq, diast.1), 140.4 (Cq, diast.2),
135.8 (Cq), 133.9 (Cq, diast.1), 133.5 (Cq, diast.2), 132.9 (CHAr), 132.7
(CHAr), 132.6 (CHAr), 132.5 (CHAr), 132.3 (d, 4J¼2.9 Hz, Cq), 132.2
(CHAr), 132.1 (CHAr), 130.5 (CHAr), 130.4 (CHAr), 129.8 (CHAr, diast.1),
129.6 (CHAr, diast.2), 129.5 (d, 4J¼3.4 Hz, Cq), 129.0 (CHAr, diast.1),
128.9 (CHAr, diast.2), 128.8 (CHAr, diast.1), 128.7 (CHAr, diast.2), 128.6
(CHAr), 128.5 (CHAr), 128.3 (CHAr), 127.2 (CH, diast.1), 126.9 (CH,
diast.2), 122.4 (d, 3J¼8.0 Hz, CHAr), 122.1 (d, 3J¼6.8 Hz, CHAr), 119.9
(Cq, diast.2),119.8 (Cq, diast.1),116.0 (d, 2J¼22.7 Hz, CH, diast.1),115.9
(d, 2J¼22.7 Hz, CH, diast.2), 115.7 (d, 2J¼21.6 Hz, CH, diast.1), 115.6 (d,
2J¼21.6 Hz, CH, diast.2), 93.1 (Cq, diast.1), 92.9 (Cq, diast.2), 82.3 (Cq,
diast.2), 82.2 (Cq, diast.1), 64.2 (CH, diast.1), 64.1 (CH, diast.2), 63.5
(CH), 49.2 (CH, diast.2), 49.1 (CH, diast.1), 43.1 (CH2, diast.2), 43.0
(CH2, diast.1), 33.0 (CH2), 32.9 (CH2), 25.6 (CH2), 25.0 (CH2), 24.9
4.2.25. N-Cyclohexyl 2-[N-(p-nitrophenylacetyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(p-tolyl)-imidazolidin-5-yl)phenylamino]-2-phenylacetamide
10g. White solid (0.57 g, 76%, EtOH/DMF). IR (KBr, cmꢁ1): 3361, 3031,
1715, 1682, 1650, 1519, 1345. 1H NMR (400 MHz, CDCl3)
d 8.00e7.96
(m, 2H, HAr), 7.71 (s, diast.2, 0.34H, HAr), 7.55 (s, diast.1, 0.66H, HAr),
7.37e6.67 (m, 19H, HAr), 6.03 (s, diast.1, 0.66H, CH), 5.90 (s, diast.2,
0.34H, CH), 5.38e5.07 (m, 2H, NHþCH), 4.74e4.60 (m, 2H, CH2),
3.77e3.67 (m,1H, CH cyclohexyl), 3.32e3.19 (m, 2H, CH2), 2.16 (s, 3H,
CH3), 1.88e0.86 (m, 10H). 13C NMR (100 MHz, CDCl3)
d 169.9 (Cq,
diast.2), 169.7 (Cq, diast.1), 169.4 (Cq), 168.2 (Cq, diast.2), 168.1 (Cq,
diast.1), 154.0 (Cq), 146.7 (Cq), 142.4 (Cq, diast.1), 142.3 (Cq, diast.2),
140.2 (Cq), 140.0 (Cq), 135.7 (Cq), 135.6 (Cq), 131.6 (Cq), 130.4 (CHAr),
130.1 (CHAr), 129.6 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.4 (CHAr),
128.1 (CHAr), 123.4 (CHAr), 120.7 (CHAr), 65.2 (CH, diast.1), 64.4 (CH,
diast.2), 63.8(CH, diast.1), 63.1 (CH, diast.2), 48.9 (CH), 42.9 (CH2), 41.6
(CH2, diast.2), 41.4 (CH2, diast.1), 32.7 (CH2), 25.4 (CH2), 24.8 (CH2),
24.7 (CH2), 20.7 (CH3).
(CH2). 19F NMR
d
ꢁ112.0 (diast.1, 0.63), ꢁ112.3 (diast.2, 0.37), ꢁ117.3.
