A novel convenient approach to the synthesis of 2-substituted analogs of ornithine and homolysine

Article abstract of DOI:10.1007/s11172-005-0204-9

A novel efficient method for the synthesis of earlier unknown 2-substituted analogs of ornithine and homolysine from substituted 5-aminopentyl- and 3-midopropylhydantoins (prepared from cyclic imines and amino and amido ketones) was developed. Hydrolysis

Full text of DOI:10.1007/s11172-005-0204-9

2866
Russian Chemical Bulletin, International Edition, Vol. 53, No. 12, pp. 2866—2870, December, 2004
A novel convenient approach to the synthesis of 2ꢀsubstituted analogs
of ornithine and homolysine
ꢀ
V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
A novel efficient method for the synthesis of earlier unknown 2ꢀsubstituted analogs of
ornithine and homolysine from substituted 5ꢀaminopentylꢀ and 3ꢀamidopropylhydantoins (preꢀ
pared from cyclic imines and amino and amido ketones) was developed. Hydrolysis of hydantoins
with a solution of Ba(OH) gave the target amino acids in high yields.
2
Key words: 3ꢀacyllactams, amino ketones, cyclic imines, hydantoins, amino acids,
Bucherer—Bergs reaction.
In recent years, 5,5ꢀdisubstituted hydantoins attract
Hydantoins are most conveniently synthesized by
the Strecker reaction modified by Bucherer and Bergs
(Scheme 1).
much attention not only as convenient precursors in the
synthesis of αꢀamino acids but also as substances with a
broad spectrum of biological activity, e.g., as antiꢀ
1
convulsants, antiparasitic and antiarrhythmic drugs, and
Scheme 1
2
aldose reductase inhibitors. Being stable crystalline subꢀ
stances, hydantoins can be convenient starting materials
for the synthesis of other compounds. Acid or basic hyꢀ
drolysis of 5,5ꢀdisubstituted hydantoins gives αꢀsubstiꢀ
tuted analogs of natural amino acids, which are of great
interest for bioorganic and medicinal chemistry and pharꢀ
macology; they are also important as the basis for many
alkaloids, biologically active substances, and modern
drugs.
The aim of the present work was to develop a method
for the synthesis of 2ꢀsubstituted derivatives of basic amino
acids from amino carbonyl compounds.
Carbonyl compounds are widely used in modern orꢀ
ganic synthesis as starting reagents for preparation of variꢀ
ous natural compounds, especially amino acids and their
analogs. However, analysis of the literature data has reꢀ
vealed that amino ketones and cyclic imines are virtually
not used in the synthesis of amino acids.
However, it turned out that the Bucherer—Bergs reacꢀ
tion with fiveꢀ and sixꢀmembered cyclic imines (2ꢀphenylꢀ
pyrroline and 2ꢀphenylpiperideine) yields complex mixꢀ
tures mainly containing the starting imines. The course of
the reaction is insensitive to variations in solvent and
temperature or use of basic catalysts such as hydrazine or
1,1ꢀdimethylhydrazine. Nevertheless, a sevenꢀmembered
cyclic imine (2ꢀphenyltetrahydroazepine) was converted
into the corresponding hydantoin, namely, 5ꢀ(5ꢀaminoꢀ
pentyl)ꢀ5ꢀphenylimidazolidineꢀ2,4ꢀdione in 87% yield.
The reaction is of general character and can be carried out
with imines containing aromatic, heteroaromatic, and
bulky aliphatic substituents. Under optimized reaction
conditions, hydantoins 1a—f were obtained in yields from
high to almost quantitative. Products 1a—f are derivatives
of 2ꢀsubstituted homolysines (Scheme 2).
The syntheses of the starting compounds, namely,
3
6
ꢀaminohexanones, fiveꢀmembered cyclic imines,
4
5
Nꢀ(4ꢀRꢀ4ꢀoxobutyl)acetamides, and 3ꢀacyllactams were
described earlier; sixꢀ and sevenꢀmembered imines were
prepared according to a known procedure.6
We assumed that amino ketones and cyclic imines
can form hydantoins of 2ꢀsubstituted analogs of basic
amino acids (ornithine, lysine, and homolysine). Subseꢀ
quent acid or basic hydrolysis of hydantoins can open up
a convenient route to artificial analogs of these amino
acids.
Apparently, under such conditions, sevenꢀmembered
cyclic imines partially hydrolyze to aminohexanones, and
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2749—2753, December, 2004.
