Thermolysis reactions of N-alkyl-N′-CBZ amino acid amides. A route to substituted imidazolidine-2,4-diones

Article abstract of DOI:10.1016/j.tetlet.2018.01.086

Reaction of N-alkyl-N′-CBZ amino acid amides under microwave conditions in water and in the presence of an acid catalyst results in the formation of N-substituted imidazolidine-2,4-diones in good yields.

Full text of DOI:10.1016/j.tetlet.2018.01.086

Tetrahedron Letters 59 (2018) 938–940
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Tetrahedron Letters
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Thermolysis reactions of N-alkyl-N0-CBZ amino acid amides.
A route to substituted imidazolidine-2,4-diones
⇑
Marc Casale, David A. Hunt
Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, NJ 08628, USA
a r t i c l e i n f o
a b s t r a c t
Reaction of N-alkyl-N0-CBZ amino acid amides under microwave conditions in water and in the presence
of an acid catalyst results in the formation of N-substituted imidazolidine-2,4-diones in good yields.
Ó 2018 Elsevier Ltd. All rights reserved.
Article history:
Received 19 January 2018
Accepted 28 January 2018
Available online 5 February 2018
Keywords:
Cyclization reaction
CBZ-protected amino acid amides
Imidazolidine-2
4-Diones
Hydantoins
Introduction and discussion
toluene sulfonic acid and concentrated sulfuric acid likewise did
not afford 4 (Scheme 2).
b-Phenylethylamino acid amides of the general structure 3 have
been shown to be effective fungicidal agents against various spe-
cies of phytopathogenic fungi, especially Plasmopara viticola.1 Dur-
ing the course of investigation of these compounds, we found that
such compounds can undergo tandem cyclization reactions when
subjected to Bischler-Napieralski reaction conditions to afford
dihydroimidazoisoquinolin-3(2H)-ones 4.2 This reaction was
observed to be a one-pot, tandem cyclization affording dihydroim-
idazoisoquinolin-3(2H)-one products in low yields when the aro-
matic ring of 3 was appropriately electronically activated. When
the aromatic ring was electron deficient or lacked appropriate acti-
vation, the cyclization was arrested at the imidazolidine-2,4-dione
5 (Scheme 1).
These results prompted us to further investigate the reaction in
order to determine if the dihydroimidazoisoquinolin-3(2H)-ones 4
were formed through the intermediacy of the imidazolidine-2,4-
dione derivatives 5. To test the hypothesis, preparation of the
arylethylamino imidazolidine-2,4-dione 5a and 5b were required
and prepared in excellent yield from the condensation reaction of
the requisite imidazolidine-2,4-dione 7 and b-arylethyl bromide
6. However, neither 5a nor 5b afforded 4 in significant quantities
upon reaction with POCl3. Compound 4 was only observed via
GC–MS in trace quantities when 5a and a significant excess of
POCl3 was added. Treatment of 5a and 5b with acids such as p-
While attempting to characterize the amino acid amides of the
type 3 by GC–MS, we observed a molecular ion corresponding to
the imidazolidine-2,4-dione derivative 4; indeed, the mass spec-
trum and GC retention time for 5b was identical to that observed
for 3b thereby indicating that the imidazolidine-2,4-dione was
formed via high temperature heating of the corresponding amino
acid amide. To date, this type of thermal-mediated cyclization
has not been reported in the literature and the quantitative conver-
sion of 3–5 observed in the GC–MS at high temperatures repre-
sents a novel route toward imidazolidine-2,4-dione compounds
with potential industrial and drug design applications. A some-
what similar reaction utilizing a Tf2O-mediated cyclization of
amino amides in dichloromethane has been reported.3 Imidazo-
lidine-2,4-dione (hydantoin) compounds have been widely
employed as anticonvulsant medications rendering their synthesis
an important area of research.4 Armed with this information, we
have focused on defining the scope and limitations of the conver-
sion of 3–5 (Table 1).
Initial efforts to carry out the cyclization under purely ther-
mal conditions were met with limited success. For example, sim-
ple, CBZ-protected phenylethylamino acid amides such as
alanine and valine were shown to cyclize under different ther-
molysis conditions such as in DMSO and when no solvent was
used. However, significant thermal degradation of both reactants
and solvent in addition to low product yields were observed in
these reactions, even when the reactions were carried out in a
Biotage microwave synthesizer. Cyclization attempts utilizing
⇑
Corresponding author.
E-mail address: hunt@tcnj.edu (D.A. Hunt).
https://doi.org/10.1016/j.tetlet.2018.01.086
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.