4.2.26. N-Cyclohexyl 2-[N-(p-chlorobenzoyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(p-tolyl)-imidazolidin-5-yl)phenylamino]-2-phenylacetamide
10h. White solid (0.35 g, 49%, i-PrOH). IR (KBr, cmꢁ1): 3267, 3033,
4.2.29. N-Cyclohexyl 2-[N-(p-chlorophenoxyacetyl)-N-[3-(3-benzyl-
2,4-dioxo-1-(m-trifluoromethylphenyl)-imidazolidin-5-yl)phenyl-
amino]-2-(p-tolyl)acetamide 10l. White solid (0.42 g, 51%, EtOH/
DMF). IR (KBr, cmꢁ1): 3347, 3033, 1771, 1713, 1668, 1603. 1H NMR
1714,1683. 1H NMR (400 MHz, CDCl3)
d 7.37e6.81 (m, 21H, HAr), 6.58
(br s, 1H, HAr), 6.19 (s, diast.1, 0.93H, CH), 6.13 (s, diast.2, 0.07H, CH),
5.58 (d, J¼8.2 Hz, diast.2, 0.07H, NH), 5.42 (d, J¼7.8 Hz, diast.1, 0.93H,
NH), 5.10 (s, 1H, CH), 4.64 (s, 2H, CH2), 3.83e3.73 (m, 1H, CH
cyclohexyl), 2.24 (s, diast.1, 2.79H, CH3), 2.10 (s, diast.2, 0.21H, CH3),
(200 MHz, CDCl3) d 7.82 (br s, 2H, HAr), 7.43e7.28 (m, 10H, HAr),
7.17e7.13 (m, 3H, HAr), 6.95e6.80 (m, 4H, HAr), 6.66e6.62 (m, 2H,
HAr), 6.02 (s, 1H, CH), 5.40 (br s, 2H, NHþCH), 4.75 (s, 2H, CH2), 4.10
(s, 2H, CH2), 3.82e3.67 (m, 1H, CH cyclohexyl), 2.25 (s, diast.1, 2H,

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M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2628
CH3), 2.17 (s, diast.2, 1H, CH3), 1.90e1.55 (m, 5H), 1.42e0.92 (m, 5H).
13C NMR (50 MHz, CDCl3)
168.1 (Cq), 167.5 (Cq), 156.6 (Cq), 154.1
J¼3.3 Hz, diast.2, CHAr), 93.2 (Cq, diast.2), 93.0 (Cq, diast.1), 82.2 (Cq),
63.7 (CH), 63.5 (CH), 49.2 (CH), 43.2 (CH2, diast.1), 43.1 (CH2,
diast.2), 33.0 (CH2), 32.9 (CH2), 25.7 (CH2), 25.0 (CH2), 24.9 (CH2).
d
(Cq), 139.1 (Cq), 138.5 (Cq), 136.8 (Cq), 135.3 (Cq), 131.5 (CHAr), 130.3
(CHAr), 129.6 (CHAr), 129.2 (CHAr), 129.1 (CHAr), 128.8 (CHAr), 128.6
(CHAr), 128.3 (CHAr), 126.8 (Cq), 126.2 (Cq), 121.2 (Cq), 116.7 (Cq),
116.0 (CHAr), 66.6 (CH2), 64.6 (CH), 63.2 (CH), 48.9 (CH), 43.1 (CH2),
32.7 (CH2), 25.5 (CH2), 24.8 (CH2), 24.7 (CH2), 21.1 (CH3).
4.2.33. N-Cyclohexyl 2-[N-(o-hydroxybenzoyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-trifluoromethylphenyl)-imidazolidin-5-yl)phenylamino]-
2-(p-tolyl)acetamide 10p. White solid (0.31 g, 40%, EtOH). IR (KBr,
cmꢁ1): 3376, 3034, 1778, 1715, 1673, 1642. 1H NMR (200 MHz, CDCl3)
4.2.30. N-Cyclohexyl 2-[N-(p-nitrophenylacetyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-trifluoromethylphenyl)-imidazolidin-5-yl)phenylamino]-
2-phenylacetamide 10m. White solid (0.59 g, 74%, EtOH/DMF). IR
(KBr, cmꢁ1): 3364, 3032, 1772, 1718, 1649, 1600. 1H NMR (400 MHz,
d 9.83 (br s, 1H, OH), 7.94 (s, 1H, HAr), 7.37e6.95 (m, 17H, HAr), 6.71 (d,
J¼8.4 Hz, 1H, HAr), 6.61 (d, J¼7.5 Hz, 1H, HAr), 6.28e6.20 (m, 1.96H,
HArþ0.96H diast.1, CH), 6.13 (s, diast.2, 0.04H, CH), 5.59 (d, J¼7.9 Hz, 1H,
NH), 5.28 (s, 1H, CH), 4.77 (d, J¼14.5 Hz, 1H, CH2), 4.68 (d, J¼14.5 Hz,
1H, CH2), 3.92e3.83 (m,1H, CH cyclohexyl), 2.26 (s, diast.1, 2.88H, CH3),
2.16 (s, diast.2, 0.12H, CH3), 1.95e1.05 (m, 10H). 13C NMR (50 MHz,
CDCl3) d 7.96e6.10 (m, 22H, HAr), 6.05 (br s, diast.2, 0.24H, CH), 5.94 (br
s, diast.1, 0.76H, CH), 5.54e5.10 (m, 2H, NHþCH), 4.75e4.66 (m, 2H,
CH2), 3.74e3.65 (m, 1H, CH cyclohexyl), 3.35e3.27 (m, 2H, CH2),
1.84e1.51 (m, 5H), 1.24e0.79 (m, 5H). 13C NMR (100 MHz, CDCl3)
CDCl3) d 171.0 (Cq), 168.8 (Cq), 168.4 (Cq), 157.3 (Cq), 154.1 (Cq), 141.5
(Cq), 138.7 (Cq), 136.8 (Cq), 135.4 (Cq), 132.5 (Cq), 132.0 (CHAr), 131.3
(CHAr), 130.6 (CHAr), 130.5 (CHAr), 129.5 (CHAr), 129.3 (CHAr), 129.0
(CHAr), 128.8 (CHAr), 128.6 (CHAr), 128.2 (CHAr), 128.1 (CHAr), 125.3
(CHAr),122.1 (CHAr), 121.0 (q, J¼3.9 Hz, CHAr),118.9 (CHAr),118.2 (CHAr),
117.2 (CHAr), 116.5 (q, J¼3.8 Hz, CHAr), 65.6 (CH), 63.2 (CH), 49.2 (CH),
43.0 (CH2), 32.7 (CH2), 25.4 (CH2), 24.8 (CH2), 24.7 (CH2), 21.1 (CH3).
