Synthesis of 3-substituted dihydro-1-phenylamino-1h-pyrrolo[1,2-a] imidazole-2,5(3h,6h)-diones from α-amino acid phenylhydrazides and levulinic acid

Article abstract of DOI:10.1002/ejoc.200400112

α-Amino acid phenylhydrazides 1 readily react with levulinic acid to produce the imidazolidin-4-one intermediates 4, which undergo a second ring closure to afford the dihydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione derivatives 5. It has been established that the solvent polarity has a great influence on the rate of the second condensation reaction, but not on the first. A mechanism, supported by experimental evidence, has been proposed to explain how the imidazolidin-4-one intermediates 4, obtained as expected as a mixture of two diastereoisomers, give a single isomer for the bicyclic derivatives 5; the absolute stereochemistry of these compounds has been determined by X-ray crystallographic analysis. Wiley-VCH Verlag GmbH & Co, KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400112

FULL PAPER
Synthesis of 3-Substituted Dihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-
2,5(3H,6H)-diones from α-Amino Acid Phenylhydrazides and Levulinic Acid
Giancarlo Verardo,*[a] Paola Geatti,[a] Marcello Merli,[b] and Elena E. Castellarin[a]
Dedicated to the memory of Professor Angelo G. Giumanini, University of Udine[‡]
Keywords: Amino acids / Cyclization / Heterocycles / Hydrazides / Levulinic acid
α-Amino acid phenylhydrazides 1 readily react with levulinic
acid to produce the imidazolidin-4-one intermediates 4,
which undergo a second ring closure to afford the dihydro-
1H-pyrrolo[1,2-a]imidazole-2,5-dione derivatives 5. It has
been established that the solvent polarity has a great influ-
ence on the rate of the second condensation reaction, but
not on the first. A mechanism, supported by experimental
evidence, has been proposed to explain how the imidazoli-
din-4-one intermediates 4, obtained as expected as a mixture
of two diastereoisomers, give a single isomer for the bicyclic
derivatives 5; the absolute stereochemistry of these com-
pounds has been determined by X-ray crystallographic ana-
lysis.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Results and Discussion
Introduction
When an α-amino acid phenylhydrazide of type 1 and
levulinic acid (2a) were mixed under appropriate experimen-
tal conditions, a cyclocondensation reaction took place
yielding the imidazolidin-4-one intermediate 4, which rap-
idly underwent a second ring closure affording the bicyclic
compound 5 (Scheme 1).
We initially examined the behaviour of 2a with the phe-
nylhydrazides of alanine (1a), phenylalanine (1b), leucine
(1c) and methionine (1d) whose side chains do not induce
further reactions other than the double ring closure to 5.[1]
On the basis of previous results[1] obtained from 1 and ke-
tones, we decided to carry out the reaction in refluxing tolu-
ene but, in this case, the addition of an acidic catalyst (p-
toluenesulfonic acid, PTSA) to improve the reactivity of
both 2a and the imine 3 was not necessary due to the pres-
ence of the carboxylic function in 2a. We did not observe
any significant difference in reactivity among these phenyl-
hydrazides, and all afforded the bicyclic derivatives 5 in high
yield within five hours using a slight excess of 2a.
We have recently described the synthesis of 3-phenylam-
ino-substituted imidazolidin-4-ones[1] from the reaction of
some phenylhydrazides of natural α-amino acids (1) with
several carbonyl compounds. We now wish to report an ex-
tension of this reaction employing levulinic acid (2a), which
bears two reactive sites. The use of this γ-keto acid allowed
us to obtain a series of 1-phenylamino-substituted dihydro-
1H-pyrrolo[1,2-a]imidazole-2,5-diones containing both the
2-pyrrolidinone and 4-imidazolidinone moieties, which are
recognized as important frameworks for cognition-enhanc-
ing activity.[2] We are aware of only two reports of this ring
system[3] but none of the compounds described in these pa-
pers have the phenylamino group at the 1-position because
the authors used α-amino amides as starting materials.
Thus, considering the potential interest of our compounds,
we have optimised the experimental conditions and investi-
gated the reaction mechanism.