M. Casale, D.A. Hunt / Tetrahedron Letters 59 (2018) 938–940
939
Scheme 1.
Scheme 2.
Table 1 (continued)
Imidazolidine-2,5-dione
5e
Table 1
Preparation of imdiazolidine-2,5-diones.
Conditions
Yield
O
Microwave Synthesizer
6 h; 200 °C
21.0% PTSA by weight
89%
NH
O
O
R
N
R'
NH
O
.
N
H3CO
H3CO
Imidazolidine-2,5-dione
Conditions
Yield
73%
Microwave Synthesizer
6 h; 200 °C
17.4% PTSA by weight
5a
O
Microwave Synthesizer
10 h; 200 °C
20.7% PTSA by weight
79%
5f
NH
O
CH3
NH
N
CH3
N
H3CO
O
O
H3CO
Microwave Synthesizer
6 h; 200 °C
35.7% PTSA by weight
68%
71%
5b
O
NH
CH3
N
various other polar solvent systems such as water, 1,4-dioxane,
and acetonitrile all failed to induce any product formation. Inter-
estingly, efforts making use of an acid catalyst in deionized
water have led to successful cyclization. p-Toluene sulfonic acid
was used in ratios ranging between 17.4 and 37.8 wt% of the
substrate. Additionally, all of the reactions studied were run at
a temperature of 200 °C in the Biotage microwave synthesizer.
H3CO
O
Microwave Synthesizer
12 h; 200 °C
21.2% PTSA by weight
5c
O
NH
CH3
N
O
OCH3
Microwave Synthesizer 10 h;
200 °C
19.5% PTSA by weight
73%
5d
O
NH
CH3
N
O
Scheme 3.

940
M. Casale, D.A. Hunt / Tetrahedron Letters 59 (2018) 938–940
However, the reaction times required for significant cyclization
to occur (as determined by 1H NMR) varied and ranged between
6 and 12 h (Scheme 3).
References
1. Hunt DA, Lavanish JM, Asselin M, Los M. Fungicidal amino acid amides,
(American Cyanamid). EP 493,683; 1992.
2. Cherney E, Macor J, Papanagapolous C, Hunt DA. Tetrahedron Lett.
2014;55:4837–4839.
3. Liu H, Yang ZM, Pan ZY. Org Lett. 2014;16:5902–5905.
Conclusion
4. Trisovic NP, Uscumlic GS, Petrovic SD. Hem Ind. 2009;63:17–31.
5. Konnert L, Lamaty F, Martinez J, Colacino E. Chem Rev. 2017;117:13757–13809.
6. Meusel M, Gutschow M. Org Prep Proced Int. 2004;36:391–443.
7. General procedure for the preparation of Imidazolidine-2,4-diones 5 from amino acid
amides 3. Preparation of 3-(3,4-dimethoxyphenethyl)-5-methylimidazolidine-2,4-
dione 5a. Benzyl (S)-(1-((3,4-dimethoxyphenethyl)amino)-1-oxopropan-2-
yl)carbamate (155 mg was charged to a 5 ml Biotage Microwave Synthesizer
vial along with 27 mg PTSA, 3.0 ml DI water, and a magnetic stir bar. The vial
was sealed and heated in the Biotage Microwave Synthesizer at 200 °C for 6
hours and an absorption level of setting of low. Dilution of the aqueous layer to
10 mL with water then washing with portions of DCM (2 ꢀ 20 mL). The
combined organic layers were washed with 2 ꢀ 20 ml portions of NaHCO3 (2 ꢀ
20 mL), dried over MgSO4, filtered, condensed, and characterized with proton
NMR. Purification was accomplished via column chromatography on the Biotage
In light of the ongoing interest in hydantoin derivatives as
indicated by recent review articles,5,6 this methodology7 serves
to complement currently existing methods for the preparation
of these valuable derivatives. Six derivatives of 3 have success-
fully been observed to form 5 under microwave reaction condi-
tions with isolated purified yields ranging from 68 to 89%. Future
work will involve examining the results of cyclization experi-
ments using other N-protecting groups on 3 such as BOC and
FMOC groups. Other amino acid side chains will also be studied
such as hydrophilic side chains and sterically unhindered glycine
compounds. Finally, other solvent systems and catalysts will be
examined under catalytic conditions in an effort to shorten reac-
tion times.
Isolera using
a gradient of 7:3 ethyl acetate:hexanes to 9:1 ethyl acetate
hexanes. A 10 g silica gel column was used along with a 20 ml/min flow rate.
Fractions containing purified hydantoin product were condensed and
characterized via NMR and IR spectroscopy. The product was obtained as a
light yellow solid (81 mg, 73%), mp 115 °C, IR (cmꢁ1): 3230.3, 1712.8; 1H NMR
(400 MHz; CDCl3): d 6.76–6.75 (m, 2H, J = 1.96 Hz), 6.73 (s, 1H), 5.31 (s, 1H),
4.02–3.96 (q of d, 1H, J = 7.05 Hz, J0 = 1.39 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.74–
3.69 (sextet, 2H, J = 3.91 Hz), 2.90–2.86 (t, 2H, J = 7.49 Hz), 1.35–1.34 (d, 3H, J =
7.16 Hz); 13C NMR (400 MHz; CDCl3): d 174.3, 156.9, 148.9, 147. 8, 130.2, 121.0,
112.1, 111.2, 55.9, 52.7, 39.7, 33.4, 17.7. Calc’d for C14H18N2O4: C, 60.42; H, 6.52;
N, 10.07. Found: C: 60.38; H, 6.84; N, 9.73.
Acknowledgements
We wish to thank The College of New Jersey for their generous
support of this work.