d
169.8 (Cq), 168.6 (Cq), 168.2 (Cq, diast.1), 168.0 (Cq, diast.2), 154.0
(Cq), 153.9 (Cq), 146.7 (Cq), 142.3 (Cq), 140.4 (Cq), 136.9 (Cq, diast.1),
136.8 (Cq, diast.2), 135.3 (Cq, diast.1), 135.2 (Cq, diast.2), 133.6 (Cq),
131.4 (q, 2J¼33.0 Hz, Cq),130.3(CHAr),130.0 (CHAr),129.6(CHAr),129.5
(CHAr), 128.8 (CHAr),128.6 (CHAr),128.4 (CHAr),128.3 (CHAr),123.5 (q,
1J¼272.5 Hz, Cq). 123.4 (CHAr), 122.6 (CHAr), 121.1 (CHAr), 116.451
(CHAr), 64.9 (CH, diast.1), 64.3 (CH, diast.2), 63.4 (CH, diast.1), 62.8 (CH,
diast.2), 48.9 (CH), 43.0 (CH2), 41.5 (CH2, diast.1), 41.3 (CH2, diast.2),
32.7 (CH2), 32.6 (CH2), 25.4 (CH2), 25.3 (CH2), 24.7 (CH2), 24.6 (CH2).
4.2.34. N-Cyclohexyl 2-[N-(p-chlorophenoxyacetyl)-N-[3-(3-benzyl-
2,4-dioxo-1-(m-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-
tolyl)acetamide 10q. White solid (0.41 g, 53%, EtOH/DMF). IR (KBr,
cmꢁ1): 3277, 3079, 1778, 1721, 1650, 1614. 1H NMR (200 MHz, CDCl3)
4.2.31. N-Cyclohexyl 2-[N-(p-chlorobenzoyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-trifluoromethylphenyl)-imidazolidin-5-yl)phenylamino]-
2-(p-chlorophenyl)acetamide 10n. White solid (0.44 g, 54%, EtOH/
DMF). IR (KBr, cmꢁ1): 3359, 3035, 1772, 1719, 1684, 1631. 1H NMR
d 7.98e6.62 (m, 21H, HAr), 6.05 (br s, diast.1, 0.75H, CH), 5.98 (br s,
diast.2, 0.25H, CH), 5.60e5.22 (m, 2H, CHþNH), 4.81e4.65 (m, 2H, CH2),
4.24e4.03 (m, 2H, CH2), 3.83e3.65 (m, 1H, CH cyclohexyl), 2.25 (s,
diast.1, 2.25H, CH3), 2.19 (s, diast.2, 0.75H, CH3), 1.98e1.61 (m, 5H),
(200 MHz, CDCl3)
d
7.96 (s, diast.1, 0.8H, HAr), 7.92 (s, diast.2, 0.2H,
1.40e0.85 (m, 5H). 13C NMR (50 MHz, CDCl3)
d 168.6 (Cq), 168.3 (Cq,
HAr), 7.37e6.89 (m, 20H, HAr), 6.21 (s, diast.1, 0.8H, CH), 6.15 (s, diast.2,
0.2H, CH), 5.73 (d, J¼8.3 Hz, diast.2, 0.2H, NH), 5.63 (d, J¼8.1 Hz, 0.8H,
NH), 5.24 (s, 1H, CH), 4.78e4.70 (m, 2H, CH2), 3.91e3.72 (m, 1H, CH
diast.2), 168.0 (Cq, diast.1), 167.6 (Cq, diast.2), 167.5 (Cq, diast.1), 162.8
(d, J¼246.1 Hz, Cq), 156.5 (Cq), 153.9 (Cq), 138.9 (Cq), 138.5 (Cq), 137.6
(d, J¼10.5 Hz, Cq), 135.3 (Cq), 131.3 (CHAr), 130.3 (CHAr), 130.0 (CHAr),
129.2 (CHAr), 129.1 (CHAr), 128.9 (CHAr), 128.7 (CHAr), 128.5 (CHAr),
128.2 (CHAr), 126.6 (Cq), 126.1 (Cq), 116.0 (CHAr), 115.1 (CHAr), 111.4 (d,
J¼21.3 Hz, CHAr), 107.6 (d, J¼26.9 Hz, CHAr), 66.5 (CH2), 64.7 (CH,
diast.2), 64.4(CH, diast.1), 63.5 (CH, diast.2),63.1(CH, diast.1),48.9(CH),
42.9 (CH2), 32.7 (CH2), 25.4 (CH2), 24.7 (CH2), 24.7 (CH2), 21.1 (CH3).