The phenylhydrazide of tryptophan (1e) is slightly soluble
in refluxing toluene giving, after the addition of 2a, an un-
manageable brown gum. To avoid this problem, toluene was
substituted by iPrOH and the reaction was carried out at
80 °C; however, even after long reaction times (30 h), al-
though the DI-MS and NMR analyses of the reaction mix-
ture showed the presence of the desired bicyclic compound
5e, a large amount (40%, HPLC yield) of the 4-imidazolidi-
none intermediate 4e was still present. Thus, to improve the
conversion of 4e into 5e, when the HPLC analysis of the
reaction mixture in iPrOH showed the complete disappear-
[a]
`
Dipartimento di Scienze e Tecnologie Chimiche, Universita di
Udine,
Via del Cotonificio 108, 33100 Udine, Italy
Fax: ϩ 39-0432-558803
E-mail: giancarlo.verardo@uniud.it
[b]
[‡]
`
Dipartimento di Scienze della Terra, Universita di Pavia, CNR-
IGG Ϫ Sezione di Pavia
Via Ferrata 1, 27100 Pavia, Italy
Fax: ϩ 39-0382-505880
E-mail: merli@crystal.unipv.it
A great scientist, teacher, mentor, and friend
Eur. J. Org. Chem. 2004, 2833Ϫ2839
DOI: 10.1002/ejoc.200400112
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G. Verardo, P. Geatti, M. Merli, E. E. Castellarin
FULL PAPER
Scheme 1
ance of the starting phenylhydrazide 1e (2 h), the tempera- tored the reaction between the phenylhydrazide of phenyl-
ture was raised to 110Ϫ120 °C (oil bath) and toluene was alanine (1b) and levulinic acid (2a) by HPLC both in EtOH
added in small portions in order to remove iPrOH by azeo- and iPrOH at 80 °C: after 90 min the analysis of both the
tropic distillation. The resulting mixture was refluxed for reaction mixtures showed the complete conversion of 1b
an additional six hours affording, after workup, the desired into 4b and only traces (2%, HPLC yield) of the bicyclic
bicyclic compound 5e in 87% yield. The phenylhydrazide of compound 5b. The imidazolidin-4-one 4b was by far the
histidine (1f) exhibited a similar behaviour, therefore the main product (90%, HPLC yield) after five hours. Since this
same reaction conditions as used for 1e were employed.
behaviour might be due to the lower reaction temperature
The low rate of conversion of 4e,f into the bicyclic com- (80 °C instead of 110Ϫ120 °C with toluene), the same reac-
pounds 5e,f in iPrOH, prompted us to investigate how the tion was carried out both in nBuOH and DMF at 110Ϫ120
solvent influenced the reaction. For this purpose we moni- °C (oil bath). As previously observed, the conversion into
Scheme 2
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3-Substituted Dihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones
FULL PAPER
4b occurred rapidly (1 h, as in toluene at 110Ϫ120 °C) but
The HPLC profile of all the reactions between 1b and 2b
it was still the major product (75%, HPLC yield), even after shows two peaks with similar intensity for the 4-imidazolid-
prolonged reaction times (24 h). These findings allow us to inone intermediate 6. As previously observed with carbonyl
infer that the rate of the first condensation reaction leading groups bearing different substituents,[1] this could be an in-
to 4 does not depend on the nature of the solvent used, dication that 6 is present as two diastereoisomers in a 1:1
while the second ring closure affording 5, even though it is ratio. In fact, the DI-MS analysis of the residue obtained
an intramolecular reaction, is slower and is strongly solvent from the reaction carried out in iPrOH (80 °C, 25 h)
dependent. A plausible explanation of such behaviour could showed the presence of a single compound with a fragmen-
be the different ability of the solvent system to solvate the tation pattern consistent with 6, while the 13C NMR spec-
zwitterionic intermediate 4. In a non-polar solvent such as trum exhibits two close signals for each different carbon
toluene, 4 is an intimate ion pair (4iip), thus the proton atom according to the existence of two very similar mol-
transfer between nitrogen at the 1-position of the imidazol- ecules.
idinone ring and the carboxylate, fundamental to obtain the
Otherwise, when 1aϪf were used in conjunction with 2a,
second condensation reaction to 5, is extremely easy and the HPLC monitoring invariably showed a single peak for
fast (Scheme 2). Otherwise, in polar solvents such as al- 4aϪf, but the 13C NMR spectrum of the residue obtained
cohols and DMF, the solvent-separated ion pair is more from the reaction of 1b with 2a in iPrOH (80 °C, 1.5 h)
stable and the proton transfer is slower.
shows, as in the case of 6, two close signals of similar inten-
When 2a was substituted by the corresponding ethyl ester sity for each different carbon atom of 4b. These results con-
2b the reaction rate drastically decreased without acid ca- firmed that, as expected, the imidazolidinones 4 are also
talysis both in iPrOH and toluene, as observed previously present as two diastereoisomers; the HPLC conditions em-
with several ketones.[1] In fact, the HPLC analysis of the ployed did not allow their separation.
reaction between 1b and 2b in iPrOH at 80 °C showed the
At this point, since the reaction between 1 and 2 afforded
complete conversion of 1b into the 5-benzyl-2-[2-(ethoxy- 4 as a diastereoisomeric mixture, it was obvious to suppose
carbonyl)ethyl]-3-(phenylamino)imidazolidin-4-one (6) and that the second ring closure also led to a mixture of two
1
only traces (1%, HPLC yield) of the bicyclic adduct 5b after diastereoisomers. Surprisingly, the H and 13C NMR spec-
25 h. In toluene, working at 110 °C, the reaction leading to tra of the bicyclic compounds 5 reveal a single set of peaks
6 was faster (8 h) but the intermediate 6 was still present consistent with the presence of a single isomer.