066ꢀ5285/04/5312ꢀ2866 © 2004 Springer Science+Business Media, Inc.
1

New route to ornithine and homolysine analogs
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 12, December, 2004 2867
Scheme 2
Scheme 4
Hydanꢀ
toin
R
Yield
(%)
87
Hydanꢀ
toin
1d
R
Yield
(%)
Hydanꢀ
toin
R
Yield
(%)
93
95
80
Hydanꢀ
toin
3d
R
Yield
(%)
95
1
1
1
a
b
c
Ph
4ꢀFC H
4ꢀClC H4 88
2ꢀThienyl 75
2ꢀFuryl
But
95
1e
1f
77
75
85
6
4
3
3
3
a
b
c
Ph
Bn
Me
4ꢀMeC H4
2ꢀThienyl
6
6
3e
87
1
g
3ꢀPyridyl
only the amino ketone form is involved in the hydantoin
formation. To verify this assumption, we synthesized
Hydantoins were hydrolyzed under a number of both
acid and basic conditions, but incomplete hydrolysis preꢀ
vented amino acids from being isolated in the indiꢀ
vidual state.
6
ꢀaminohexanones by acid hydrolysis and decarboxylaꢀ
5
tion of sevenꢀmembered 3ꢀacyllactams. It turned out
that these amino ketones afford hydantoins in high yields
Our attempts to hydrolyze hydantoins modified with
8
9
(
Scheme 3).
Ts or Boc groups bound to the amide and imide N atoms
also failed.
Nevertheless, we found the conditions for complete
hydrolysis of hydantoin 1a with an aminoalkyl fragment:
Scheme 3
heating in a saturated Ba(OH) solution in an autoclave
2
at 185 °C for 24 h afforded 2ꢀphenylhomolysine (4)
(
Scheme 5).
Scheme 5
Earlier,7 it was demonstrated that 5ꢀphthalimidoꢀ
pentanꢀ2ꢀone gives the corresponding hydantoin in
0% yield. We assumed that use of amido ketones instead
8
of fiveꢀmembered cyclic imines would facilitate the
Bucherer—Bergs reaction. Starting from Nꢀ(4ꢀoxoꢀ
4
alkyl)acetamides 2, we obtained hydantoins 3a—e
Under these conditions, the hydrolysis of 5ꢀ(5ꢀaminoꢀ
(
Scheme 4).
pentyl)ꢀ5ꢀtertꢀbutylimidazolidineꢀ2,4ꢀdione (1f) unexꢀ
pectedly gave a nineꢀmembered cyclic urea derivative 5,
probably through intramolecular attack of the aminopentyl
fragment on the carbamide CO group followed by hydroꢀ
lysis of the intermediate cyclic amide (Scheme 6).
Hydrolysis of hydantoins 3 could give earlier unknown
8
ornithine and homolysine derivatives. It was shown that
5
,5ꢀdisubstituted hydantoins are very resistant to both
acid and basic hydrolysis. The described methods for puꢀ
rification of amino acids from hydantoins are based on
precipitation of the latter in acidic media. However,
hydantoins and amino acids containing aminoalkyl groups
differ only slightly in solubility, which makes the target
amino acids more difficult to isolate.
In 5ꢀ(3ꢀacetylaminopropyl)ꢀ5ꢀphenylimidazolidineꢀ
2,4ꢀdione (3a), the acetamido group is not hydrolyzable
under these conditions. Yet it is hydrolyzed with a stoiꢀ
chiometric amount of H SO to give 2ꢀphenylornithine
2
4
(6) in high yield (Scheme 7).

2868
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 12, December, 2004
Nenajdenko et al.
Scheme 6
in butanol, with the iodine vapor, or under UV light. Preparative
chromatography was carried out on silica gel (63—200 mesh,
Merck).
Nꢀ(4ꢀOxoalkyl)acetamides 2 were prepared as described
earlier.2
Synthesis of hydantoins 1a—f (general procedure). A mixture
of an amino carbonyl compound (6ꢀaminohexanone, 7ꢀsubstiꢀ
tuted tetrahydroazepine, or amido ketone) (10 mmol), ammoꢀ
nium bicarbonate (3.5 g, 44 mmol), sodium cyanide (12 mmol),
conc. aqueous ammonia (3 mL), ethanol (10 mL), and water
10 mL) was heated at 60—70 °C for 25 h; completion of the
(
reaction was checked by TLC (BuOH—H O—AcOH, 4 : 1 : 1;
2
spot visualization with a solution of ninhydrin in butanol (violet
color)). The reaction mixture was evaporated to dryness and the
residue was finely ground, refluxed in anhydrous EtOH (20 mL)
for 5 min, and filtered hot. The filtrate was concentrated and
recrystallized from EtOH (2 mL).