cyclohexyl), 1.98e0.97 (m, 10H). 13C NMR (50 MHz, CDCl3)
d 169.8
(Cq), 168.1 (Cq), 167.9 (Cq), 154.0 (Cq), 141.3 (Cq), 136.8 (Cq, diast.2),
136.7 (Cq, diast.1), 135.7 (Cq, diast.2), 135.6 (Cq, diast.1), 135.3 (Cq),
134.7 (Cq, diast.1), 134.6 (Cq, diast.2), 133.7 (Cq), 132.7 (Cq), 132.6
(Cq),131.8 (CHAr),131.6 (q, J¼30.6 Hz, Cq),129.8 (CHAr),129.5 (CHAr),
128.9 (CHAr), 128.8 (CHAr), 128.6 (CHAr), 128.3 (CHAr), 127.9 (CHAr),
125.5 (CHAr), 125.4 (CHAr), 123.5 (q, J¼272.8 Hz, Cq), 121.8
(CHAr),121.1 (q, J¼4.0 Hz, CHAr), 116.4 (q, J¼4.0 Hz, CHAr), 64.9 (CH,
diast.2), 64.5 (CH, diast.1), 63.1 (CH, diast.2), 62.9 (CH, diast.1), 49.0
(CH), 43.0 (CH2), 32.8 (CH2), 25.4 (CH2), 24.8 (CH2), 24.7 (CH2).
4.2.35. N-Cyclohexyl 2-[N-(p-nitrophenylacetyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-
phenylacetamide 10r. White solid (0.41 g, 54%, EtOH/DMF). IR (KBr,
cmꢁ1): 3358, 3034, 1767, 1716, 1651, 1604, 1494, 1347. 1H NMR
(400 MHz, CDCl3)
d 8.06e8.04 (m, 2H, HAr), 7.89e7.64 (m, 1H, HAr),
4.2.32. N-Cyclohexyl 2-[N-(3-phenylpropargyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-trifluoromethylphenyl)-imidazolidin-5-yl)phenylamino]-
2-(p-chlorophenyl)acetamide 10o. White solid (0.28 g, 35%, EtOH).
IR (KBr, cmꢁ1): 3276, 3064, 1777, 1722, 1684, 1649. 1H NMR
7.42e6.92 (m, 16H, HAr), 6.81e6.70 (m, 2H, HAr), 6.42 (br s, 1H, HAr),
6.14 (br s, diast.1, 0.65H, CH), 5.99 (br s, diast.2, 0.35H, CH), 5.42 (br s,
1H, NH), 5.19 (br s, diast.2, 0.35H, CH), 5.08 (br s, diast.1, 0.65H, CH),
4.74e4.71 (m, 2H, CH2), 3.84e3.74 (m, 1H, CH cyclohexyl), 3.41 (d,
J¼15.4 Hz, 1H, CH2), 3.3 7 (d, J¼15.4 Hz, 1H, CH2), 1.94e1.56 (m, 5H),
1.40e1.25 (m, 2H), 1.34e0.90 (m, 3H). 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3) d 8.11 (s, diast.1, 0.76H, HAr), 8.06 (s, diast.2, 0.24H,
HAr), 7.35e6.81 (m, 21H, HAr), 6.09 (s, diast.1, 0.76H, CH), 6.03 (s,
diast.2, 0.24H, CH), 5.88e5.83 (m, 1H, NH), 5.46 (s, diast.1, 0.76H,
CH), 5.39 (s, diast.2, 0.24H, CH), 4.74 (d, J¼14.4 Hz, diast.1, 0.76H,
CH2), 4.69 (d, J¼14.3 Hz, diast.2, 0.24H, CH2), 4.65 (d, J¼14.4 Hz,
diast.1, 0.76H, CH2), 4.53 (d, J¼14.3 Hz, diast.2, 0.24H, CH2),
3.78e3.72 (m, 1H, CH cyclohexyl), 1.92e1.54 (m, 5H), 1.38e0.95 (m,
d
170.1 (Cq), 168.6 (Cq), 168.4 (Cq), 163.1 (d, 1J¼246.1 Hz, Cq), 154.1
(Cq), 147.0 (Cq), 142.6 (Cq), 140.3 (Cq), 137.9 (d, 3J¼8.9 Hz, Cq), 135.5
(Cq), 134.3 (Cq), 133.0 (Cq), 132.3 (CHAr), 131.8 (CHAr), 130.7 (CHAr),
130.4 (CHAr), 129.0 (CHAr), 128.9 (CHAr), 128.7 (CHAr), 125.7 (CHAr),
123.7 (CHAr), 114.9 (CHAr), 111.7 (d, 2J¼22.5 Hz, CH), 107.2 (d,
2J¼25.7 Hz, CH), 65.3 (CH, diast.2), 64.6 (CH, diast.1), 63.7 (CH,
diast.2), 63.2 (CH, diast.1), 49.2 (CH), 43.3 (CH2), 41.7 (CH2), 33.0
(CH2), 25.6 (CH2), 25.1 (CH2), 25.0 (CH2), 24.9 (CH2).
