Synthesis of 1-aminoimidazolidin-4-one and 1-aminoimidazolidin-2-one based compounds: an interesting divergence in methodology

Article abstract of DOI:10.1016/j.tetlet.2006.08.022

An examination of the methods required for the amination of 2- and 4-imidazolidinones is described.

Full text of DOI:10.1016/j.tetlet.2006.08.022

Tetrahedron Letters 47 (2006) 7497–7499
Synthesis of 1-aminoimidazolidin-4-one and
1-aminoimidazolidin-2-one based compounds:
an interesting divergence in methodology
Benjamin E. Blass,* Keith Coburn, Neil Fairweather, Andrew Fluxe, Steve Hodson,
Chris Jackson, John Janusz, Wenlin Lee, Jim Ridgeway, Ron White and Shengde Wu
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040,
United States
Received 21 June 2006; accepted 9 August 2006
Available online 1 September 2006
Abstract—An examination of the methods required for the amination of 2- and 4-imidazolidinones is described.
ꢀ 2006 Published by Elsevier Ltd.
Imidazolidinones constitute a class of heterocyclic
compounds with wide ranging biological activities. The
2-imidazolidinone and 4-imidazolidinone scaffolds can
be found in compounds with CCR3 and 5-HT2c receptor
antagonists activity,1 angiogenic,2 and antibacterial3
properties, and in phosphodiesterase inhibitors.4 We
recently became interested in both of these scaffolds
as part of our ongoing efforts to explore diverse chemi-
cal space for drug discovery. We were particularly
interested in the preparation of the aza analogs of
both of these structures, as very few examples have been
reported to date. The majority of the literature in this
area is focused on aminohydantoins. Further, the direct
aminations of the parent 2- and 4-imidazolidinones have
not been reported to date, nor have the reduction of the
corresponding N-nitroso compounds.
Preparation of the 2-imidazolidinone 2 was slightly
more complicated. 4-tert-Butyl benzaldehyde (4) was
converted to the nitro alkene, which readily underwent
a
Michael condensation with 4-methoxyphenethyl
amine. Reduction with zinc dust to the diamine,5 followed
by cyclization with carbonyldiimidazole provided 2, the
second test substrate (Scheme 2).
Our initial investigations focused on the amination of
the 2-imidazolidinones. Nitrosation of this scaffold was
readily accomplished by treatment of 2 with sodium ni-
trite in glacial acetic acid at room temperature. Reduc-
tion to the desired product, 5, was then accomplished
with the addition of zinc dust at 8–15 ꢁC (83%, Scheme
3).6 Control of the temperature during the zinc addition
was critical to maintain selectivity and avoid formation
of the original starting material, 2, via N–N bond reduction.
We chose to explore the methods for amination of these
compounds with two simple model systems (1 and 2),
both of which could be prepared from readily available
materials. Thus, for the preparation of 1, N-Boc glycine
(3) was converted to the amide via EDCI coupling with
the 4-methoxyphenethyl amine. Deprotection with
TFA, followed by condensation with 4-tert-butyl benz-
aldehyde in the presence of cesium carbonate provided
1 (Scheme 1).
O
O
N
a, b, c
O
NH
NHBoc
HO
3
1
Scheme 1. Reagents and conditions: (a) EDCI, 4-OMe phenethyl-
amine, CH2Cl2, (b) TFA/CH2Cl2 1/1, (c) 4-t-butylbenzaldehyde,
Cs2CO3, MeOH, 60 ꢁC.
*
Corresponding author. Tel.: +1 513 403 9685; fax: +1 513 622
4296; e-mail: bblass2@fuse.net
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.08.022