5
ꢀ(5ꢀAminopentyl)ꢀ5ꢀphenylimidazolidineꢀ2,4ꢀdione (1a).
Yield 87%, m.p. 185 °C. Found (%): C, 63.96; H, 7.14.
–
1
C H N O . Calculated (%): C, 64.35; H, 7.33. IR, ν/cm
:
14
19
2
3
Scheme 7
1
1
1
550 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
.10—1.40 (m, 6 H, CH —CH —CH —CH —CH ); 1.75—2.00
2 3 2
2
2
2
2
2
(
4
m, 2 H, C—CH —CH ); 2.50 (m, 2 H, CH NH ); 3.95 (br.s,
2 2 2 2
3
H, NH , NH); 7.25 (t, 1 H, H (4), J = 8 Hz); 7.33 (t, 2 H,
2 Ar H
3
H (3), H (5), JH = 8 Hz); 7.50 (d, 2 H, H (2), H (6),
3
Ar
Ar
Ar
Ar
13
JH = 8 Hz). C NMR ((CD ) SO), δ: 23.4, 26.3, 33.1, 38.4,
3 2
4
1
1
1.5 (—CH —CH —CH —CH —CH —NH ); 67.8 (C—CH );
2 2 2 2 2 2 2
25.4 (C (3), C (5)); 127.1 (CAr(4)); 128.1 (CAr(2), C (6));
Ar
Ar
Ar
40.5 (C—Phꢀ4); 161.3 (HNCONH), 179.9 (HNCOC).
ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(4ꢀfluorophenyl)imidazolidineꢀ2,4ꢀdione
1b). Yield 87%, m.p. 99 °C. Found (%): C, 59.60; H, 6.50.
5
(
–
1
C H FN O . Calculated (%): C, 60.20; H, 6.50. IR, ν/cm
1
1
:
14
18
3
2
1
550 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
2 3 2
.10—1.40 (m, 6 H, CH —CH —CH —CH —CH ); 1.75—2.00
2
2
2
2
2
(
m, 2 H, C—CH —CH ); 2.50 (m, 2 H, CH NH ); 3.95 (br.s,
2 2 2 2
3
3
7
H, NH , NH); 7.17 (t, 1 H, H (2), H (6), J = 8.9 Hz);
2 Ar Ar H
3
3
.52 (dd, 2 H, H (3), H (5), J = 8.9 Hz, J = 5.24 Hz).
Ar
Ar
H
F
1
3
C NMR ((CD ) SO), δ: 23.4, 26.3, 33.1, 38.4, 41.5
3
2
(
1
—CH —CH —CH —CH —CH —NH ); 67.8 (C—CH );
2 2 2 2 2 2 2
2
14.8 (d, C (3), C (5), JF = 22.2 Hz); 128.1 (d, C (2),
Ar Ar Ar
Thus, the behavior of cyclic imines and amino and
3
1
C (6), J = 8.9 Hz); 136.5 (CAr(1)); 161.5 (d, C (4), J =
amido ketones in the synthesis of hydantoins containing
an aminoꢀ or amidoalkyl fragment at the quaternary C
atom was studied. The efficient method for the synthesis
of earlier unknown hydantoins with 5ꢀaminopentyl and
Ar
F
Ar
F
2
33 Hz); 157.1 (HNCONH); 176.5 (HNCOC).
ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(4ꢀchlorophenyl)imidazolidineꢀ2,4ꢀ
dione (1c). Yield 87%, m.p. 175 °C. Found (%): C, 63.96; H, 7.14.
5
–1
C H ClN O . Calculated (%): C, 64.35; H, 7.33. IR, ν/cm
1
1.05—1.35 (m, 6 H, CH —CH —CH —CH —CH ); 1.73—1.91
:
14
18
3
2
3
ꢀ(Nꢀacetylamino)propyl fragments was developed. It was
1
550 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
2 3 2
found that their complete hydrolysis in a Ba(OH) soluꢀ
2
2 2 2 2 2
tion at a high temperature affords 2ꢀsubstituted ornithine
and homolysine derivatives.