5H). 13C NMR (100 MHz, CDCl3)
d 168.7 (Cq), 167.8 (Cq, diast.2),167.7
(Cq, diast.1), 155.0(Cq, diast.2), 154.9 (Cq, diast.1), 154.4 (Cq), 140.6
(Cq, diast.2), 140.5 (Cq, diast.1), 137.0 (Cq, diast.2), 136.9 (Cq, diast.1),
135.6 (Cq), 134.9 (Cq, diast.2), 134.8 (Cq, diast.1), 133.3 (Cq), 132.9
(CHAr), 132.7 (CHAr), 132.4 (Cq), 132.1 (CHAr), 131.7 (q, 2J¼32.4 Hz,
Cq), 131.6 (CHAr), 130.4 (CHAr), 130.2 (Cq), 129.8 (CHAr), 129.6 (CHAr),
129.0 (CHAr), 128.9 (CHAr), 128.8 (CHAr), 128.7 (CHAr), 128.6 (CHAr),
128.5 (CHAr), 128.4 (CHAr), 127.0 (CHAr, diast.2), 126.7 (CHAr, diast.1),
123.8 (q, 1J¼272.8 Hz, Cq), 122.5 (CHAr, diast.2), 122.4 (CHAr, diast.1),
121.1 (Cq), 119.9 (CHAr), 117.2 (q, 3J¼3.7 Hz, diast.1, CHAr), 117.1 (q,3
4.2.36. N-Cyclohexyl 2-[N-(p-chlorobenzoyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-
chlorophenyl)acetamide 10s. White solid (0.21 g, 28%, EtOH/DMF). IR
(KBr, cmꢁ1): 3359, 3032, 1773, 1715, 1686, 1625. 1H NMR (200 MHz,
CDCl3)
d 7.42e6.79 (m, 21H, HAr), 6.18 (s, diast.1, 0.86H, CH), 6.13 (s,
diast.2, 0.14H, CH), 5.66 (d, J¼8.1 Hz, diast.2, 0.14H, NH), 5.50 (d,

~
M. Sanudo et al. / Tetrahedron 68 (2012) 2621e2629
2629
J¼8.3 Hz, diast.1, 0.86H, NH), 5.15 (s, 1H, CH), 4.73 (s, 2H, CH2),
Supplementary data
3.90e3.75 (m, 1H, CH cyclohexyl), 2.02e0.98 (m, 10H). 13C NMR
(50 MHz, CDCl3)
d
169.9 (Cq),168.3 (Cq),167.9 (Cq),162.8 (d, 1J¼245.9,
Crystallographic information file (CIF) of compound 10k (CCDC
852635). Copies of 1H and 13C NMR of the products and a plot of
structure 10k. Supplementary data related to this article can be
found in the online version, at doi:10.1016/j.tet.2012.01.073. These
data includes MOL files and InChiKeys of the most important
compounds described in this article.
Cq), 153.9 (Cq), 141.3 (Cq), 135.5 (d, 3J¼13.2 Hz, Cq), 134.8 (Cq), 133.7
(Cq),132.9 (Cq),132.8 (Cq),131.9 (CHAr), 131.8 (CHAr), 131.4 (Cq), 130.2
(d, 3J¼9.2 Hz, CHAr), 129.9 (Cq), 129.8 (CHAr), 128.9 (CHAr), 128.8
(CHAr), 128.2 (CHAr), 127.9 (CHAr), 125.6 (CHAr), 114.5 (d, 4J¼3.3 Hz,
CHAr),111.4 (d, 2J¼21.0 Hz, CHAr),107.3 (d, 2J¼26.9 Hz, CHAr), 64.7 (CH,
diast.2), 64.5 (CH, diast.1), 63.4 (CH, diast.2), 63.1 (CH, diast.1), 49.0
(CH), 43.0 (CH2), 32.8 (CH2), 25.4 (CH2), 24.8 (CH2), 24.7 (CH2).
