Facile one-pot synthesis of 5-substituted hydantoins

Article abstract of DOI:10.1039/b719675j

5-Substituted and 5,5-disubstituted hydantoins are synthesised from the corresponding aldehydes or ketones, using a one-pot, gallium(iii) triflate-catalysed procedure that is compatible with a range of substrates and solvents.

Full text of DOI:10.1039/b719675j

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile one-pot synthesis of 5-substituted hydantoins†
Ross G. Murray,a David M. Whitehead,b Franck Le Stratb and Stuart J. Conway*a
Received 20th December 2007, Accepted 4th February 2008
First published as an Advance Article on the web 14th February 2008
DOI: 10.1039/b719675j
5-Substituted and 5,5-disubstituted hydantoins are synthe-
sised from the corresponding aldehydes or ketones, using
a one-pot, gallium(III) triflate-catalysed procedure that is
compatible with a range of substrates and solvents.
thiohydantoin),20 combination of carbodiimides and a,b-
unsaturated carboxylic acids, and the treatment of nitriles with
organometallic reagents followed by potassium cyanide and
ammonium carbonate.21,22 Both microwave23 and solid phase24,25
technologies have been employed in the synthesis of hydantoins.
There are also more esoteric syntheses of hydantoins that involve
complex rearrangements.1,26,27
We have investigated a Lewis acid-catalysed variation of the
Bucherer–Bergs reaction, which is compatible with a range of
organic solvents and that commences from simple aldehyde or
ketone starting materials. Lewis acid catalysis engenders the
possibility of chiral catalysis and ultimately an enantioselective
reaction. Herein, we report the development of a one-pot, Lewis
acid-catalysed, hydantoin synthesis that is compatible with a range
of substrates and organic solvents.
The mechanism of the Bucherer–Bergs reaction (Scheme 1)
mirrors that of the Strecker synthesis until the formation of the
amino nitrile. At this point, the Strecker synthesis is complete,
whereas in the Bucherer–Bergs reactions, the amino nitrile goes
on to react with carbon dioxide. As enantioselective Lewis acid-
catalysed Strecker reactions are well documented,28,29 our initial
investigations focused on the conversion of amino nitriles to
hydantoins by treatment with carbon dioxide.
Literature from 1934 details one example of the conversion
of 2-amino-2-methylpropionitrile to 5,5-dimethylhydantoin by
treatment with carbon dioxide in water.32 In our hands, this
reaction only proceeded in 9% yield, although this could be
improved to 50% yield by conducting the reaction in a preformed
solution of aqueous carbonic acid (Table 1).
The hydantoin scaffold is an important structural component
that is present in a number of natural products1–5 and pharma-
cologically important compounds.1,6–12 More recently, hydantoin-
derived guanine oxidation products have emerged as markers
of oxidative cell damage. These hydantoins are significant DNA
lesions that are targeted by repair enzymes and may be implicated
in cancer, aging and neurological disorders.13–17 Synthetically,
hydantoins are important precursors to amino acids, via either
acid-, base- or enzyme-catalysed hydrolysis. The Bucherer–Bergs
reaction (Scheme 1) is the most commonly used method for the
synthesis of hydantoins.18 This multicomponent reaction com-
mences from an aldehyde or a ketone and their ready availability
makes the Bucherer–Bergs reaction an attractive method for the
synthesis of hydantoins. However, the use of water and ethanol