(m, 2 H, C—CH —CH ); 2.50 (s, 2 H, CH NH ); 3.95 (br.s,
2 2 2 2
3
4 H, NH , NH); 7.37 (d, 2 H, H (3), H (5), J = 8.55 Hz);
2
Ar
Ar
H
13
7
.51 (d, 2 H, HAr(2), HAr(6), 3JH = 8.55 Hz). C NMR
(
(CD ) SO), δ: 23.3, 26.2, 29.9, 38.5, 41.4 (CH —CH —CH —
3
2
2
2
2
Experimental
CH —CH —NH ); 67.5 (C—CH ); 127.4 (CAr(3), CAr(5));
2
2
2
2
1
28.0 (C (2), C (6)); 121.9 (C (1)); 139.6 (CAr(4)); 161.1
Ar Ar Ar
1H and 13C NMR spectra were recorded on a Varian
VXRꢀ400 spectrometer (400 and 100 MHz, respectively) in
CDCl , CD OD, D O, and DMSOꢀd with Me Si as the interꢀ
(HNCONH); 179.5 (HNCOC).
5ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(2ꢀthienyl)imidazolidineꢀ2,4ꢀdione (1d).
Yield 77%, m.p. 203 °C. Found (%): C, 53.56; H, 6.01.
C H N O S. Calculated (%): C, 53.91; H, 6.41. IR, ν/cm :
12 17 3 2
1550 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
2 3 2
3
3
2
6
4
–
1
nal standard; the chemical shifts are given in ppm to within
.01 ppm. IR spectra were recorded on a URꢀ20 spectrophoꢀ
1
0
tometer (thin film for liquids and Nujol for solids). TLC analysis
was performed on Silufol UVꢀ254 plates; spots were visualized
1.10—1.40 (m, 6 H, CH —CH —CH —CH —CH ); 1.85—2.05
2 2 2 2 2
(m, 2 H, C—CH —CH ); 2.50 (s, 2 H, CH NH ); 4.10 (br.s,
2
2
2
2
3
3
in an acidified solution of KMnO , with a solution of ninhydrin
2 H, NH ); 6.99 (dd, 1 H, H (4), J = 4.78 Hz, JH = 3.45 Hz);
2 Ar H
4

New route to ornithine and homolysine analogs
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 12, December, 2004 2869
3
7
4
4
1
1
.04 (d, 1 H, HAr(3), 3JH = 3.45 Hz); 7.43 (d, 1 H, H (5), J
=
2 H, C—CH ); 1.77 (s, 3 H, CH CO); 1.70—2.00 (m, 2 H,
2 3
C—CH —CH —CH —NH); 2.76 (Ph—CH ); 2.96—3.06
2 2 2 2
Ar
H
1
3
.78 Hz). C NMR ((CD ) SO), δ: 23.2, 26.3, 32.6, 38.5,
1.2 (—CH —CH —CH —CH —CH —NH ); 66.5 (C—CH );
3
2
(m, 2 H, CH —NH); 7.11—7.15 (m, 2 H, HAr); 7.17—7.25
2
2
2
2
2
2
2
2
24.3 (C (5)); 125.5 (C (3)); 127.3 (C (4)); 144.2 (C (2));
(m, 3 H, HAr); 7.69 (s, 1 H, CONHCO); 7.90 (m, 1 H,
Ar
Ar
Ar
Ar
13
58.9 (HNCONH); 177.1 (HNCOC).
ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(2ꢀfuryl)imidazolidineꢀ2,4ꢀdione (1e).
Yield 75%, m.p. 103 °C. Found (%): C, 57.06; H, 6.46.
C H N O . Calculated (%): C, 57.36; H, 6.82. IR, ν/cm
540 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
.10—1.40 (m, 6 H, CH —CH —CH —CH —CH ); 1.81—2.05
m, 2 H, C—CH —CH ); 2.50 (m, 2 H, CH NH ); 6.34 (m,
2 2 2 2
H, H (4)); 6.39—6.41 (m, 1 H, H (5)); 7.60 (s, 1 H, HAr(3)).
Ar Ar
C NMR ((CD ) SO), δ: 22.7, 26.2, 33.1, 34.2, 41.4
CH CONH). C NMR ((CD ) SO), δ: 22.6 (CH CO); 23.7
3 3 2 3
5
(CH —CH —CH ); 34.4 (C—CH —CH ); 38.5 (CH —NH);
2 2 2 2 2 2
42.2 (Ar—CH ); 66.6 (C—CH ); 126.6 (CAr(4)); 127.8
2
2
–
1
:
(C (2), C (6)); 130.2 (C (3), C (5)); 135.6 (CAr(1)); 158.8
Ar Ar Ar Ar
12
17
3
3
1
1
1
(
(NHCONH); 169.1 (CH CONH); 179.0 (CCONH).