References and notes
1. Ware, E. Chem. Rev. 1950, 46, 403e470.
4.2.37. N-Cyclohexyl 2-[N-(2-chloroacetyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-
tolyl)acetamide 10t. White solid (0.25 g, 37%, EtOH/DMF). IR (KBr,
cmꢁ1): 3252, 3034, 1769, 1711, 1678, 1602. 1H NMR (400 MHz,
2. (a) Claeys, D. D.; Stevens, C. V.; Dieltiens, N. Eur. J. Org. Chem. 2008, 171e179; (b)
Muccioli, G. G.; Martin, D.; Scriba, G. K. E.; Poppitz, W.; Poupaert, J. H.; Wouters,
J.; Lambert, D. M. J. Med. Chem. 2005, 48, 2509e2517; (c) Zha, C.; Brown, G. B.;
Brouillette, W. J. J. Med. Chem. 2004, 47, 6519e6528; (d) Jansen, M.; Potschka,
€
H.; Brandt, C.; Loscher, W.; Dannhardt, G. J. Med. Chem. 2003, 46, 64e73.
CDCl3)
d 7.82 (br s, 1H, HAr), 7.47e6.37 (m, 16H, HAr), 6.16e4.98 (m,
3. (a) Kumar, V.; Kaushik, M. P.; Mazumdar, A. Eur. J. Org. Chem. 2008, 1910e1916;
(b) Zhang, D.; Xing, X.; Cuny, G. D. J. Org. Chem. 2006, 71, 1750e1753.
4. (a) Hotha, S.; Yarrow, J. C.; Yang, J. G.; Garrett, S.; Renduchintala, K. V.; Mayer, T.
U.; Kapoor, T. M. Angew. Chem., Int. Ed. 2003, 42, 2379e2382; (b) Maiti, B.;
Chanda, K.; Sun, C.-M. Org. Lett. 2009, 11, 4826e4829.
3H, 2CHþNH), 4.70e4.52 (m, 2H, CH2), 3.65e3.50 (m, 3H, CHþCH2),
2.14 (s, diast.1, 2H, CH3), 2.08 (s, diast.2, 1H, CH3), 1.31e1.45 (m, 5H),
1.25e0.82 (m, 5H). 13C NMR (100 MHz, CDCl3)
d 168.6 (Cq), 168.2
(Cq, diast.2), 167.9 (Cq, diast.1), 166.3 (Cq, diast.1), 166.1 (Cq, diast.2),
162.6 (d, J¼246.1 Hz, Cq), 153.8 (Cq), 139.3 (Cq, diast.2), 139.2 (Cq,
diast.1), 138.3 (Cq, diast.1), 138.2 (Cq, diast.2), 137.4 (d, J¼10.6 Hz,
Cq), 135.3 (Cq), 133.8 (Cq), 131.4 (CHAr), 130.1 (CHAr), 130.0 (CHAr),
129.9 (CHAr), 129.8 (CHAr), 129.1 (Cq), 128.9 (CHAr), 128.6 (CHAr),
128.4 (CHAr), 128.0 (CHAr), 115.1 (d, J¼2.8 Hz, CHAr), 111.2 (d,
J¼21.4 Hz, CHAr), 107.5 (d, J¼26.5 Hz, CHAr), 64.9 (CH, diast.1), 64.7
(CH, diast.2), 63.3 (CH, diast.1), 63.0 (CH, diast.2), 48.6 (CH), 42.7
(CH2), 42.3 (CH2), 32.5 (CH2), 32.5 (CH2), 25.3 (CH2), 24.7 (CH2), 24.5
(CH2), 21.0 (CH3, diast.1), 20.9 (CH3, diast.2).
5. Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.; Linget,
J. M.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med. Chem. 2003, 46, 4533e4542.
ꢁ
6. (a) Tachibana, K.; Imaoka, I.; Shiraishi, T.; Yoshino, H.; Nakamura, V.; Ohta, M.;
Kawata, V.; Taniguchi, V.; Ishikura, V.; Tsunenari, T.; Saito, H.; Nagamuta, M.;
Nakagawa, T.; Takanashi, K.; Onuma, E.; Sato, H. Chem. Pharm. Bull. 2008, 56,
1555e1561; (b) Sun, C.; Robl, J. A.; Wang, T. C.; Huang, Y.; Kuhns, J. E.; Lupisella,
J. A.; Beehler, B. C.; Golla, R.; Sleph, P. G.; Seethala, R.; Fura, A.; Krystek, S. R., Jr.;
An, Y.; Malley, M. F.; Sack, J. S.; Salvati, M. E.; Grover, G. J.; Ostrowski, J.; Ha-
mann, L. G. J. Med. Chem. 2006, 49, 7596e7599.