as solvents gives rise to solubility problems with a number of
substrates, and the inclusion of ammonium carbonate can lead
to problems with sublimation, causing the reaction to often be
conducted within a sealed tube or acid digestion bomb. Other
methods of furnishing hydantoins include the treatment of a-
amino amides with triphosgene,19 the reaction of amino acids
with acetic anhydride and ammonium thiocyanate (to give the
To determine whether the volatility of amino nitrile 1 con-
tributed to the poor yield, the reaction was repeated using the
less volatile 2. This reaction gave a yield of 50%, prompting us to
consider whether two equivalents of the aminonitrile are required
for the reaction to proceed. It was postulated that the amino
Table 1 Initial optimisation for the conversion of amino nitriles to
hydantoins
Scheme 1 Intermediates in the proposed mechanism of the Bucher-
er–Bergs reaction.30,31
aEaStCHEM, School of Chemistry and Centre for Biomolecular Sciences,
University of St Andrews, North Haugh, St Andrews, Fife, U.K. KY16
9ST. E-mail: sjc16@st-andrews.ac.uk; Fax: +44 (0)1334 463808; Tel: +44
(0)1334 463478
Entry
R
Solvent
Time Yield
bSanofi-aventis, Department of Isotope Chemistry and Metabolite Synthesis,
Alnwick Research Centre, Willowburn Avenue, Alnwick, Northumberland,
U.K. NE66 2JH
1
2
3
4
5
CH3
CH3
Cyclopropyl
Cyclopropyl
Cyclopropyl
Water
15 h
24 h
12 h
6 h
9%
50%
50%
77%
Carbonic acid solution
Carbonic acid solution
Water & Hu¨nig’s base (3 eq)
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data, 1H and13C NMR spectra, and optimisation
of the one-pot reaction. See DOI: 10.1039/b719675j
CH2Cl2 & Hu¨nig’s base (3 eq) 12 h
90–94%
988 | Org. Biomol. Chem., 2008, 6, 988–991
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Table 2 Screening for the optimum solvent
Table 3 The synthesis of amino nitriles
Amino nitrile
R1
R2
Reaction time
Yield
1a
5b
6c
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C4H9
20 h
20 h
20 h
20 h
20 h
40 h
24 h
20 h
30%
82%
C5H11
Entry
Solvent
Yield
tBu
23%
2c
Cyclopropyl
Ph
3-MeOPh
Ph
62%e/88%f
46%
1
2
3
4
5
6
Dichloromethane
Ethyl acetate
Ethanol
Diethyl ether
Toluene
90–94% (n = 2)
61–80% (n = 2)
71–75% (n = 2)
65%
7d
8d
9d
10c
41%
24%
7%
C4H9
45%
Water
32–75%a
a Conditions used: KCN, NH4Cl, H2O, rt.33 b Conditions used: KCN,
◦
NH4Cl, NH4OH, H2O, MeOH, 4 C → rt.34 c Conditions used: KCN,
a Adding solid CO2 gave 75% yield, bubbling CO2 (g) gave 32% yield.
◦
NH4Cl, NH4OH, H2O, 4 C → rt.34 d Conditions used: KCN, NH4Cl,
DMSO, H2O, rt.35 e Isolated as HCl salt. f Isolated as the free amino nitrile.
nitrile was hydrolysing to give the ketone, hydrogen cyanide and
ammonia. The ammonia might then act as a base, either preventing
further amino nitrile hydrolysis, or playing a role in the reaction
itself. To investigate whether the addition of a base would improve
the yield of hydantoin 4, the reaction was repeated in the presence
of Hu¨nig’s base (3 equivalents) and a yield of 77% was obtained. At
this stage our working hypothesis was that the carbon dioxide was
dissolving in the water to form carbonic acid and this was reacting
with the amino nitrile. We were thus gratified to find that, when
dichloromethane was employed as the solvent, 2 was converted to
the corresponding hydantoin (4) in excellent (90–94%) yield. This
high yield was maintained when strictly anhydrous conditions were
employed. Failure to include Hu¨nig’s base resulted in no product
formation, indicating that the base plays a vital role in the reaction
when organic solvent is used.
