Solid-phase synthesis of 2-aminoimidazolones

Article abstract of DOI:10.1021/ol990910p

(equation presented) A solid-phase route for the preparation of 2-aminoimidazolones has been developed which can incorporate diverse functionality at each position of the molecule. Resin-bound S-methyl isothioureas were converted to structures of type I b

Full text of DOI:10.1021/ol990910p

ORGANIC
LETTERS
1
999
Vol. 1, No. 9
351-1353
Solid-Phase Synthesis of
-Aminoimidazolones
1
2
Mengmeng Fu, Monica Fernandez, Marie L. Smith, and John A. Flygare*
Tularik Inc., Two Corporate DriVe, South San Francisco, California 94080
flygare@tularik.com
Received August 4, 1999
ABSTRACT
A solid-phase route for the preparation of 2-aminoimidazolones has been developed which can incorporate diverse functionality at each
position of the molecule. Resin-bound S-methyl isothioureas were converted to structures of type I by using commercially available Fmoc-
protected amino acids. Products of structure II were accessed by reaction of the S-methyl isothiourea with 5-substituted oxazolones.
The 2-aminoimidazolone ring (1, 2) is a structural component
protected amino acids were coupled to a resin-bound
S-methyl isothiourea to produce 2-aminoimidazolones 1.
Aldehydes were used to synthesize 5-substituted oxazolones,
which were added to the S-methyl isothiourea to produce
compounds of structure 2.
1
of compounds that inhibit NF-κB activation and protein
2
kinase C. In the context of our program to generate libraries
Scheme 1 shows our general procedure for the synthesis
of 2-aminoimidazolones. For our initial studies, Rink Amide
MBHA resin was used (Scheme 1, R ) H) to produce
1
compounds that were unsubstituted in the 2-amino position.
The reaction of Fmoc-NCS in methylene chloride with the
free amino group of Rink Amide MBHA resin was rapid,
reaching completion in 15 min, as indicated by a negative
of small heterocyclic rings with potential intracellular
biological activity, we report the synthesis of 2-aminoimi-
dazolones on the solid phase. There are several reports of
solution-phase routes to these compounds. Our priority was
to develop a method that utilized diversity reagents that are
commercially available. Consistent with this goal, Fmoc-
4
ninhydrin test. The resin was deprotected using 20%
3
piperidine in DMF, and methyl iodide treatment yielded the
S-methyl isothiourea 4. Fmoc-protected amino acids (5 equiv)
were coupled to the resin using HOBT/HBTU/NMM
(
1:1:2) to yield 5, and the resin was deprotected using 20%
(
1) (a) Roshak, A.; Jackson, J. R.; Chabot-Fletcher, M.; Marshall, L. A.
piperidine in DMF. The intramolecular cyclization was
accomplished by heating the resin at 80 °C for 24 h in
DMSO. The resin was washed (DMF, CH Cl ) and dried
2 2
for 10 min under a stream of nitrogen to yield 6. Modest
J. Pharmacol. Exp. Ther. 1997, 283, 955-961. (b) Breton, J. J.; Chabot-
Fletcher, M. J. Pharmacol. Exp. Ther. 1997, 282, 459-466.
(2) DiMartino, M.; Wolff, C.; Patil, A.; Nambi, P. Inflamm. Res. 1995,
4
4, S123-S124.
(
3) (a) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.
Tetrahedron Lett. 1992, 33, 5933-5936. (b) Dalkafouki, A.; Ardisson, J.;
Kunesch, N.; Lacombe, L.; Poisson, J. E. Tetrahedron Lett. 1991, 32, 5325-
5
1
328. (c) Garratt, P. J.; Thorn, S. N.; Wrigglesworth, R. Tetrahedron Lett.
991, 32, 691-694. (d) Kwon, C.-H.; Tahir Iqbal, M.; Wurpel, J. N. D. J.
(4) (a) Kearney, P. C.; Fernandez. M.; Flygare, J. A. Tetrahedron Lett.
1998, 39, 2663-2666. (b) Kearney, P. C.; Fernandez, M.; Flygare, J. A. J.
Org. Chem. 1998, 63, 196-200.
Med. Chem. 1991, 34, 1845-1849.
1
0.1021/ol990910p CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/25/1999

