Solution and soluble polymer syntheses of 3-aminoimidazoline-2,4-diones

Article abstract of DOI:10.1039/a807067i

3-Aminoimidazoline-2,4-dione derivatives have been synthesized from a combination of α- and aza-amino acids by both solution phase and soluble polymer supported approaches; this soluble polymer methodology combines clean product isolation with recycling o

Full text of DOI:10.1039/a807067i

Solution and soluble polymer syntheses of 3-aminoimidazoline-2,4-diones
Juyoung Yoon,† Chang-Woo Cho, Hyunsoo Han and Kim D. Janda*
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, 10550 N.
Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: kdjanda@scripps.edu
Received (in Corvallis, OR, USA) 9th September 1998, Accepted 6th November 1998
R1
3-Aminoimidazoline-2,4-dione derivatives have been syn-
thesized from a combination of a- and aza-amino acids by
both solution phase and soluble polymer supported ap-
proaches; this soluble polymer methodology combines clean
product isolation with recycling of the original matrix.
R1
H2N
Boc
H
i
N
Z
N
Boc
Boc
+
Z
N
N
N
CO2H
R2
H
H
O
R2
3
4
5
ii
O
R1
R1
H
H
N
Boc iii
N
O2N
O
N
N
H2N
N
Molecular diversity based on combinatorial organic synthesis is
now being used for rapid lead generation in both drug discovery
and the development of biologically active compounds with
potential therapeutic value.1 Recently, solid-phase synthesis of
heterocycles bearing one or more nitrogen atoms such as
diketopiperazines,2 diazines,3 and hydantoins4 has received
considerable attention due to their medicinal importance.
Hence, development of strategies for the mixture/parallel
synthesis of additional heterocyclic structures either in solution
or on a polymer support is of key interest.
The synthesis and structure assignment of hexahydro-
1,2,4-triazine-3,6-dione 2, isomeric with 3-aminoimidazoline-
2,4-dione 1, has been rather cryptic for over 30 years.5–7 It has
been demonstrated6,7 that a hexahydro-1,2,4-triazine-3,6-dione
could be prepared by the reaction of N-[N-(phenylthiocar-
bonyl)glycyl]-NA-(benzyloxycarbonyl)hydrazine with lead ace-
tate.8 A similar cyclization of ethyl semicarbazinoacetate
[H2NNHC(O)NHCH2CO2Et] with NaOEt9 was discovered to
lead to 1 rather than 2. A more recent attempt10 to synthesize
1,2,4-triazine-3,6-diones by the reaction of hydrazine with a-
lactams gave mainly 1.11 If 1 or 2 could be made in a controlled
H
O
R2
O
R2
6
8
iv, v
O
R1
R2
NH
N
O2N
O2CCl
HN
O
9
7
Scheme 1 Reagents and conditions: i, DCC, DMAP; ii, H2/Pd-C; iii, 7 (1.1
equiv.), Et3N (1.1 equiv.); iv, TFA–CH2Cl2 (1:1 v/v); v, dilution, Et3N (1.1
equiv.).
After removal of the benzyloxycarbonyl (Z) group, nitrophenyl
chloroformate was introduced to generate an activated inter-
mediate for the cyclization reaction. Removal of the Boc group
was performed using TFA–CH2Cl2 (1:1), followed by cycliza-
tion in Et3N–CH2Cl2 (1:100 v/v) at 25 °C, and the desired
unracemized 3-aminoimidazoline-2,4-diones 9 were obtained
in approximately 75% yield.