7. (a) Cachet, N.; Genta-Jouve, G.; Regalado, E. L.; Mokrini, R.; Amade, P.; Culioli,
G.; Thomas, O. P. J. Nat. Prod. 2009, 72, 1612e1615; (b) Carr, G.; Chung, M. K. W.;
Mauk, A. G.; Andersen, R. J. J. Med. Chem. 2008, 51, 2634e2637; (c) Aberle, N. S.;
Lessene, G.; Watson, K. G. Org. Lett. 2006, 8, 419e421.
8. (a) Zancanella, M. A.; Romo, D. Org. Lett. 2008, 10, 3685e3688; (b) Hupp, C. D.;
Tepe, J. J. Org. Lett. 2008, 10, 3737e3739; (c) Hupp, C. D.; Tepe, J. J. J. Org. Chem.
2009, 74, 3406e3413.
9. (a) Ocasio, C. A.; Scanlan, T. S. ACS Chem. Biol. 2006, 1, 585e593; (b) Sergent, D.;
Wang, Q.; Sasaki, N. A.; Ouazzani, J. Bioorg. Med. Chem. Lett. 2008, 18, 4332e4335.
4.2.38. N-Cyclohexyl 2-[N-(3-phenylpropargyl)-N-[3-(3-benzyl-2,4-
dioxo-1-(m-fluorophenyl)-imidazolidin-5-yl)phenylamino]-2-(p-
chlorophenyl)acetamide 10u. White solid (0.41 g, 54%, EtOH/DMF).
IR (KBr, cmꢁ1): 3273, 3088, 2212, 1776, 1722, 1684, 1632. 1H NMR
ꢀ
~
ꢀ
ꢀ
ꢀ
10. (a) Vazquez, J.; García-Jareno, A.; Mondragon, L.; Rubio-Martinez, J.; Perez-Paya,
E.; Albericio, F. ChemMedChem. 2008, 3, 979e985; (b) Gavrilyuk, J. I.; Evindar,
G.; Batey, R. A. J. Comb. Chem. 2006, 8, 237e246; (c) Stilz, H. U.; Guba, W.; Ja-
(400 MHz, CDCl3) d 7.46e6.85 (m, 21H, HAr), 6.75e6.61 (m, 1H, HAr),
6.08 (s, diast.1, 0.74H, CH), 6.02(s, diast.2, 0.26H, CH), 5.78(d, J¼8.2 Hz,
diast.2, 0.26H, NH), 5.69 (d, J¼7.8 Hz, diast.1, 0.74H, NH), 5.37 (s,
diast.1, 0.74H, CH), 5.32 (s, diast.2, 0.26H, CH), 4.73 (d, J¼14.5 Hz,
diast.1, 0.74H, CH2), 4.65 (d, J¼14.6, diast.2, 0.26H, CH2), 4.64 (d,
J¼14.5 Hz, diast.1, 0.74H, CH2), 4.41 (d, J¼14.6 Hz, diast.2, 0.26H, CH2),
3.83e3.72 (m, 1H, CH cyclohexyl), 1.94e1.55 (m, 5H), 1.37e0.94 (m,
€
blonka, B.; Just, M.; Klingler, O.; Konig, W.; Wehner, V.; Zoller, G. J. Med. Chem.
2001, 44, 1158e1176.
11. Recent examples: (a) Dumbris, S. M.; Díaz, D. J.; McElwee-White, L. J. Org. Chem.
2009, 74, 8862e8865; (b) Werner, S.; Turner, D. M.; Chambers, P. G.; Brum-
mond, K. M. Tetrahedron 2008, 64, 6997e7007; (c) Zhao, B.; Du, H.; Shi, Y. J. Am.
Chem. Soc. 2008, 130, 7220e7221; (d) Murray, R. G.; Whitehead, D. M.; Strat, F.
L.; Conway, S. J. Org. Biomol. Chem. 2008, 6, 988e991; (e) Volonterio, A.; Ramirez
de Arellano, C.; Zanda, M. J. Org. Chem. 2005, 70, 2161e2170; (f) Evindar, G.;
Batey, R. A. Org. Lett. 2003, 5, 1201e1204.