Table 4 Scope of the amino nitrile to hydantoin reaction
Hydantoin
R1
R2
Reaction timea
Yield
11
12
13b
13b
4
14
15
16
17
Ph
H
17 h
9 h
73%
87%
0%
62%
94%
90%
60%
62%
47%
C5H11
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C4H9
tBu
18 h
17 h
12 h
20 h
24 h
12 h
14 h
tBu
Cyclopropyl
Ph
3-MeOPh
Ph
C4H9
Using dichloromethane as the solvent, a range of bases was
investigated. Both Hu¨nig’s base and triethylamine promoted the
formation of 4 in excellent yield. Pyridine and DBU failed to
promote hydantoin formation of 4, indicating that those bases
with a pKb of approximately 11 are optimal. However, pKb is not
the only factor that affects the reaction, as the use of tributylamine
(pKb = 10.9) only afforded a 14–25% yield of the hydantoin 4.
Having established that either triethylamine or Hu¨nig’s base
would effectively promote hydantoin formation, a range of
reaction solvents were investigated, but none was superior to
dichloromethane (Table 2). The reaction proceeded in good yield
when ethyl acetate, ethanol and diethyl ether were used as solvents.
Moderate yields were obtained when toluene and water were used.
A range of amino nitriles (1, 2, 5–10) was then chosen so as
to investigate the scope of the reaction. The amino nitriles were
synthesised as shown in Table 3. Problems with solubility were
encountered during the synthesis of the aromatic amino nitriles,
hence DMSO or methanol was used as a co-solvent. The isolation
of pure amino nitriles proved a challenge and we eventually found
it convenient to purify the amino nitriles by crystallisation as their
hydrochloride salts.
a Time of exposure to CO2. b Ethanol was used as the solvent as pinacolone-
derived amino nitrile is insoluble in dichloromethane.
The reaction times vary as each reaction was continued until no
starting material was present by TLC analysis. In the case of 13,
successful reaction was only observed when using ethanol as a sol-
vent, due to the insolubility of 6 (free amine) in dichloromethane.
Both the steric and electronic nature of the amino nitrile affect
the reaction, as lower yields were observed when 8 and 9 were
subjected to the reaction conditions. In contrast, 7 was converted
into the corresponding hydantoin in excellent yield (90%). It
proved impossible to isolate 2-amino-2-phenylacetonitrile using
the above conditions, however, commercially obtained material
was used to evaluate the conversion of this amino nitrile to
the corresponding hydantoin (11). Both N-allyl and N-benzyl
substituted aminonitriles, derived from cyclopropyl methyl ketone
and the corresponding primary amine, were submitted to our
optimised conditions. In neither case was any hydantoin formed.
This seems to indicate that N-substitution interferes with the
formation of a hydantoin.
The amino nitrile salts were converted to the free amino nitriles,
and these were transformed to hydantoins using the conditions
described in Table 4. It can be seen that both aliphatic and aromatic
methyl ketones can be converted to the corresponding hydantoins
in good yield.
Although the above conversion of amino nitriles to hydantoins
is useful, it is limited by the difficulty associated with the isolation
and purification of the amino nitriles. It was therefore desirable
to develop a one-pot synthesis of hydantoins from ketones or
aldehydes. The formation of imines from aldehydes and amines is
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often spontaneous. However, the formation of imines from amines
and the less electrophilic ketones often requires the presence of a
Brønsted or Lewis acid catalyst. The formation of an amino nitrile
from an imine may also require the presence of a Brønsted or Lewis
acid. In addition, it is possible that the addition of a Lewis acid
may assist in the conversion of the amino nitrile to hydantoin,
by interaction with carbon dioxide. Olah and co-workers have
recently shown that a range of N-substituted amino nitriles can
be formed from the corresponding amine, ketone and TMSCN
using gallium(III) triflate as a Lewis acid catalyst.36 We have
extended these conditions to use ammonia, giving the free amino
nitriles, which were then transformed in situ to the hydantoin.
Optimisation studies (Scheme 2 and see ESI†) were conducted on
2-acetonaphthalene (18), as it had proved impossible to isolate
a pure sample of the corresponding amino nitrile for use in the
reaction described above.