7498
B. E. Blass et al. / Tetrahedron Letters 47 (2006) 7497–7499
The interesting difference in selectivity between these
O
O
two apparently similar ring systems is not easily ex-
plained. One could argue that the 4-imidazolidinone
ring system contains a basic nitrogen that may be pro-
tonated under acidic conditions, thus activating the
N–N bond to reductive cleavage. However, reports
in the literature of successful, selective reduction of
other N-nitroso systems to the corresponding N-amino
compound suggest that protonation alone cannot
explain the difference reported here. The empirical
observation that hydride reagents fail to produce the
desired product, 6, and that hydrogenation conditions
are not selective for nitroso reduction versus N–N bond
cleavage is also a surprising and unexplained result.
O
NH
N
a, b, c, d
H
2
4
Scheme 2. Reagents and conditions: (a) CH3NO2, NH4OAc, AcOH,
reflux, (b) 4-OMe phenethylamine, THF, rt, (c) Zn, HCl, EtOH, (d)
CDI, DMF, 50 ꢁC.
O
O
O
O
NH2
N
N
In summary we have developed a method for the
preparation of the previously unknown 1-amino imidazo-
lidin-4-one and 1-aminoimidazolidin-2-one based struc-
tures from the parent imidazolidinone core in good
yield. We have further demonstrated that the nature of
the reductive conditions employed is critical to the
successful formation of the desired products.
NH
a, b
N
2
5
Scheme 3. Reagents and conditions: (a) NaNO2, AcOH, 25 ꢁC, (b)
AcOH, Zn, 8–15 ꢁC.
References and notes
We then turned our attention to the 4-imidazolidinone
scaffold. While the nitrosation of 1 was accomplished
using similar conditions to the 2-imidazolidinone scaf-
fold, we were surprised to discover that reduction to
the amine was far more difficult. In our hands, the
zinc/acetic acid method employed for the reduction of
the 2-nitroso-2-imidazolidinone was not selective in the
4-imidazolidinone series. The only product observed in
the 4-imidazolidinone class was the original starting
material, 1, a result of reduction of the N–N bond.
Similar results were observed with palladium on carbon
and hydrogen, palladium on alumina and hydrogen, and
titanium trichloride. Further, tin chloride in a variety of
solvents, both with and without microwave irradiation,
left the nitroso compound unchanged. Similar results
were observed with sodium borohydride, sodium cyano-
borohydride, and even lithium aluminum hydride.7 All
of these procedures have been previously reported
to be effective in the reduction of various nitroso
compounds without concomitant reduction of the
N–N bond. To our surprise, the only conditions that
produced reasonable quantities of the desired 1-amino-
imidazolidin-4-one (6) was reduction with zinc dust in
the presence of ammonium chloride at 80 ꢁC for
10 min with microwave irradiation (72%, Scheme 4).8
1. (a) Hudkins, R. L.; Zulli, A. L.; Reddy, D. R.; Gingrich, D.
E.; Tao, M.; Becknell, N. C.; Diebold, J. L.; Underiner, T.
L. U.S. Patent 2005143442, 2005; (b) Goodacfre, C. J.;
Bromidge, L. P.; Clapham, D.; King, F. D.; Lovell, P. J.;
Allen, M.; Campbell, L. P.; Holland, V.; Riley, G. J.; Starr,
K. R.; Trail, B. K.; Wood, M. D. Biorg. Med. Chem. Lett.
2005, 15, 4989–4993.
2. Gong, L.; Wilhelm, R. S. U.S. Patent 2005090504, 2005.
3. (a) Ochiai, H.; Watanabe, Y.; Murotani, Y.; Fukuda, H.;
Yoshino, O.; Minami, S.; Hayashi, T.; Momonoi, K. GB
2233330, 1991; (b) Araujo, M. A.; Born, J.; Capela, R.;
Casimiro, C.; Chambel, P.; Gomes, P.; Iley, J.; Lopes, F.;
Morais, J.; Moreira, R.; Oliveira, E.; Rosario, V.; Vale, N.
J. Med. Chem. 2005, 888–892.
4. Godfrey, J. D., Jr.; Mueller, R. H.; Zahler, R. EP, 1989.
5. Mouhtaram, M.; Jung, L.; Stambach, J. F. Tetrahedron
1993, 49, 1391–1400.
6. Preparation of 5: To a solution of 5-(4-tert-butylphenyl)-1-
[2-(4-methoxyphenyl)ethyl]-2-imidazolidinone (6 g, 17 mmol)
in glacial acetic acid (120 mL), is slowly added a solution of
sodium nitrite (1.52 g, 22 mmol) in water (10 mL). After
30 min, the suspension is cooled to 8 ꢁC, via a water–ice
bath. Zinc (1 g) is added with a rise in temp to 15 ꢁC. A
second portion of zinc (1 g) is added at 8 ꢁC, with a temp
rise to 12 ꢁC. The final addition of zinc (1.3 g, 50 mmol
total) is made at 7.8 ꢁC. The temp is allowed to rise slowly
and the solution is allowed to stir at 12–17 ꢁC for 1 h. The
mixture is cooled in an ice-bath and is diluted with CH2Cl2
(60 mL) and water (25 mL). NH4OH (175 mL) is added,
keeping the temp 627 ꢁC. The CH2Cl2 is separated, and the
aqueous layer is washed with CH2Cl2 (2 · 75 mL). The
combined organics are dried (Na2SO4), and evaporated to
give a colorless oil. The oil is diluted with Et2O (25 mL) and
is cooled in an ice-bath. HCl in Et2O (12 mL, 24 mmol) is
slowly added. Hexanes (10 mL) is slowly added and the
suspension is allowed to stir at room temp overnight. The
suspension is filtered, washed with hexanes, to give the title
compound. Yield: 5.7 g (83%). 1H NMR (DMSO-d6):
d 7.47 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.04
(d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.67
O
O
O
O
N
a, b
N
N
NH
NH2
6
1
Scheme 4. Reagents and conditions: (a) NaNO2, AcOH, MeOH, 0 ꢁC,
(b) Zn, NH4Cl, MeOH.