With a sound solution phase strategy in hand we extended our
methodology to a soluble polymer supported synthesis. In this
scenario linear homopolymer [polyethylene glycol monomethyl
ether (MeO-PEG)] served as our carrier for polymer synthesis
and purification. We have demonstrated the advantages of using
liquid phase synthesis through the construction of both peptide/
small molecule combinatorial libraries14 and as a reagent/
catalyst support.15
O
O
R
HN
NH
NH
N
NH2
HN
R
O
O
1
2
Linker 10 was prepared via the oxidation of 4-(tert-
butoxy)benzaldehyde with Ag2O. This acid was coupled to
MeO-PEG5000-amine and upon deprotection with TFA gave
phenol 11 which was now ready for the first diversity step
coupling (Scheme 2). The amino acid was introduced in the
form of isocyanate 1216 and this building block was attached to
11 granting 13; the second point of diversity, Boc-aza-amino
acid 4 was added to deprotected 13 providing PEG-14. It should
be stressed that the unique physical properties of the MeO-PEG
homopolymer allowed each coupling/deprotection reaction to
be purified by precipitation of the modified homopolymer.
Furthermore, reaction progress was conveniently monitored by
1H and 13C NMR spectroscopy. Finally, after removal of the
Boc group, 14 could be base-cyclized and thus cleaved from the
support generating a variety of 3-aminoimidazoline-2,4-diones
in greater than 90% purity and in 62–80% yield (Table 1). The
structures of the products were confirmed by 1H, 13C NMR and
FAB mass as well as IR spectroscopy.§ For example, 1H NMR
analysis of 9d in [2H6]DMSO clearly shows a doublet at d 2.49
for NCH3 and a quartet for NH at d 5.43. Also, all of the
compounds showed distinct peaks in their IR spectra at 1775
and 1725 cm21 which is indicative of a 3-aminoimidazoline-
2,4-dione structure.5 Lastly, it was possible to regenerate PEG-
11 and reapply this material in another round of synthesis. This
was accomplished by simple treatment of the isolated reaction
fashion they should make interesting targets for combinatorial
synthesis/drug discovery as they are structurally rigid, possess
ample hydrogen donor/acceptor functionality and contain two
points for diversity generation. Herein we describe our synthetic
approach to 3-aminoimidazoline-2,4-diones 1, our application
of this strategy to a soluble polymer support, and our ability to
design a methodology that allows regeneration of the resin.
As detailed vide supra examples relating to the controlled
syntheses of 3-aminoimidazoline-2,4-dione derivatives have
been sparse. In 1985, a concise one step synthesis from a-amino
acids and tert-butyl carbazate was reported by Lalezari,12
however, this report also detailed a major problem with this
synthetic tack which induced racemization of the product. To
avoid this unwanted racemization, our solution phase approach
utilized Et3N or Pri2NH at room temperature for the cyclization
step, allowing optical activity‡ to be preserved.
As shown in Scheme 1, N-benzyloxycarbonyl protected
amino acids were used as convenient starting materials in the
solution phase synthesis. Thus, protected amino acids were
coupled with our previously described Boc-protected aza-
amino acids13 using DCC and DMAP in typically 95% yield.
† Present address: Department of Chemistry, Silla University, 1-1 San,
Kwaebop-dong, Sasang-gu, Pusan, 617-736 Korea.