2
3 2
3
Nꢀ[3ꢀ(4ꢀMethylꢀ2,5ꢀdioxoimidazolidinꢀ4ꢀyl)propyl]acetꢀ
amide (3c). Yield 80%, m.p. 120 °C. Found (%): C, 50.81;
H, 6.97. C H N O . Calculated (%): C, 50.69; H, 7.09. IR,
2
2
2
2
2
1
9
15
3
3
1
3
–1
1
ν/cm : 1650 (H CCONH); 1720 ((HN) C=O). H NMR
3 2
3
2
(
CH —CH —CH —CH —CH —NH ); 64.6 (C—CH ); 106.7,
((CD ) SO), δ: 1.11—1.61 (m, 7 H, C—CH —CH , CH CO);
3 2 2 2 3
2
2
2
2
2
2
2
1
10.4, 142.7, 152.6 (CAr(2), CAr(3), CAr(4), CAr(5)); 160.1
1.76 (s, 3 H, CH C); 2.96 (m, 2 H, CH —NH); 7.84 (m, 1 H,
3 2
CONHCO); 7.89 (s, 1 H, CONHCO). C NMR ((CD ) SO),
3 2
δ: 22.6 (CH CO); 23.55 (CH —CH —CH ); 23.6 (H C—C);
3 2 2 2 3
13
(
HNCONH); 177.1 (HNCOC).
ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(tertꢀbutyl)imidazolidineꢀ2,4ꢀdione (1f).
Yield 75%, m.p. 165 °C. Found (%): C, 59.12; H, 9.33.
5
34.7 (C—CH —CH ); 38.3 (CH —NH); 61.8 (C—CH ); 156.3
2
2
2
2
–
1
C H N O . Calculated (%): C, 59.72; H, 9.61. IR, ν/cm
1
0
CH —CH ); 1.50 (t, 2 H, C—CH —CH , J = 7 Hz); 1.70 (t,
2
:
(NHCONH); 169.0 (CH CONH); 178.5 (CCONH).
3
12
23
3
2
1
550 (CCONH); 1680 ((HN) C=O). H NMR ((CD ) SO), δ:
Nꢀ{3ꢀ[4ꢀ(4ꢀMethylphenyl)ꢀ2,5ꢀdioxoimidazolidinꢀ4ꢀyl]proꢀ
pyl}acetamide (3d). Yield 95%, m.p. 120 °C. Found (%):
C, 62.13; H, 6.62. C H N O . Calculated (%): C, 62.27;
2
3 2
t
.90 (s, 9 H, Bu ); 1.10—1.40 (m, 6 H, CH —CH —CH —
2
2
2
3
2
2
2
2
H
15 19
3
3
3
–1
H, CH NH , J = 7 Hz); 4.20 (br.s, 2 H, NH ); 7.80 (s, 1 H,
H, 6.62. IR, ν/cm : 1650 (H CCONH); 1720 ((HN) C=O).
2
2
H
2
3
2
2
1
3
1
CONHCO). C NMR ((CD ) SO), δ: 15.9 ((H C) C); 15.2,
H
NMR ((CD ) SO), δ: 1.16—1.48 (m,
H,
3
2
3
3
3 2
1
8,5, 22.3, 23.8, 28.3, 32.7 (CH —CH —CH —CH —CH ,
CH —CH —CH ); 1.51—1.73 (m, 2 H, C—CH ); 1.77 (s, 3 H,
2 2 2 2
2
2
2
2
2
(
(
H C) C); 63.7 (HNCOC); 153.5 (HNCONH); 173.0
CH CO); 1.70—2.00 (m, 2 H, C—CH —CH —CH —NH);
3 2 2 2
3
3
HNCOC).
ꢀ(5ꢀAminopentyl)ꢀ5ꢀ(3ꢀpyridyl)imidazolidineꢀ2,4ꢀdione (1g).
Yield 85%, m.p. 175 °C. Found (%): C, 59.12; H, 6.75.