(20%, HPLC yield) after 100 h. The addition of an acidic
X-ray diffraction analysis of 3-(1H-indol-3-ylmethyl)-7a-
catalyst (PTSA) to the reaction carried out in toluene in- methyldihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-
creased the rate of both the ring closures, giving the com- 2,5(3H,6H)-dione (5e) confirmed the presence of a single
plete conversion into 5b after 30 h.
diastereoisomer and allowed us to determine its absolute
Figure 1. ORTEP drawing of 5e
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G. Verardo, P. Geatti, M. Merli, E. E. Castellarin
FULL PAPER
configuration. The ORTEP drawing of 5e, crystallized from signal, as further evidence of the syn stereochemistry of the
CHCl3 with a molecule of solvent, is shown in Figure 1. CH3 group, is shifted upfield by 0.5Ϫ0.7 ppm for 5b,d,e due
The following features should be noted (see Figure 1 for to the shielding effect of the aromatic side chains (phenyl,
atom numbering):
indolyl and imidazolyl, respectively) present in these com-
the bicyclic skeleton is distorted, with the N2ϪC8ϪC9 pounds. The 13C NMR spectra of all the compounds 5 dis-
and N3ϪC12ϪC13 bond angles particularly small (105.6° play the CH3 signal at ca. δ ϭ 25.0 ppm.
and 104.8°, respectively) for an sp2-hybridized carbon atom;
To explain the unexpected stereochemical course of this
the imidazolidinone moiety, which is almost planar with reaction, we suggest the following mechanism (Scheme 3):
small distortions due to the steric requirements of the sub- compound 1 reacts with 2a to form the imine 3, which
stituents, has an N2ϪC10ϪN3 bond angle of 98.1°, which promptly cyclizes to give a mixture of the two dia-
is much smaller than that expected for an sp3-hybridized stereoisomes 4(A) and 4(B). At this point, only 4(B) has the
carbon atom;
correct geometry to allow the second ring closure leading
the phenylamino group is oriented anti to both the amino to 5, while 4(A), which has a disfavoured structure probably
acid side chain and the methyl group and is almost perpen- due to steric hindrance, isomerises to 4(B) via the imine 3.
dicular to the imidazolidinone ring (the C7ϪN1ϪN2ϪC8
To test the proposed mechanism the two diastereoisomers
torsion angle is Ϫ84.8°);
6A and 6B, obtained from the reaction of 1b with 2b in
the two nitrogen atoms of the phenylhydrazide moiety iPrOH (80 °C, 20 h), were isolated by preparative TLC
and the phenyl ring are approximately coplanar (the (Et2O on basic alumina). The two compounds (6A and 6B)
C2ϪC7ϪN1ϪN2 torsion angle is Ϫ14.3°);
were separately dissolved in toluene and the solutions were
the methyl group deriving from levulinic acid is oriented heated to reflux in order to obtain 5b. The HPLC monitor-
syn to the amino acid side chain and eclipsed to the in- ing confirmed the epimerisation of the starting isomer to
dole ring.
the other in both the reaction mixtures and showed that
The configuration at C9 (C3 following the IUPAC while this process was faster with 6A than with 6B, the rate
convention) is S since it derives from the α-chiral centre of of formation of 5b was much slower but quite similar in
the starting phenylhydrazide 1e and it does not undergo any both cases (Table 1).
modification during the condensation reactions leading to
In conclusion, we have easily synthesised a series of bi-
5e. Therefore, the absolute configuration at C10 (C7a fol- cyclic compounds, namely dihydro-1H-pyrrolo[1,2-a]imid-
lowing the IUPAC convention) determined by X-ray dif- azole-2,5-diones, with a rigid framework containing natural
fraction analysis is R; presumably the C7a and, even more amino acid moieties. Contrary to what we expected, NMR
so, the C3 stereochemistry of all the other bicyclic deriva- spectroscopy and X-ray diffraction analysis showed that
tives 5 is the same.
only one of the two possible diastereoisomers was formed.