intramolecular cyclization. Compounds 1f-h were generated
from amino acids linked to the Rink Amide MBHA resin.
For these compounds the 2-amino group of the 2-aminoimi-
dazolone did not serve as the attachment point to the resin.
Despite the additional step of coupling this group to the resin,
the yields and purities of these compounds compare well
with those that are not substituted in this position. In general,
the isolated yields and purities of all entries are high,
demonstrating the efficiency of each step in the sequence.
To access unsaturated structures of the general type 2, we
initially attempted to add an aldehyde to the resin-bound
Scheme 1a
2
-aminoimidazolinone 7, generated from Fmoc-glycine.
a
Legend: (a) (i) Fmoc-NCS, CH
2 2
Cl , (ii) 20% piperidine in
DMF, (iii) MeI, DMF; (b) (i) HOBT, HBTU, NMM, DMF, (ii)
2
6
0% piperidine in DMF; (c) DMSO, 80 °C; (d) 95% aqueous TFA,
0 °C.
Although there are reports of solution-phase reactions that
accomplish a similar transformation, all of our efforts to
6
carry out this reaction on the solid phase failed.
To overcome this problem, an oxazolone was added to the
resin bound S-methyl isothiourea 4 as shown in Scheme 2.
heating (60 °C) was required to cleave the 2-aminoimida-
zolone from the resin with 95% aqueous trifluoroacetic acid.
5
Table 1 summarizes the yields and substrates used for this
reaction. Bulky substituents such as a tert-butyl group in the
R
4
position (compound 1a) are still able to complete the
Scheme 2a
Table 1. Synthesis of 2-Aminoimidazolones
a
Legend: (a) DMF, EtONa (2 equiv), 100 °C; (b) 95% aqueous
TFA, 60 °C.
The S-methyl isothiourea 4 was generated from Rink
Amide MBHA resin in a procedure identical with that
outlined in Scheme 1. Treatment of 4 with the oxazolone 9
(5) General procedure for the synthesis of 2-aminoimidazolones: Rink
Amide MBHA resin (0.5 g, 0.34 mmol) was placed into a plastic syringe,
and DMF (10 mL, 5 min, 3×) was added. The resin was treated with 20%
piperidine in DMF (10 mL, 20 min, 2×) and washed with DMF (10 mL,
3
0 s, 3×), MeOH (10 mL, 30 s, 3×), and CH2Cl2 (10 mL, 30 s, 3×). Fmoc-
NCS in CH2Cl2 (0.25 M, 10 mL, 2 h) was added to the resin followed by
CH2Cl2 (10 mL, 30 s, 3×) and DMF (10 mL, 30 s, 3×) washes. A mixture
of 20% piperidine in DMF (10 mL, 20 min, 2×) was added, the resin was
washed with DMF (10 mL, 30 s, 3×), and a DMF solution of CH3I (0.5
M, 7 mL, 1 h, 3×) was added. The resin was washed with DMF (10 mL,
3
0 s, 3×), 17 mL of a DMF solution of HOBT(0.1 M)/HBTU(0.1 M)/
NMM(0.2 M) was added followed by Fmoc-R-tert-butyl glycine (0.6 g, 5
equiv) (Table 1, compound 1a), and the resin was agitated for 4 h. The
resin was washed with DMF (10 mL, 30 s, 5×) and treated with 20%
piperidine in DMF (10 mL, 20 min, 2×), followed by a DMF wash (10
mL, 30 s, 5×). DMSO was added (10 mL), and the resin was heated at 80
°
C for 24 h. After it was cooled to room temperature, the resin was washed
a
Yields were determined using the loading level of the starting resin
with DMF (10 mL, 30 s, 3×), MeOH (10 mL, 30 s, 3×), and DCM (10
mL, 1 min, 5×). The resin was dried under nitrogen for 10 min and cleaved
with 95% aqueous TFA at 60 °C for 4 h. The cleavage eluant was collected,
and are based on isolated product.
1352
Org. Lett., Vol. 1, No. 9, 1999

and sodium ethoxide yielded the unsaturated 2-aminoimi-
7
dazolone 10. The long reaction times (10 h) were necessary
Table 2. Synthesis of Unsaturated 2-Aminoimidazolones
to ensure that the product was completely deacylated. If the
reaction was stopped earlier, products were isolated with a
phenylacetate group on the one position of the imidazolone
ring. Cleavage of 10 with 95% aqueous trifluoroacetic acid
yielded the unsaturated 2-aminoimidazolone 2.
Table 2 summarizes the yields and substrates used for this
reaction. The proton NMR spectra of the product alkenes
showed that they were formed as a 1/1 mixture of E/Z
5
isomers. Although the diversity of the R position is limited
by the small number of commercially available oxazolones,
these compounds can be synthesized readily from the
corresponding aldehyde.
8
Following a literature procedure, hippuric acid was treated
with an aldehyde in the presence of acetic anhydride and
sodium acetate and heated to 80 °C for 2 h:
The oxazolone precipitated from the crude reaction mixture
when the solution was poured into water. This allowed us
a
Yields were determined using the loading level of the starting resin
and are based on isolated product.
to incorporate aldehydes as the diversity unit in the R
position.
5
In summary, we have shown that 2-aminoimidazolones
can be produced in good yields and with acceptable purities
from a resin-bound S-methyl isothiourea. The procedure
utilizes Fmoc-protected amino acids and aldehydes as the
diversity agents in the construction of the rings. The
chemistry involved occurs under mild conditions and should
find use in combination with other solid- and solution-phase
chemistries.
and the resin was washed with 95% aqueous TFA (5 mL, 1×) and MeOH
5 mL, 2×). The eluant and washes were combined and dried with a
Speedvac. The compound was purified with preparative HPLC (Dynamax-
0A C18 column, 0.1% solutions of TFA, water/acetonitrile 9/1 to 2/8 eluant
(
6
gradient over 40 min, 21 mL/min flow rate), to yield the product as a
crystalline solid. H NMR (400 MHz, DMSO-d6): δ 4.02 (s, 1H), 0.95 (s,
9
2
1
1
1
3
H). C NMR (100 MHz, DMSO-d6): δ 173.88, 158.17, 66.88, 34.52,
5.00. FAB HR-MS: calcd m/z for C7H13N3O 156.1137 (M + H ), obsd
+
56.1137.
Supporting Information Available: Procedures for the
formation of 2-aminoimidazolones 1 and 2 and characteriza-
tion data for 1a-h and 2a-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
6) Schuisky, P.; Twistel, W.; Grivas, S. Heterocycles 1998, 48, 1431-
444.
7) Mukerjee, A. K.; Joseph, K.; Homami, S.-S.; Tikdari, A. M.
Heterocycles 1991, 32, 1317-1325.
1
(
(
8) (a) Homani, S.-S.; Mukerjee, A. K. Indian J. Chem 1991, 30B, 288-
2
8
89. (b) Kumar, P.; Mishra, H. D.; Mukerjee, A. K. Synthesis 1980, 836-
38.
OL990910P
Org. Lett., Vol. 1, No. 9, 1999
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