PEG-11 with 1
M
NaOH which in effect removed any previous
Chem. Commun., 1998, 2703–2704 2703

O
This supports our assumption that there was no sign of racemization in our
OBut
24
synthetic scheme. {before recrystallization: [a]D 239.0 (c 1.06, MeOH),
HO
24
after first recrystallization: [a]D 238.8 (c 1.06, MeOH), after second
10
24
recrystallization: [a]D 240.3 (c 1.04, MeOH)}
i, ii
§ Selected data for 9a: mp 189–191 °C; dH([2H6]DMSO, 400 MHz) 8.00 (br
s, 1H), 5.40 (br s,1H), 3.87 (d, 2H), 2.51 (d, 3H); dC([2H6]DMSO, 101
MHz) 169.8, 156.5, 44.5, 36.9; n(CHCl3)/cm21 3024, 1772, 1724, 1211;
HRMS [FAB, (M + 1)+]: calc. 130.0617, found 130.1612. For 9b: mp
182–185 °C; dH(CD3OD, 400 MHz) 3.99 (q, 1H), 2.55 (s, 3H), 1.27 (d, 3H);
dC(CD3OD, 101 MHz) 172.5, 155.1, 50.1, 34.9, 14.8; n(CHCl3)/cm21
3006, 1768, 1724, 1214; HRMS [FAB, (M + 1)+]: calc. 144.0773, found
O
MeO-PEG-O
OH
N
H
11
iii
O
R1
O
MeO-PEG-O
MeO-PEG-O
N
H
CO2But
24
O
144.0766; [a]D 239.0 (c 1.06, MeOH). For 9c: mp 138–140 °C;
N
H
dH(CDCl3, 400 MHz) 6.73 (br s, 1H), 4.32 (br s, 1H), 3.90 (d, 1H), 2.72 (s,
3H), 2.23 (m, 1H), 1.04 (d, 3H), 0.91 (d, 3H); dC(CDCl3, 101 MHz) 171.3,
156.9, 60.9, 38.0, 30.2, 18.6, 15.9; n(CHCl3)/cm21 3024, 1774, 1718, 1208;
13
vi
ii, iv
O
R1
O
24
H
N
N
R2
HRMS [FAB, (M + Na)+]: calc. 194.0905, found 194.0914; [a]D 273.0
Boc
(c 0.69, CHCl3). For 9d: dH(DMSO, 400 MHz) 8.17 (s, 1H), 5.53 (q, 1H),
3.97 (d, 1H), 2.49 (d, 3H), 1.77 (m, 1H), 1.18–1.34 (m, 2H), 0.90 (d, 3H),
0.84 (t, 3H); dC(CD3OD, 101 MHz) 169.6, 154.2, 57.3, 34.3, 33.6, 20.8,
11.2, 8.0; n(CHCl3)/cm21 3024, 2986, 1774, 1718, 1214; HRMS [FAB,
(M+1)+]: calc. 186.1242, found 186.1239. For 9e: mp 210–213 °C;
dH(CDCl3, 400 MHz) 7.30 (m, 5H), 5.45 (br s, 1H), 4.26 (q, 1H), 4.23 (m,
1H), 3.28 (dd, 1H), 2.90 (dd, 1H), 2.58 (d, 3H) ; dC(CDCl3, 101 MHz)
170.6, 155.5, 134.6, 129.4, 128.9, 127.6, 61.0, 56.9, 37.8; n(CHCl3)/cm21
3011, 1762, 1724, 1227; HRMS [FAB, (M + 1)+]: calc. 220.1086, found
N
O
N
H
H
O
14
ii, v
O
O
N
R1
R2
MeO-PEG-O
NH
+
OH
N
H
HN
O
11
9
24
220.1094; [a]D 263.9 (c 0.39, MeOH). For 9f: mp 125–128 °C;
R1
O
dH(CDCl3, 400 MHz) 7.30 (m, 5H), 7.16 (d, 2H), 6.86 (d, 2H), 5.24 (s, 1H),
4.35 (br s, 1H), 4.15 (m, 1H), 3.95 (d, 2H), 3.78 (s, 3H), 3.23 (dd, 1H), 2.69
(dd, 1H); dC(CDCl3, 101 MHz) 170.6, 159.4, 155.6, 134.9, 130.7, 129.3,
128.9, 127.7, 127.5, 113.8, 56.9, 55.2, 53.9, 37.8; n(CHCl3)/cm21 3011,
1755, 1737, 1215; HRMS [FAB, (M + Na)+]: calc. 348.1324, found
C
N
CO2But
12
Scheme 2 Reagents and conditions: i, MeO-PEG-CH2CH2NH2, DCC,
DMAP; ii, TFA–CH2Cl2 (1:1 v/v); iii, 12, Et3N; iv, 4, DCC; v, dilution,
24
348.1335; [a]D 276.0 (c 0.42, MeOH). For 9g: dH(CDCl3, 400 MHz)
Pri2NEt (1.1 equiv.), vi, 1
M NaOH.
