The synthesis of a series of 3,5-disubstituted tetrahydro-1H-imidazole-2,4-diones utilizing lithium aluminum hydride

Article abstract of DOI:10.1081/SCC-120003149

A series of 3,5-disubstituted tetrahydro-1H-imidazole2,4-diones were synthesized from the corresponding urea methyl ester precursors utilizing lithium aluminum hydride as the cyclization agent.

Full text of DOI:10.1081/SCC-120003149

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THE SYNTHESIS OF A SERIES OF 3,5-DISUBSTITUTED
TETRAHYDRO- 1H-IMIDAZOLE-2,4-DIONES UTILIZING
LITHIUM ALUMINUM HYDRIDE
M. Lee Sanders a & I. O. Donkor a
a Department of Pharmaceutical Sciences , University of Tennessee Health Science Center ,
Memphis, TN, 38163, U.S.A.
Published online: 21 Aug 2006.
To cite this article: M. Lee Sanders & I. O. Donkor (2002) THE SYNTHESIS OF A SERIES OF 3,5-DISUBSTITUTED TETRAHYDRO-
1H-IMIDAZOLE-2,4-DIONES UTILIZING LITHIUM ALUMINUM HYDRIDE, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:7, 1015-1021, DOI: 10.1081/SCC-120003149
To link to this article: http://dx.doi.org/10.1081/SCC-120003149
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SYNTHETIC COMMUNICATIONS, 32(7), 1015–1021 (2002)
THE SYNTHESIS OF A SERIES OF
3,5-DISUBSTITUTED TETRAHYDRO-
1H-IMIDAZOLE-2,4-DIONES UTILIZING
LITHIUM ALUMINUM HYDRIDE
*
M. Lee Sandersand I. O. Donkor
Department of Pharmaceutical Sciences,
University of Tennessee Health Science Center,
Memphis, TN 38163, USA
ABSTRACT
A
series of 3,5-disubstituted tetrahydro-1H-imidazole-
2,4-diones were synthesized from the corresponding urea
methyl ester precursors utilizing lithium aluminum hydride
as the cyclization agent.
Lithium aluminum hydride (LAH) is a versatile reagent utilized in a
variety of synthetic reactions. The most predominant role of LAH in the
organic laboratory is its use in the reduction of various functional groups.
LAH has long been identified as a reagent for the transformation of alkyl
esters to the corresponding alcohols.1 It has also been demonstrated that the
urea functional group is quite stable in the presence of LAH.2 Therefore, as
a part of a program aimed at synthesizing urea-based peptidomimetic
calpain inhibitors, LAH was employed as the reducing agent in an attempt
*Corresponding author.
1015
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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SANDERS AND DONKOR
to transform urea methyl esters 1–4 to the corresponding alcohols. However,
upon reacting LAH with compounds 1–4 it was observed that cyclization
to the corresponding tetrahydro-1H-imidazole-2,4-diones (hydantoins)
occurred rather than reduction of the methyl ester group to the alcohol
(Scheme 1). 3,5-Disubstituted tetrahydro-1H-imidazole-2,4-diones have pre-
viously been synthesized from urea methyl ester precursors utilizing a variety
of reagents.3–17 However, to our knowledge this is the first report describing
the use of LAH as a cyclization agent in the transformation of urea methyl
esters to the corresponding tetrahydro-1H-imidazole-2,4-diones. In this
report we describe the synthesis of four 3,5-disubstituted tetrahydro-
1H-imidazole-2,4-diones (5–8) using LAH as the cyclization agent to further
demonstrate the versatility of this reagent in organic synthesis.
Scheme 1. R1 ¼ i-Pro, CH2Ph, (CH2)2Ph R2 ¼ i-Pro, CH2Ph.
EXPERIMENTAL
All reagents and solvents were purchased from either Aldrich
Chemical Company or Advanced ChemTech Inc. and used without
further purification. Melting points were obtained utilizing a Thomas
1
Hoover capillary melting point apparatus and were uncorrected. H NMR
spectra were determined at 300 MHz and 13C NMR spectra at 75 MHz
(Bruker ARX 300 instrument). Elemental analyses were obtained from
Atlantic Microlab, Inc. (Norcross, GA).
General Procedure 1. Reaction of L-Amino Acids
with Alkyl Isocyanates
The reactions were conducted utilizing a modified procedure of Hill
and DePree.18 To a solution of L-amino acid methyl ester hydrochloride
(1 equivalent) and toluene (3 equivalents) at 50ꢀC was slowly added triethyl-
amine (1.5 equivalents). After 15 min, isocyanate (1.1 equivalents) was
added portion wise over a 30 min interval. The mixture was stirred at
50ꢀC for 16h. After the reaction mixture was cooled to room temperature,