The 1H NMR spectra of the bicyclic compounds bearing In addition to the 2-pyrrolidinone and 4-imidazolidinone
non-aromatic side chains at the 3-position, such as 5a,c,d, frameworks, which are recognized as important for cog-
exhibit a singlet for the CH3 protons at δ ϭ 1.6 ppm. This nition-enhancing activity, these bicyclic derivatives present
Scheme 3
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3-Substituted Dihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones
FULL PAPER
Table 1. Results of the epimerization of 6A and 6B[a]
rated. The residue was triturated in hexane to give 5aϪd in a spec-
troscopically pure form.
Time Relative percentages[b]
Relative percentages[b]
3,7a-Dimethyldihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-
2,5-(3H,6H)-dione (5a): White solid (0.441 g, 94%), m.p. 178Ϫ180
°C. [α]D ϭ ϩ3.5 (c ϭ 2.0, MeOH). IR (KBr): ν˜ ϭ 3298, 1705,
starting from 6A
starting from 6B
[h]
6A
6B
5b
6B
6A
5b
1
1600, 1495, 1402, 1377, 1356, 1227, 991, 754, 698 cmϪ1. H NMR
3
8
11
15
30
60
49
39
34
33
27
10
51
57
59
57
40
19
0
4
7
10
31
71
81
17
28
27
26
19
9
2
4
8
10
32
71
(CDCl3): δ ϭ 1.47 (d, J ϭ 7.3 Hz, 3 H, *CHCH3), 1.63 (s, 3 H,
CCH3), 2.00Ϫ2.56 (m, 3 H, CH2CHH), 2.58Ϫ2.86 (m, 1 H,
CH2CHH), 4.47 (q, J ϭ 7.3 Hz, 1 H, *CH), 6.57 (s, 1 H, NH),
6.66Ϫ6.79 (m, 2 H, Ar-H), 6.83Ϫ6.98 (m, 1 H, Ar-H), 7.09Ϫ7.25
(m, 2 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 17.9, 26.1, 30.7, 33.7,
52.1, 82.3, 113.5, 121.5, 129.1, 146.1, 173.2, 177.5 ppm. MS (70 eV,
EI): m/z (%) ϭ 259 (36) [Mϩ], 152 (22), 134 (13), 124 (66), 108 (11),
98 (100), 92 (10), 77 (13), 65 (7), 55 (8). C14H17N3O2 (259.31):
calcd. C 64.85, H 6.61, N 16.20; found C 64.88, H 6.58, N 16.22.
68
65
64
49
21
[a]
Reactions were carried out in toluene at reflux temperature
[b]
(110Ϫ120 °C, oil bath) under Ar. The relative percentages were
determined by HPLC.
3-Benzyl-7a-methyldihydro-1-phenylamino-1H-pyrrolo[1,2-a]-
imidazole-2,5-(3H,6H)-dione (5b): White solid (0.509 g, 84%), m.p.
Ͼ 235 °C. [α]D ϭ Ϫ6.0 (c ϭ 2.0, MeOH). IR (KBr): ν˜ ϭ 3273
broad, 3030, 1713, 1603, 1498, 1399, 1377, 1347, 1306, 1262, 990,
an amino nitrogen atom that could affect the pharmaco-
logical properties and could be attractive for the design of
new structures having biological activity.
754, 697, 578 cmϪ1 1H NMR (CDCl3): δ ϭ 0.94 (s, 3 H, CH3),
.
2.00Ϫ2.48 (m, 3 H, CH2CHH), 2.55Ϫ2.80 (m, 1 H, CH2CHH),
3.08Ϫ3.30 (m, 2 H, *CHCH2), 4.68 (app t, J ϭ 5.5 Hz, 1 H, *CH),
6.10 (s, 1 H, NH), 6.66Ϫ6.79 (m, 2 H, Ar-H), 6.84Ϫ6.99 (m, 1 H,
Ar-H) 7.12Ϫ7.40 (m, 7 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ
25.0, 30.9, 35.2, 36.9, 58.4, 82.1, 113.8, 121.7, 127.1, 128.4, 129.1,
130.1, 136.2, 145.9, 171.3, 178.3 ppm. MS (70 eV, EI): m/z (%) ϭ
335 (88) [Mϩ], 228 (13), 200 (100), 134 (26), 131 (20), 103 (10), 98
(93), 91 (28), 77 (21), 65 (18), 55 (12). C20H21N3O2 (335.41): calcd.
C 71.61, H 6.31, N 12.53; found C 71.68, H 6.38, N 12.50.