2.25 (s, 3 H, CH —Ar); 2.96—3.06 (m, 2 H, CH —NH);
3
2
5
7.11—7.15 (m, 2 H, HAr); 7.17—7.25 (m, 3 H, HAr); 7.69 (s,
1
3
1 H, CONHCO); 7.90 (m, 1 H, CH CONH). C NMR
3
–
1
C H N O . Calculated (%): C, 59.53; H, 6.92. IR, ν/cm
1
1
:
((CD ) SO), δ: 21.2 (CH —Ar); 22.6 (CH CO); 23.7
13
18
4
2
3 2
3
3
1
555 (CCONH); 1685 ((HN) C=O). H NMR ((CD ) SO), δ:
(CH —CH —CH ); 35.2 (C—CH —CH ); 38.0 (CH —NH);
2 2 2 2 2 2
66.6 (C—CH ); 126.6 (C (4)); 127.8 (C (2), CAr(6)); 130.2
2 Ar Ar
2
3 2
.10—1.40 (m, 6 H, CH —CH —CH —CH —CH ); 1.85—2.05
2
2
2
2
2
(
m, 2 H, C—CH —CH ); 2.50 (m, 2 H, CH NH ); 4.10 (br.s,
(CAr(3), CAr(5)); 135.6 (CAr(1)); 158.8 (NHCONH); 169.1
2
2
2
2
3
3
2
7
1
8
H, NH ); 7.40 (dd, 1 H, H (5), J = 7.94 Hz, J = 4.64 Hz);
(CH CONH); 179.0 (CCONH).
2
Ar
H
H
3
3
4
4
.88 (ddd, 1 H, H (6), J = 7.94 Hz, J = 1.32 Hz, J =
H
.99 Hz); 8.51 (dd, 1 H, H (4), J = 4.64 Hz, J = 1.32 Hz);
.69 (d, 1 H, HAr(2), J = 1.99 Hz). C NMR ((CD ) SO),
Nꢀ{3ꢀ[2,5ꢀDioxoꢀ4ꢀ(2ꢀthienyl)imidazolidinꢀ4ꢀyl]propyl}acetꢀ
amide (3e). Yield 87%, m.p. 120 °C. Found (%): C, 51.29;
H, 5.27. C H N O S. Calculated (%): C, 51.23; H, 5.37. IR,
Ar
H
H
3
4
Ar
H
H
4
13
H
3 2
12 15
3
3
–
1
1
δ: 23.0, 25.9, 31.4, 38.1, 40.6 (CH —CH —CH —CH —
ν/cm : 1650 (H CCONH); 1720 ((HN) C=O). H NMR
3 2
2
2
2
2
CH —NH ); 72.9 (C—CH ); 123.4, 133.2, 134.9, 146.7, 148.9
((CD ) SO), δ: 1.20—1.35 (m, 2 H, CH —CH —CH ); 1.75
3 2 2 2 2
2
2
2
(
C (2), C (3), C (4), C (5), CAr(6)); 157.1 (HNCONH);
(s, 3 H, CH CO); 1.70—2.00 (m, 2 H, C—CH —CH —
3 2 2
Ar
Ar
Ar
Ar
1
76.5 (HNCOC).
Nꢀ[3ꢀ(2,5ꢀDioxoꢀ4ꢀphenylimidazolidinꢀ4ꢀyl)propyl]acetꢀ
CH —NH); 2.90—3.05 (m, 2 H, CH —NH); 7.01 (dd, 1 H,
2 2
3
3
H (4), J = 5.13 Hz, J = 3.76 Hz); 7.06 (dd, 1 H, H (3),
Ar
H
H
Ar
3
3
amide (3a). Yield 93%, m.p. 120 °C. Found (%): C, 56.71;
H, 6.01. C H N O . Calculated (%): C, 56.85; H, 6.13. IR,
ν/cm : 1650 (H CCONH); 1720 ((HN) C=O). H NMR
JH = 3.76 Hz, JH = 1.37 Hz); 7.47 (dd, 1 H, HAr(5),
3JH = 5.13 Hz, JH = 1.37 Hz); 7.65 (s, 1 H, CONHCO); 7.92
(t, 1 H, CH CONH, J = 7 Hz). C NMR ((CD ) SO), δ:
3 H 3 2
3
14
17
3
3
–
1
1
3
13
3
2
(
(
(CD ) SO), δ: 1.20—1.35 (m, 2 H, CH —CH —CH ); 1.75
22.5 (CH CO); 23.8 (CH —CH —CH ); 35.9 (C—CH —CH );
3 2 2 2 2 2
38.1 (CH —NH); 66.0 (C—CH ); 124.5, 125.8, 128.3,
2 2
3
2
2
2
2
s, 3 H, CH CO); 1.70—2.00 (m, 2 H, C—CH —CH —
3
2
2
CH —NH); 2.90—3.05 (m, 2 H, CH —NH); 7.20 (t, 1 H,
143.2 (CAr); 156.7 (NHCONH); 169.0 (CH CONH); 175.4
(CCONH).