TETRAHYDRO-1H-IMIDAZOLE-2,4-DIONES
1017
water (5 ml) was added followed by dichloromethane (10 ml). The organic
layer was successively treated with saturated sodium bicarbonate (5 ml),
water (5 ml), 1N hydrochloric acid (5 ml), water (5 ml), and brine (5 ml).
The organic layer was dried over magnesium sulfate, filtered, and concen-
trated in vacuo to obtain a white solid. The compounds were purified by
recrystalization from ethyl acetate/hexane to obtain the product in 53–71%
yield. Compounds 1–4 were synthesized utilizing this procedure.
Methyl-(2S)-2{[(benzylamino)carbonyl]amino}-
3-phenylpropanoate (1)
Compound 1 was synthesized from a solution of 0.57 g (2.66 mmoles)
of L-phenylalanine methyl ester hydrochloride, 0.85 ml of toluene, 0.56ml
triethylamine (3.99 mmoles), and 0.36ml benzyl isocyanate (2.92 mmoles).
Recrystalization gave 1 as a white solid, 0.92 g (71%), m.p. 94–96ꢀC.
1H NMR (CDCl3): d 3.01–3.06ppm (m, 2H, PhCH 2CH), 3.66 (s, 3H,
OCH3), 4.28 (dd, 2H, PhCH2NHCO), 4.77 (t, 1H, PhCH2CHCOOCH3),
7.10–7.29 ppm (m, 10H, phenyl protons). Anal. calcd for C18H20N2O3: C,
69.21; H, 6.45; N, 8.97. Found: C, 69.05; H, 6.49, N, 9.05.
Methyl-(2S)-2{[(phenethylamino)carbonyl]amino}-
3-phenylpropanoate (2)
Compound 2 was synthesized from a solution of 0.51 g (2.37 mmoles)
of L-phenylalanine methyl ester hydrochloride, 0.76ml of toluene,
0.50 ml triethylamine (3.56mmoles) and 0.36ml phenethyl isocyanate
(2.61 mmoles). Recrystalization gave 2 as a white solid, 0.68 g (68%), m.p.
110–111ꢀC. H NMR (CDCl3): d 2.79 (dd, 2H, PhCH2CH), 3.01–3.14 ppm
1
(m, 2H, PhCH2CH2NH), 3.32–3.50 ppm (m, 2H, PhCH2CH2NH), 3.70 (s,
3H, OCH3), 4.34–4.38 ppm (t, 1H, PhCH2CHCOOCH3), 4.69 ppm (d, 1H,
NH), 4.74–4.79 ppm (m, 1H, NH), 7.10–7.30 ppm (m, 10H, phenyl protons).
Anal. calcd for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58. Found: C, 69.87; H,
6.81; N, 8.54.
Methyl-(2S)-2{[(isopropylamino)carbonyl]amino}-
3-phenylpropanoate (3)
Compound 3 was synthesized from a solution of 0.62 g (2.89 mmoles)
of L-phenylalanine methyl ester hydrochloride, 0.92 ml of toluene, 0.61 ml

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SANDERS AND DONKOR
triethylamine (4.34 mmoles), and 0.31 ml of isopropyl isocyanate
(3.18 mmoles). Recrystalization gave 3 as a white solid, 0.69 g (58%), m.p.
115ꢀC. H NMR (CDCl3): d 0.97–1.01 (dd, 6H, CH3CHCH3), 2.72–2.98
1
(m, 2H, PhCH2CH), 3.54–3.66 (m, 1H, CH3CHCH3), 3.59 (s, 3H, OCH3),
4.35–4.43 (m, 1H, PhCH2CHCOOCH3), 5.94 (d, 1H, NH), 6.00 (d, 1H, NH),
7.14–7.31 ppm (m, 5H, phenyl protons). Anal. calcd for C14H20N2O3: C,
63.62; H, 7.63; N, 10.60. Found: C, 63.65; H, 7.58; N, 10.74.
Methyl-(2S)-2{[(benzylamino)carbonyl]amino}-3-
methylbutanoate (4)
Compound 4 was synthesized from a solution of 0.50 g (2.99 mmoles)
of L-valine methyl ester hydrochloride, 0.96ml of toluene, 0.63 ml tri-
ethylamine (4.49 mmoles), and 0.41 ml benzyl isocyanate (3.29 mmoles).
Recrystalization gave 4 as a white solid, 0.42 g (53%), m.p. 82–84ꢀC.
1H NMR (CDCl3):
d
0.84 (d, 3H, CH3CHCH3), 0.93 (d, 3H,
CH3CHCH3), 2.03–2.15 ppm (m, 1H, CH3CHCH3), 3.69 (s, 3H, OCH3),
4.36(d, 2H, PhCH 2NHCO), 4.43 (d, 1H, CH3OCOCHNHCO),
7.23–7.35 ppm (m, 5H, phenyl protons). Anal. calcd for C14H20N2O3: C,
63.62; H, 7.63; N, 10.60. Found: C, 63.78; H, 7.62; N, 10.51.
General Procedure 2. Preparation of 3,5-Disubstituted
Tetrahydro-1H-imidazole-2,4-diones
To a stirring solution of the urea methyl ester compounds (1–4)
(0.326mmoles) in excess anhydrous tetrahydrofuran was added lithium alu-
minum hydride (0.652 mmoles) under nitrogen at room temperature. After
30 min, water was slowly added to the mixture followed by product extrac-
tion with dichloromethane. The organic layer was washed with water
(3 Â 10 ml), dried over magnesium sulfate, and evaporated to obtain the
crude product. Flash chromatography (2 : 1 ethyl acetate : hexanes) on
silica gel was utilized to obtain the product in purified form. Compounds
5–8 were synthesized utilizing this procedure.
3,5-Dibenzyltetrahydro-1H-imidazole-2,4-dione (5)
Compound
5 was synthesized as a white solid from 0.10 g
(0.326mmoles) of 1 in 34% yield, 0.03 g, m.p. 146ꢀC. H NMR (CDCl3):
d 2.79 (dd, 1H, PhCH2CH), 3.14 (dd, 1H, PhCH2CH), 4.15 (ddd, 1H,
1