Experimental Section
General: All reagents were of commercial quality (Aldrich, Fluka)
and were used without further purification. The α-amino acid phe-
nylhydrazides 1aϪd, [4] and 1e and 1f[1] were prepared as described
previously. The reactions were monitored by high performance
liquid chromatography (HPLC) performed with a Waters M-45 ap-
paratus on an Alltech Adsorbosphere C18 column (250 ϫ 4.6 mm,
particle size 5 µm, flow rate 1 mL/min, detection at 254 nm) using
the following mobile phase: 50:50 MeCN/H2O with 1.4% NEt3 (v/
v) adjusted to pH 7.3 with H3PO4. Preparative TLC was performed
on basic Al2O3 60 F254 plates (20 ϫ 20 cm, 1.5 mm thickness,
Merck) and visualized under UV light. Direct inlet mass spectra
(DI-MS) were obtained with a Fisons TRIO 2000 gas chromato-
graph-mass spectrometer, working in the positive ion 70 eV electron
impact mode. Spectra were recorded in the range 35Ϫ450 u. Tem-
peratures between 150 and 250 °C were found to be suitable to
volatilise all the compounds into the ion source. IR spectra were
obtained with a Nicolet FT-IR Magna 550 spectrophotometer
using the KBr technique for solids and recorded in the range
3-Isobutyl-7a-methyldihydro-1-phenylamino-1H-pyrrolo[1,2-a]-
imidazole-2,5-(3H,6H)-dione (5c): White solid (0.452 g, 83%), m.p.
148Ϫ150 °C. [α]D ϭ Ϫ22.5 (c ϭ 2.0, MeOH). IR (KBr): ν˜ ϭ 3228
broad, 2961, 1721, 1605, 1496, 1396, 1374, 1348, 1241, 750 cmϪ1
.
1H NMR (CDCl3): δ ϭ 0.99 (d, J ϭ 6.3 Hz, 3 H, CH3CHCH3),
1.08 (d, J ϭ 6.4 Hz, 3 H, CH3CHCH3), 1.36Ϫ1.55 [m, 1 H,
CH(CH3)2], 1.62 (s, 3 H, CCH3), 1.62Ϫ2.87 (m, 6 H, CCH2CH2
ϩ *CHCH2), 4.43 (dd, J1 ϭ 11.2, J2 ϭ 3.9 Hz, 1 H, *CH), 6.60 (s,
1 H, NH), 6.63Ϫ6.79 (m, 2 H, Ar-H), 6.81Ϫ6.92 (m, 1 H, Ar-H),
7.08Ϫ7.26 (m, 2 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 21.3, 23.2,
25.2, 26.2, 30.4, 33.4, 41.4, 55.7, 82.5, 113.4, 121.3, 129.1, 146.2,
173.0, 178.1 ppm. MS (70 eV, EI): m/z (%) ϭ 301 (40) [Mϩ], 194
(11), 166 (45), 134 (7), 124 (14), 108 (20), 98 (100), 93 (12), 92 (13),
77 (11). C17H23N3O2 (301.39): calcd. C 67.73, H 7.70, N 13.95;
found C 67.68, H 7.75, N 13.90.
4000Ϫ400 cmϪ1 1H and 13C NMR spectra were recorded on a
.
Bruker AC-F 200 spectrometer at 200 and 50 MHz, respectively,
using CDCl3 at room temperature or [D6]DMSO at 40 °C as sol-
vents. NMR peak locations are reported as δ values from TMS.
1
Some H multiplets are characterized by the term app (apparent):
7a-Methyl-3-[2-(methylthio)ethyl]dihydro-1-phenylamino-1H-
pyrrolo[1,2-a]imidazole-2,5-(3H,6H)-dione (5d): White solid
(0.520 g, 90%), m.p. 127Ϫ130 °C. [α]D ϭ Ϫ31.0 (c ϭ 1.0, MeOH).
IR (KBr): ν˜ ϭ 3241 broad, 2915, 1719, 1694, 1602, 1497, 1396,
this refers only to their appearance and may be an oversimpl-
ification. Optical rotations were determined at 20 °C (concentration
in g/100 mL of solvent) using a POLAX-D polarimeter purchased
from ATAGO (Japan). Elemental analyses were performed with a
Carlo Erba Mod. 1106 elemental analyser. Melting points were de-
termined with an automatic Mettler (Mod. FP61) melting point
apparatus and are not corrected.