2
2
3
3
3
HAr(4), J = 7.95 Hz); 7.30 (t, 2 H, H (3), H (5), J =
H
H
Ar
Ar
3
7
(
7
.95 Hz); 7.50 (t, 1 H, H (2), H (6), J = 7.95 Hz); 7.65
Hydrolysis of hydantoins 1a,f and 3a to amino acids (general
procedure). A mixture of hydantoin (5 mmol) and barium hydrꢀ
oxide octahydrate (3.17 g, 10 mmol) in 20 mL of water was
heated in a steel autoclave (oil bath, 165—185 °C) for 24 h,
cooled to room temperature, and transferred to a flask. Ammoꢀ
nium bicarbonate (1.2 g) was added and the reaction mixture
was slightly refluxed for 3 to 4 h. The precipitate of barium
carbonate that formed was filtered off and the filtrate was evapoꢀ
rated to dryness in a rotary evaporator. The residue was trituꢀ
rated in a porcelain mortar with hot anhydrous ethanol, the
precipitate was filtered off, and the filtrate was evaporated to
dryness. The resulting residue was recrystallized from anhydrous
Ar
Ar
H
3
s, 1 H, CONHCO); 7.92 (t, 1 H, CH CONH, JH =
3
1
3
.01 Hz). C NMR ((CD ) SO), δ: 22.5 (CH CO); 24.3
3 2 3
(
CH —CH —CH ); 36.2 (C—CH —CH ); 38.5 (CH —NH);
2 2 2 2 2 2
6
7.7 (C—CH ); 125.5 (CAr(2), CAr(6)); 126.5 (CAr(4)); 128
2
(
(
CAr(3), CAr(5)); 141.5 (CAr(1)); 156.7 (NHCONH); 169.0
CH CONH); 175.4 (CCONH).
3
Nꢀ[3ꢀ(4ꢀBenzylꢀ2,5ꢀdioxoimidazolidinꢀ4ꢀyl)propyl]acetamide
3b). Yield 95%, m.p. 120 °C. Found (%): C, 62.11; H, 6.52.
(
–
1
C H N O . Calculated (%): C, 62.27; H, 6.62. IR, ν/cm
:
15
19
3
3
1
1
650 (H CCONH); 1720 ((HN) C=O). H NMR ((CD ) SO),
3 2 3 2
δ: 1.16—1.48 (m, 2 H, CH —CH —CH ); 1.51—1.73 (m,
2
2
2

2870
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 12, December, 2004
Nenajdenko et al.
ethanol and dried with continuous stirring at 80 to 90 °C in vacuo
1610 (COOH). 1H NMR (D O), δ: 1.63—1.95 (m, 2 H,
2
(
oil pump, 1—1.5 h).
CH —CH —CH ); 2.29—2.50 (m, 2 H, CCH CH ); 3.10 (m,
2 H, CH NH ); 7.45—7.50 (m, 5 H, H ). C NMR (CD OD),
2 2 Ar 3
2
2
2
2
2
13
In the hydrolysis of 5ꢀphenylꢀ5ꢀ(3ꢀacetylaminoproꢀ
pyl)hydantoin 3a, the reaction mixture from the autoclave was
δ: 23.3 (CH —CH —CH ); 36.0 (CH CCOOH); 39.25
2 2 2 2
treated with conc. H SO (0.52 mL). The precipitate of barium
(CH NH ); 66.3 (CH CCOOH); 127.0 (C (2), C (6)); 130.4
2 2 2 Ar Ar
2
4
sulfate that formed was filtered off, the aqueous phase was conꢀ
centrated, and the product was extracted from the dry residue
with hot methanol (30 mL). The solvent was removed and the
product was dried in vacuo (oil pump).
(C (3), C (5)); 130.7 (C (4)); 136.5 (C (1)); 171.8 (COOH).
Ar Ar Ar Ar
References
2
,7ꢀDiaminoꢀ2ꢀphenylheptanoic acid (4) was obtained in 50%
1
. M. L. Werbel, E. F. Elslager, P. J. Islip, and A. M. D. Closier,
J. Med. Chem., 1977, 20, 1569.
yield, m.p. 175 °C (decomp.). Found (%): C, 58.17; H, 8.75.