5H). 13C NMR (100 MHz, CDCl3)
d 168.5 (Cq, diast.2), 168.4 (Cq,
diast.1), 167.5 (Cq, diast.2), 167.3 (Cq, diast.1), 162.7 (d, 1J¼245.7 Hz,
Cq), 154.7 (Cq, diast.2),154.6 (Cq, diast.1),154.0 (Cq),140.1 (Cq),137.5
(d, 3J¼10.6 Hz, Cq), 135.3 (Cq), 134.7 (Cq, diast.2), 134.6 (Cq, diast.1),
133.5 (Cq, diast.2),133.2 (Cq, diast.1),132.6 (CHAr),132.5 (CHAr),132.3
(CHAr), 132.1 (Cq), 131.8 (CHAr), 131.2 (CHAr), 130.1 (CHAr, diast.1),
130.0 (CHAr, diast.2), 129.6 (Cq), 129.4 (CHAr), 128.7 (CHAr), 128.623
12. (a) Lecinska, P.; Corres, N.; Moreno, D.; Garcia-Valverde, M.; Marcaccini, S.;
~
Torroba, T. Tetrahedron 2010, 66, 6783e6788; (b) Sanudo, M.; Garcia-Valverde,
M.; Marcaccini, S.; Delgado, J. J.; Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74,
2189e2192; (c) Corres, N.; Delgado, J. J.; Garcia-Valverde, M.; Marcaccini, S.;
~
Rodriguez, T.; Rojo, J.; Torroba, T. Tetrahedron 2008, 64, 2225e2232; (d) Sanudo,
M.; Marcaccini, S.; Basurto, S.; Torroba, T. J. Org. Chem. 2006, 71, 4578e4584.
13. Ignacio, J. M.; Macho, S.; Marcaccini, S.; Pepino, R.; Torroba, T. Synlett 2005,3051e3054.
ꢀ
14. Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu, J., Bienayme, H.,
(CHAr, diast.2), 128.6 (CHAr, diast.1), 128.5 (CHAr, diast.2), 128.4 (CHAr
,
Eds.; Wiley-VCH: Weinheim, 2005; Chapter 2, pp 33e75.
diast.1), 128.2 (CHAr, diast.2), 128.2 (CHAr, diast.1), 128.1 (CHAr), 126.6
(CHAr, diast.2), 126.5 (CHAr, diast.1), 119.7 (Cq, diast.1), 119.6 (Cq,
diast.2), 114.7 (d, 4J¼2.8 Hz, CHAr), 111.3 (d, 2J¼20.3 Hz, diast.2, CHAr),
111.0 (d, 2J¼21.2 Hz, diast.1, CHAr),107.7 (d, 2J¼26.8 Hz, diast.1, CHAr),
107.3 (d, 2J¼22.7 Hz, diast.2, CHAr), 93.0 (Cq, diast.2), 92.8 (Cq, diast.1),
81.9 (Cq, diast.1), 81.8 (Cq, diast.2), 63.5 (CH, diast.2), 63.24 (CH,
diast.1), 63.3 (CH), 48.9 (CH), 42.8 (CH2), 32.7 (CH2), 32.6 (CH2), 25.4
15. Recent examples: (a) Mehta, V. P.; Modha, S. G.; Ruijter, E.; Van Hecke, K.; Van
Meervelt, L.; Pannecouque, C.; Balzarini, J.; Orru, R. V. A.; Van der Eycken, E. J. Org.
Chem. 2011, 76, 2828e2839; (b) Marcaccini, S.; Neo, A. G.; Marcos, C. F. J. Org. Chem.
2009, 74, 6888e6890; (c) Ribelin, T. P.; Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R.
F.; Cross, J. L.; Whittern, D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119e5122; (d) Gu-
levich, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. Org. Chem. 2007, 72, 7878e7885;
(e) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575e579; Review:
(f) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. In Multicomponent Reactions; Zhu, J., Bi-
ꢀ
enayme, H., Eds.; Wiley-VCH: Weinheim, 2005; Chapter 1, pp 1e32.
16. Extended experimental details about the Ugi reaction, in: Marcaccini, S.; Tor-
(CH2), 24.7 (CH2), 24.6 (CH2). 19F NMR (400 MZ, CDCl3)
d
ꢁ110.6.
roba, T. Nature Prot. 2007, 2, 632e639.
17. OSIRIS Property Explorer: http://www.organic-chemistry.org/prog/peo/. See:
Thomas Sander, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123
Allschwil, Switzerland.
Acknowledgements
18. SMART Diffractometer Control Software; Bruker Analytical X-ray Instruments:
Madison, WI, 2000.
We gratefully acknowledge financial support from the Minis-
ꢀ
terio de Ciencia e Innovacion, Spain (Project CTQ2009-12631-BQU),
19. SAINT Integration Software; Siemens Analytical X-ray Instruments: Madison, WI, 2000.
20. Sheldrick, G. M. SADABS: A Program for Absorption Correction with the Siemens
ꢀ
ꢀ
Junta de Castilla y Leon, Consejería de Educacion y Cultura y Fondo
Social Europeo (Projects BU023A09 and GR170). We thank to Marta
Mansilla and Dr. Jacinto Delgado (SCAI-Universidad de Burgos) for
the X-ray determination of compound 10k.
€
SMART system; University of Gottingen: Germany, 2001.
21. SHELXTL Program System Version 6.1; Bruker Analytical X-ray Instruments:
Madison, WI, 1998.
22. International Tables for Crystallography; Kluwer: Dordrecht, 1992; Vol. C.