1
1345, 759, 698 cmϪ1. H NMR (CDCl3): δ ϭ 1.64 (s, 3 H, CCH3),
1.70Ϫ2.00 (m, 1 H, *CHCHH), 2.13 (s, 3 H, SCH3), 2.05Ϫ2.88 (m,
7 H, *CHCHH ϩ CH2CH2 ϩ SCH2), 4.47 (dd, J1 ϭ 10.5, J2
ϭ
4.4 Hz, 1 H, *CH), 6.31 (s, 1 H, NH), 6.68Ϫ6.84 (m, 2 H, Ar-H),
6.84Ϫ7.05 (m, 1 H, Ar-H), 7.10Ϫ7.35 (m, 2 H, Ar-H) ppm. 13C
NMR (CDCl3): δ ϭ 15.4, 26.1, 30.6, 30.8, 32.4, 33.9, 56.1, 82.4,
113.7, 121.9, 129.3, 146.0, 172.0, 178.1 ppm. MS (70 eV, EI): m/z
(%) ϭ 319 (61) [Mϩ], 184 (22), 175 (19), 164 (18), 136 (42), 124
(19), 108 (17), 98 (59), 92 (26), 91 (8), 77 (26), 65 (23), 61 (100), 55
(21). C16H21N3O2S (319.42): calcd. C 60.16, H 6.63, N 13.16; found
C 60.20, H 6.60, N 13.10.
Synthesis of 5aϪd: A stirred solution of the appropriate -amino
acid phenylhydrazide (1aϪd; 1.81 mmol) in toluene (10 mL) was
gently refluxed under Ar and then levulinic acid (2a; 0.273 g,
2.35 mmol) was added to the solution. The reaction mixture was
stirred at the same temperature for 5 h (monitored by HPLC).
After evaporation of the solvent under reduced pressure, the resi-
due was dissolved in CH2Cl2 (10 mL) and vigorously stirred with
Na2CO3·10H2O (0.70 g, 2.35 mmol) for 1 h. The mixture was dried
over anhydrous Na2SO4, filtered and then the CH2Cl2 was evapo-
Synthesis of 5e,f: A stirred suspension of the appropriate -amino
acid phenylhydrazide (1e,f; 1.81 mmol) in iPrOH (30 mL) was
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G. Verardo, P. Geatti, M. Merli, E. E. Castellarin
FULL PAPER
heated under Ar at 80 °C (oil bath) and then levulinic acid (2a;
1
1121, 752, 702 cmϪ1. H NMR (CDCl3): δ ϭ 1.13 (t, J ϭ 7.1 Hz,
0.273 g, 2.35 mmol) was added to the suspension. The reaction
3 H, CH2CH3), 1.22 (s, 3 H, CCH3), 1.75 (t, J ϭ 7.1 Hz, 2 H,
mixture was stirred at the same temperature until HPLC analysis CCH2), 1.91 (broad s, 1 H, NH), 2.07Ϫ2.22 (m, 2 H, CH2CO),
showed the complete disappearance of 1 (2 h). At this point the
temperature was raised to 120 °C (oil bath) and toluene (35 mL)
was added in small portions in order to remove iPrOH by azeo-
2.85Ϫ3.14 (m, 2 H, PhCH2), 3.81 (app t, J ϭ 5.1 Hz, 1 H, *CH),
3.99 (q, J ϭ 7.1 Hz, 2 H, CH3CH2), 6.14 (s, 1 H, PhNH), 6.47Ϫ6.58
(m, 2 H, Ar-H), 6.71Ϫ6.85 (m, 1 H, Ar-H), 6.99Ϫ7.13 (m, 2 H,
tropic distillation. The resulting reaction mixture was stirred at the Ar-H), 7.14Ϫ7.37 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ
same temperature for an additional 6 h (monitored by HPLC).
After evaporation of the solvent under reduced pressure, the resi-
due was dissolved in CH2Cl2 (10 mL) and vigorously stirred with
Na2CO3·10H2O (0.70 g, 2.35 mmol) for 1 h. The mixture was dried
with anhydrous Na2SO4, filtered and, after partial evaporation of
14.7, 24.5, 29.1, 34.3, 37.9, 57.7, 61.2, 78.6, 114.4, 121.6, 127.5,
129.1, 129.5, 130.4, 137.5, 146.9, 173.9, 174.8 ppm. MS (70 eV, EI):
m/z (%) ϭ 381 (53) [Mϩ], 246 (28), 200 (29), 189 (13), 144 (36), 134
(17), 131 (30), 120 (20), 104 (28), 98 (53), 92 (74), 91 (100), 82 (23),
77 (51), 70 (29), 65 (58). C22H27N3O3 (381.47): calcd. C 69.25, H
the solvent under reduced pressure, the remaining solution (2 mL) 7.14, N 11.02; found C 69.29, H 7.10, N 11.08.
was added dropwise to hexane (50 mL) whilst stirring to form a
Compound 6B (2R,5S isomer): M.p. 143Ϫ145 °C. [α]D ϭ Ϫ51.3
solid white precipitate which was filtered. Compounds 5e,f were
obtained in a spectroscopically pure form.