C H N O . Calculated (%): C, 58.33; H, 8.88. IR, ν/cm
610 (COOH). H NMR (CD OD), δ: 1.37—1.55 (m, 4 H,
3
–
1
:
1
3
24
2
4
1
2. J. P. Rizzi, R. C. Shnur, N. J. Hutson, K. J. Kraus, and P. R.
1
Kelbaugh, J. Med. Chem., 1989, 32, 1208.
. V. G. Nenajdenko, E. P. Zakurdaev, and E. S. Balenkova,
Tetrahedron Lett., 2002, 43, 8449.
CH —CH —CH —CH —CH —NH ); 1.65—1.76 (m, 2 H,
2
2
2
2
2
2
3
CH —CH —NH ); 2.31 (m, 2 H, C—CH —CH ); 2.92 (m,
2
2
2
2
2
3
2
2
2
H, CH NH ); 7.34 (t, 1 H, H (4), J = 7.03 Hz); 7.41 (dd,
2 2 Ar H
H, HAr(3), H (5), J = 7.83 Hz, J = 7.03 Hz); 7.58 (d,
H, H (2), H (6), 3JH = 7.83 Hz). C NMR (CD OD),
3
3
4. V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, and E. S.
Ar
H
H
13
Balenkova, Tetrahedron, 2004, 60, 11719.
. V. G. Nenajdenko, A. M. Gololobov, E. P. Zakurdaev, and
E. S. Balenkova, Izv. Akad. Nauk, Ser. Khim., 2003, 52, 2338
Ar
Ar
3
5
δ: 24.5, 27.4, 28.0, 37.0, 40.5 (—CH —CH —CH —CH —
2
2
2
2
CH —NH ); 68.0 (C—CH ); 127.3 (CAr(3), CAr(5)); 129.4
2
2
2
[
Russ. Chem. Bull., Int. Ed., 2003, 52, 2473].
. A. Giovanni, D. Savoia, and A. UmaniꢀRonchi, J. Org. Chem.,
989, 54, 228.
(
C (4)); 129.8 (C (2), C (6)); 139.8 (C (1)); 175.0 (COOH).
Ar Ar Ar Ar
6
7
4
ꢀ(tertꢀButyl)ꢀ2ꢀoxoꢀ1,3ꢀdiazacyclononaneꢀ4ꢀcarboxylic acid
1
(
5) was obtained as dihydrate in 65% yield, m.p. 185—187 °C.
Found (%): C, 59.48; H, 9.83. C H N O . Calculated (%):
C, 59.48; H, 9.15. IR, ν/cm–1: 1612 (COOH). H NMR
. M. M. AbdelꢀMonem, N. E. Newton, and C. E. Weeks,
J. Med. Chem., 1974, 17, 447.
12
22
2
3
1
t
8. K. Hiroi, K. Achiva, and S. Yamada, Chem. Pharm. Bull.
Jpn), 1968, 16, 444.
9. (a) S. Kubik, R. Meissner, and J. Rebek, Tetrahedron Lett.,
994, 35, 6635; (b) T. S. Yokum, M. G. Bursavich, S. A.
(
CD OD), δ: 1.00 (s, 9 H, Bu ); 1.25—1.55 (m, 6 H,
3
(
CH —CH —CH —CH —CH ); 1.78 (m, 2 H, C—CH ); 2.63
2
2
2
2
2
2
13
(
(
4
1
m, 2 H, CH NH ); 4.88 (br.s, 2 H, NHCONH). C NMR
2 2
CD OD), δ: 24.7 (CH ); 25.3 ((H C) C); 27.9, 31.7, 33.1, 38.0,
3 2 3 3
2.2 (CH —CH —CH —CH , (H C) C); 73.1 (HNCCOOH);
1
PihaꢀPaul, D. A. Hall, and M. L. McLaughlin, Tetrahedron
Lett., 1997, 38, 4013.
2 2 2 2 3 3
61.0 (HNCONH); 180.6 (COOH).
ꢀPhenylornithine (6) was obtained in 75% yield, m.p.
33—235 °C (decomp.). Found (%): C, 63.07; H, 7.75.
2
2
–
1
C H N O . Calculated (%): C, 63.44; H, 7.74. IR, ν/cm
:
Received July 2, 2004
1
1
16
2
2