TETRAHYDRO-1H-IMIDAZOLE-2,4-DIONES
1019
PhCH2CH), 4.49 (dd, 2H, PhCH2NCO), 5.38 (s, 1H, NH), 6.98–7.26 ppm
(m, 10H, phenyl protons). 13C NMR (CDCl3); d 37.66 (CH2), 42.07 (NCH2),
58.31 (CH), 127.34, 127.74, 128.21, 128.59, 128.81, 129.27, 134.94, 135.71
(Ar), 156.90 (N(CO)N), 172.76 (CO). Anal. calcd for C17H16N2O2 0.03
H2O: C, 72.70; H, 5.76; N, 9.97. Found: C, 72.30; H; 6.09, N, 9.84.
5-Benzyl-3-phenethyltetrahydro-1H-imidazole-2,4-dione (6)
Compound
6 was synthesized as a white solid from 0.11 g
(0.326mmoles) of 2 in 41% yield, 0.04 g, m.p. 130–132ꢀC. 1H NMR
(CDCl3): d 2.67 (dd, 1H, PhCH2CH), 2.84 (t, 2H, PhCH2CH2NCO), 3.22
(dd, 1H, PhCH2CH), 3.62–3.78 ppm (m, 2H, PhCH2CH2NCO), 4.15 (ddd,
1H, PhCH2CH), 5.31 (s, 1H, NH), 7.17–7.30 ppm (m, 10H, phenyl protons).
13C NMR (CDCl3);
d 34.0 (NCH2CH2Ph), 37.6(CHCH 2Ph), 45.3
(NCH2CH2Ph), 60.1 (CHCH2Ph), 125.7, 127.9, 128.4, 140.2 (Ar), 159.0
(N(CO)N), 173.4 (CO). Anal. calcd for C18H18N2O2 0.04 H2O: C, 73.27;
H, 6.18; N, 9.49. Found: C, 72.90; H, 6.22; N, 9.20.
3-Benzyl-5-isopropyltetrahydro-1H-imidazole-2,4-dione (7)
Compound
7 was synthesized as a white solid from 0.09 g
(0.326mmoles) of 3 in 60% yield, 0.05 g, m.p. 109–111ꢀC. 1H NMR
(CDCl3): d 0.80 (d, 3H, CH3CHCH3), 1.00 (d, 3H, CH3CHCH3),
2.17–2.23 ppm (m, 1H, CH3CHCH3), 3.92 (d, 1H, HNCHCO), 4.63 (d,
2H, PhCH2NCO), 6.81 (s, 1H, NH), 7.26–7.38 ppm (m, 5H, phenyl pro-
tons). 13C NMR (CDCl3): d 16.2 (CH3CHCH3), 28.0 (CH3CHCH3), 48.7
(NCH2Ph), 64.6 (CH), 126.5, 127.1, 128.3, 142.4 (Ar), 160.0 (N(CO)N),
173.0 (CO). Anal. calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06.
Found: C, 67.28; H, 6.97; N, 11.89.
5-Benzyl-3-isopropyltetrahydro-1H-imidazole-2,4-dione (8)
Compound 8 was synthesized as a colorless oil from 0.09 g
1
(0.326mmoles) of 4 in 25% yield, 0.02 g. H NMR (CDCl3): d 1.25 (d, 6H,
NCH(CH3)2), 2.95 (dd, 1H, PhCH2CH), 3.16(dd, 1H, PhCH CH), 4.08–
2
4.19 ppm (m, 2H, PhCH2CH and NCH(CH3)2), 5.89 (s, 1H, NH), 7.12–
7.27 ppm (m, 5H, phenyl protons). 13C NMR (CDCl3): d 19.33 (CH3CHCH3),
19.42 (CH3CHCH3), 37.79 (CHCH2Ph), 43.50 (CH3CHCH3), 57.48

1020
SANDERS AND DONKOR
(CHCH2Ph), 127.33, 128.70, 129.42, 134.93 (Ar), 157.18 (N(CO)N), 173.05
(CO). Anal. calcd for C13H16N2O2 0.1 H2O: C, 66.70; H, 6.98; N, 11.97.
Found: C, 66.35; H, 7.06; N, 11.65.
ACKNOWLEDGMENT
The work was supported by grant 5 K14 HL03536from the U.S.
Public Health Service to I.O.D.
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Received in the USA March 29, 2001