(c ϭ 0.8, CH2Cl2) IR (KBr): ν˜ ϭ 3260, 2979, 1704, 1604, 1495,
1
1454, 1393, 1307, 1182, 1122, 751, 694 cmϪ1. H NMR (CDCl3):
δ ϭ 1.07 (s, 3 H, CCH3), 1.25 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 1.67
(broad s, 1 H, NH), 1.77Ϫ2.15 (m, 2 H, CCH2), 2.32Ϫ2.51 (m, 2
H, CH2CO), 3.00 and 3.31 (AB of ABX, JAB ϭ 14.4, JAX ϭ JBX ϭ
4.9 Hz, 2 H, PhCH2), 3.83 (app t, J ϭ 4.9 Hz, 1 H, *CH), 4.11 (q,
J ϭ 7.1 Hz, 2 H, CH3CH2), 5.91 (s, 1 H, PhNH), 6.44Ϫ6.59 (m, 2
H, Ar-H), 6.82Ϫ6.96 (m, 1 H, Ar-H), 7.07Ϫ7.19 (m, 2 H, Ar-H),
7.20Ϫ7.53 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 14.2, 25.1,
29.3, 33.3, 36.3, 57.5, 60.8, 78.1, 113.7, 121.1, 127.3, 128.8, 128.9,
130.2, 135.6, 146.6, 173.3, 174.1 ppm. MS (70 eV, EI): m/z (%) ϭ
381 (95) [Mϩ], 335 (16), 246 (37), 200 (41), 189 (17), 160 (17), 144
(59), 134 (26), 131 (53), 120 (22), 104 (38), 98 (78), 92 (81), 91 (100),
82 (22), 77 (39), 70 (23), 65 (43). C22H27N3O3 (381.47): calcd. C
69.25, H 7.14, N 11.02; found C 69.20, H 7.19, N 11.08.
3-(1H-Indol-3-ylmethyl)-7a-methyldihydro-1-phenylamino-1H-
pyrrolo[1,2-a]imidazole-2,5-(3H,6H)-dione (5e): White solid
(0.589 g, 87%), m.p. 166Ϫ168 °C. [α]D ϭ ϩ49.4 (c ϭ 0.4, MeOH).
IR (KBr): ν˜ ϭ 3302 broad, 3922, 1711, 1603, 1496, 1458, 1404,
1380, 1353, 1265, 1098, 746, 694 cmϪ1. 1H NMR ([D6]DMSO): δ ϭ
1.07 (s, 3 H, CH3), 1.93Ϫ2.37 (m, 3 H, CH2CHH),), 2.54Ϫ2.78 (m,
1 H, CH2CHH), 3.07Ϫ3.29 (m, 2 H, *CHCH2), 4.50 (app t, J ϭ
5.8 Hz, 1 H, *CH), 6.59Ϫ6.79 (m, 3 H, Ar-H), 6.91Ϫ7.18 (m, 4
H, Ar-H), 7.19Ϫ7.27 (m, 1 H, Ar-H), 7.31Ϫ7.41 (m, 1 H, Ar-H),
7.47Ϫ7.58 (m, 1 H, Ar-H), 8.07 (s, 1 H, PhNH), 10.86 (s, 1 H, NH)
ppm. 13C NMR (CDCl3): δ ϭ 25.2, 27.1, 30.3, 34.1, 57.6, 82.0,
109.3, 111.2, 112.3, 118.3, 119.0, 120.8, 123.9, 127.6, 128.6, 135.9,
147.0, 169.9, 177.9 ppm. MS (70 eV, EI): m/z (%) ϭ 374 (23) [Mϩ],
267 (8), 239 (22), 171 (12), 170 (80), 143 (39), 138 (11), 130 (100),
93 (12), 77 (11). C22H22N4O2 (374.44): calcd. C 70.56, H 5.93, N
14.97; found C 70.60, H 5.90, N 15.01.
X-ray Crystallographic Study: Compound 5e crystallized from
CHCl3 with a molecule of solvent. X-ray diffraction analysis of the
sample was carried out with a Bruker-Axs three circle dif-
fractometer with Smart-Apex CCD detector using graphite-mon-
3-(1H-Imidazol-4-ylmethyl)7a-methyldihydro-1-phenylamino-1H-
˚
ochromated Mo-Kα radiation (λ ϭ 0.7107 A) at 298 K. 6885 Reflec-
pyrrolo[1,2-a]imidazole-2,5-(3H,6H)-dione (5f):
White solid
tions were obtained (4393 unique reflection after merging) up to
(0.529 g, 90%), m.p. 139Ϫ140 °C. [α]D ϭ Ϫ8.0 (c ϭ 2.0, MeOH).