B. E. Blass et al. / Tetrahedron Letters 47 (2006) 7497–7499
7499
(t, J = 7.8 Hz, 1H), 3.87 (t, J = 7.8 Hz, 1H), 3.71 (s, 3H),
3.55 (m, 1H), 3.34 (t, J = 8.1 Hz, 1H), 2.64 (m, 5H), 1.29 (s,
9H). MS (M+H+) 368.
neutralized with NaHCO3, extracted with EtOAc, and
dried. Evaporation of the EtOAc yielded 2.25 g of the crude
product. MS (M+H+) 382. The material was then used
without further purification. Step 2, 3-(4-methoxyphen-
ethyl)-1-amino-2-(4-tert-butylphenyl)imidazolidin-4-one: To
a solution of crude 3-(4-methoxyphenethyl)-2-(4-tert-butyl-
phenyl)-1-nitrosoimidazolidin-4-one (0.90 g, 2.36 mmol) in
MeOH (13.0 mL) is added zinc (0.76 g, 11.69 mmol) and a
saturated solution of NH4Cl (8.0 mL). The reaction mix-
ture is irradiated in the microwave for 10 min at 80 ꢁC
followed by dilution with CH2Cl2 and H2O. The CH2Cl2
was separated, dried, and evaporated to yield 0.62 g (71%)
of the crude product that does not require further purifi-
cation. 1H NMR (CD3OD) d 7.48 (d, 2H, J = 8.3 Hz), 7.37
(d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H,
J = 8.5 Hz), 4.75 (s, 1H), 3.78 (d, 1H, J = 11.5 Hz), 3.75 (s,
3H), 3.57 (m, 1H), 3.35 (d, 2H, J = 12 Hz), 2.74 (m, 2H),
2.47 (m, 1H), 1.35 (s, 9H). MS (M+H+) 368.
7. (a) Toure, B. B.; Hall, D. G. J. Org. Chem. 2004, 69, 8429–
8436; (b) Lunn, G.; Sansone, E. B.; Keefer, L. K. J. Org.
Chem. 1984, 49, 3470–3473; (c) Klager, K.; Wilson, E. M.;
Helmkamp, G. K. J. Ind. Eng. Chem. 1960, 52, 119–120; (d)
Henry, E.; Creger, P. L. J. Am. Chem. Soc. 1960, 82, 4634–
4638; (e) Feliu, A. L. J. Labelled Compd. Radiopharm. 1988,
25, 1245–1254.
8. Preparation of 6. Step 1, 3-(4-methoxyphenethyl)-2-(4-tert-
butylphenyl)-1-nitrosoimidazolidin-4-one: To a solution
of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)imidazol-
idin-4-one (2.77 g, 7.87 mmol) in MeOH (30.0 mL) at 0 ꢁC
is added acetic acid (1.10 mL) followed by the dropwise
addition of a solution of sodium nitrite (0.83 g, 11.96 mmol)
in H2O (2.50 mL). The reaction mixture is stirred with
warming to rt for a total of 18 h. The reaction mixture is