7.28 (m, 5H), 6.21 (s, 1H), 4.26 (q, 1H), 4.21 (m, 1H), 3.21 (dd, 1H), 2.94
(dd, 1H) 2.53 (t, 2H), 1.55 (m, 1H), 0.90 (d, 3H); dC(CDCl3, 101 MHz)
170.9, 156.1, 134.5, 129.5, 128.8, 127.5, 58.4, 56.8, 37.5, 26.6, 20.3;
n(CHCl3)/cm21 3440, 3023, 1774, 1731, 1214; HRMS [FAB, (M+H)+]:
Table 1 3-Aminoimidazoline-2,4-diones generated via Scheme 2
O
24
calc. 262.1556, found 262.1563; [a]D 266.7 (c 0.59, MeOH). For 9h: mp
R1
R2
134–136 °C; dH(CD3OD, 400 MHz) 3.99 (q, 1H), 1.26 (d, 3H); dC(CD3OD,
101 MHz) 173.1, 156, 50.1 14.9; n(CHCl3)/cm21 3021, 1784, 1726, 1208;
HRMS [FAB, (M + 1)+]: calc. 130.0616, found 130.0612. For 9j: mp
150–153 °C; dH(CD3OD, 400 MHz) 3.95 (m, 1H), 1.71 (m, 1H), 1.54 (m,
1H), 1.39 (m, 1H), 0.84 (d, 6H); dC(CD3OD, 101 MHz) 171.3, 154.7, 51.3,
37.9, 21.6, 19.4, 17.1; n(CHCl3)/cm21 3023, 1793, 1724, 1208; HRMS
N
O
NH
HN
9
Compound
R1
R2
Yield (%)a
[FAB, (M + 1)+]: calc. 172.1086, found 172.1080; [a]D 278.1 (c 0.64,
24
9a
9b
9c
9d
9e
9f
9g
9h
9j
H
Me
Me
Me
Me
Me
62
73
75
78
80
MeOH). For 9k: mp 201–203 °C; dH(CD3OD, 400 MHz) 7.16 (m, 5H), 4.23
(m, 1H), 3.03 (dd, 1H), 2.89 (dd, 1H); HRMS [FAB, (M + 1)+]: calc.
206.0930, found 206.0924.
Me
Pri
Bus
Bn
Bn
Bn
Me
Bui
Bn
1 Molecular Diversity and Combinatorial Chemistry, ed. I. M. Chaiken
and K. D. Janda, American Chemical Society, Washington DC, 1996;
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p-MeOC6H4CH2 78
Bui
H
H
74
60
67
67
9k
H
a Yields are based on the conversion of 11 to 9 and are isolated yields.
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materials that had accumulated during the synthesis of 9. We
could use this PEG-11 again without any significant reduction
in loading or yield, which was confirmed by 1H NMR
analysis.
In conclusion, we have shown both solution and liquid phase
methodologies for the controlled stepwise synthesis of 3-ami-
noimidazoline-2,4-diones. In our strategy we have provided a
method that allows for the incorporation of two points of
diversity which can be drawn from a large pool of building
blocks. Finally, our approach allows for polymer regeneration
and its reuse.
Financial support of this research by the Skaggs Institute for
Chemical Biology and NIH GM56154 is gratefully acknowl-
edged. C.-W. C. wishes to thank Korea Science and Engineer-
ing Foundation (KOSEF) for a postdoctoral fellowship. We also
thank Professor R. V. Hoffman for many helpful discussions.
6 J. G. Dain, Doctoral Dissertation, Duquesne University, 1970, Diss.
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11 Professor R.V. Hoffman, Personal communication.
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16 Isocyanates 12 were prepared from tert-butyl amino acids and
triphosgene. See S. Goldschmidt and M. Wick, Liebigs Ann. Chem.,
1952, 575, 217 for this preparation.
Notes and references
‡ Optical rotation values for 9b,c,e–g,j are reported in their characterization
data (see below). In the case of 9b, there was no significant change in its
optical rotation value after a first and second recrystallization from EtOH.
Communication 8/07067I
2704
Chem. Commun., 1998, 2703–2704