IR (KBr): ν˜ ϭ 3269 broad, 1712, 1603, 1499, 1404, 1348, 1264,
θ ϭ 1.88Ϫ25.46° from a monoclinic crystal [molecular formula
˚
752, 696 cmϪ1 1H NMR (CDCl3): δ ϭ 1.18 (s, 3 H, CH3),
.
C23H23N4O2Cl3, space group P21, a ϭ 9.2329(6) A, b ϭ 12.121(1)
3
˚
˚
˚
A, c ϭ 10.987(1) A, β ϭ 99.86(2)°, V ϭ 1211.36(7) A , Z ϭ 2,
2.00Ϫ2.50 (m, 3 H, CH2CHH), 2.54Ϫ2.84 (m, 1 H, CH2CHH),
2.94Ϫ3.30 (m, 2 H, *CHCH2), 4.62 (app t, J ϭ 5.7 Hz, 1 H, *CH),
6.68Ϫ6.94 (m, 4 H, Ar-H), 7.10Ϫ7.29 (m, 3 H, Ar-H ϩ PhNH),
7.40 (s, 1 H, Ar-H), 8.25 (broad s, 1 H, NH) ppm. 13C NMR
(CDCl3): δ ϭ 25.1, 29.0, 30.9, 34.8, 56.9, 82.6, 113.3, 121.2, 129.2,
134.3, 135.1, 146.2, 171.6, 178.6 ppm. MS (70 eV, EI): m/z (%) ϭ
325 (49) [Mϩ], 218 (53), 190 (94), 172 (13), 162 (12), 138 (20), 123
(43), 121 (72), 108 (34), 98 (42), 93 (50), 92 (36), 82 (64), 81 (100),
77 (37), 65 (39). C17H19N5O2 (325.37): calcd. C 62.74, H 5.89, N
21.53; found C 62.69, H 5.90, N 21.48.
D ϭ 1.35 g/cmϪ3, linear absorption coefficient µ ϭ 0.406 mmϪ1
]
of dimension 0.040 ϫ 0.053 ϫ 0.370 mm3. Solution of the structure
was performed with the program SHELXS-86,[5] and refined with
SHELXL-97[6] using full-matrix least-squares method. Non-hydro-
gen atoms were refined anisotropically; H-atoms were placed in
the model in calculated positions and constrained. Final R for the
observed reflections on 289 parameters was 0.0746 and Rw
ϭ
0.1433 (GOF ϭ 0.961; ∆ρmax ϭ 0.38, ∆ρmin ϭ Ϫ0.26 e·AϪ3). Be-
cause of the low quality of the crystal, some atomic displacement
parameters seem to be biased, with consequent contamination of
the finer features of the crystal structure. Moreover, the data do
not allow us to solve some probable effect such as disorder. Only
general considerations about the overall set up of the structure are
therefore reliable.
˚
Synthesis of 6: A solution of 1b (0.600 g, 2.35 mmol) and ethyl levu-
linate (2b; 0.44 mL, 3.06 mmol) in iPrOH (10 mL) was stirred un-
der Ar at 80 °C until HPLC analysis showed the complete conver-
sion of 1b into the two diastereoisomers of 5-benzyl-2-[2-(ethoxy-
carbonyl)ethyl]-3-(phenylamino)imidazolidin-4-one (6) (20 h).
After evaporation of iPrOH and excess 2b under reduced pressure,
the two epimers were separated by preparative TLC on basic Al2O3
using Et2O as eluent to afford 6A (Rf ϭ 0.42, 0.350 g, 39%) as a
yellow glass and 6B (Rf ϭ 0.27, 0.360 g, 40%) as a white solid.
CCDC-231128 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: ϩ 44-1223-336033; E-mail:
deposit@ccdc.cam.ac.uk].
The two compounds 6A and 6B (0.250 g, 0.66 mmol) were separ-
ately dissolved in toluene (4 mL). The solutions were refluxed and
monitored by HPLC.
Acknowledgments
Compound 6A (2S,5S isomer): [α]D ϭ Ϫ54.5 (c ϭ 0.8, CH2Cl2). IR
(KBr): ν˜ ϭ 3265, 2981, 1712, 1603, 1497, 1454, 1392, 1307, 1185,
Financial support was obtained from MIUR (FURD 2001Ϫ2003
to GV). The authors are grateful to Dr. P. Martinuzzi for recording
2838
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2833Ϫ2839

3-Substituted Dihydro-1-phenylamino-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones
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