Fig. 1 Comparison of yields in the one- and two-pot conversions of
ketones and aldehydes to hydantoins. 11: R1 = Ph, R2 = H; 12: R1
=
t
C5H11, R2 = Me; 13: R1 = Bu, R2 = Me (EtOH is solvent); 4: cyclopropyl,
R2 = Me; 19: R1 = naphthyl, R2 = Me; 14: R1 = Ph, R2 = Me; 15: R1 =
3-MeOPh, R2 = Me; 16: R1 = Ph, R2 = Et; 17: R1 = C4H9, R2 = C4H9.
Scheme 2 The optimised conditions for the conversion of 2-acetonaph-
thalene to its corresponding hydantoin.
The methodology described herein represents a significant ad-
vance over the existing Bucherer–Bergs reaction for the synthesis
of hydantoins. In the first instance we developed conditions for
the synthesis of hydantoins from amino nitriles. Although one
example of this transformation existed in the early literature,31 we
have demonstrated that the solvent can be changed from water
to a range of organic solvents and discovered that the inclusion
of Hu¨nig’s base or triethylamine is required for the reaction
to progress in good yield. Despite these advances, however, we
have found that the synthesis and purification of unsubstituted
amino nitriles can be challenging, mainly resulting from the
difficulty of isolating the amino nitriles or their salts. In order
to address this problem, we have developed a one-pot, gallium(III)
triflate-catalysed synthesis of hydantoins. Our methodology has a
number of advantages over the existing Bucherer–Bergs reaction.
Firstly, the use of organic, rather than aqueous, solvents makes
the reaction applicable to a wide range of substrates. Secondly,
the lower temperature at which the reaction is conducted avoids
complications related to the volatility of the ammonium carbonate.
In addition, it is operationally simple to carry out the one-pot
reaction on both aldehydes and ketones.
The optimum conditions were found to involve the addition of
liquid ammonia at −78 ◦C followed by stirring at this temperature
for 3 h with gallium(III) triflate. The hydrogen cyanide solution in
dichloromethane was added at −78 ◦C and the reaction solution
allowed to warm to room temperature with stirring over 24 h,
resulting in the evaporation of most of the liquid ammonia and
leaving the dichloromethane solvent present. Hu¨nig’s base was
added and the carbon dioxide bubbled through the reaction
solution. When the gallium(III) triflate was excluded from the
reaction solution no product was isolated, indicating that Lewis
acid catalysis is required for either the formation of the imine or
formation of both the imine and the amino nitrile. Although these
conditions only gave modest yields (∼50%), they were applied
to a range of ketones in order to investigate the scope of the
reaction. It can be seen from Fig. 1 (dark bars) that the conversion
of aldehydes and ketones to the corresponding hydantoins was
achieved in modest to excellent yield (25–98%). Benzaldehyde,
heptan-2-one and cyclopropylmethyl ketone all underwent the
transformation in excellent yield. Ketone-derived hydantoins
with aromatic substituents were formed in more modest yields,
presumably due to the less electrophilic nature of the ketone. The
extended chain 17 was also formed in good yield. The yields for the
two-pot reaction (Fig. 1, light bars) are obtained by combining the
yields from Table 3 and Table 4. In all cases it can be seen that the
yields of the one-pot reaction are equal to or higher than those of
the two-pot reaction, demonstrating the advantages of the one-pot
approach. It should be noted that the one- and two-pot procedures
cannot be directly compared, as gallium(III) triflate is used in the
one-pot procedure, but not the two-pot procedure and hence two
different reactions are being considered. All compounds isolated
displayed analytical and spectroscopic data consistent with the
assigned structure.†
In summary, we have synthesised a range of 5-substituted and
5,5-disubstituted hydantoins from the corresponding aldehydes
and ketones in a one-pot procedure. We have demonstrated clearly
that gallium(III) triflate catalysis is required for this reaction to
progress.
Acknowledgements
The authors are grateful to the BBSRC and sanofi-aventis for
funding. The authors thank the technical staff of the University
of St Andrews for elemental analysis and mass spectrometry data,
and the EPSRC National Mass Spectrometry Centre for mass
spectrometry data.
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