Preparation of hydantoins by catalytic oxidative carbonylation of α-amino amides

Article abstract of DOI:10.1021/jo9016138

(Chemical Equation Presented) Hydantoins can be synthesized from the corresponding amino amides employing oxidative catalytic carbonylation using W(CO)₆ as the catalyst, I₂ as the oxidant,COas the carbonyl source, andDBUas base. Secondary amides afford the hydantoins in good to excellent yields, which decrease as the steric bulk of the N-alkyl substituent increases. 2009 American Chemical Society.

Full text of DOI:10.1021/jo9016138

pubs.acs.org/joc
solution-phase7-12 and solid-phase synthesis5,13 to prepare
Preparation of Hydantoins by Catalytic Oxidative
Carbonylation of r-Amino Amides
substituted hydantoins. The use of phosgene13 and its deri-
vatives has also been reported.12,14
To address various safety and environmental concerns15
associated with the use of phosgene and its derivatives, we
have previously reported the use of W(CO)6-catalyzed oxi-
dative carbonylation to afford cyclic ureas from primary and
secondary diamines.16-21 Herein, we would like to report the
synthesis of a series of C-5 substituted hydantoins starting
from enantiomerically pure R-amino amides via W(CO)6-
catalyzed carbonylation using I2 as oxidant (eq 1, Table 1).
Seth M. Dumbris, Delmy J. Dıaz, and
Lisa McElwee-White*
Department of Chemistry and Center for Catalysis,
University of Florida, Gainesville, Florida 32611-7200
lmwhite@chem.ufl.edu
Received August 10, 2009
Amino amides 1-4 were synthesized by reaction of the
corresponding amino acid methyl ester hydrochloride with
an amine12 (eq 2, Table 2). After purification, 1 was chosen as
substrate for optimization of the carbonylation conditions.
Initial attempts using conditions previously successful with
amino alcohol substrates21 failed to generate any observable
hydantoin. Failure to form hydantoin 1a (eq 1) under the
optimal carbonylation conditions for amines is not surpris-
ing, however, as the amide moiety of 1 is much less nucleo-
philic than the substrates we have previously studied.
Hydantoins can be synthesized from the corresponding
amino amides employing oxidative catalytic carbonyla-
tion using W(CO)6 as the catalyst, I2 as the oxidant, CO as
the carbonyl source, and DBU as base. Secondary amides
afford the hydantoins in good to excellent yields, which
decrease as the steric bulk of the N-alkyl substituent
increases.
Hydantoins have been of considerable interest as they are
frequently found as crucial moieties in many biologically
active molecules. More specifically, hydantoins substituted
at C-5 constitute an important class of heterocycles in
medicinal chemistry since derivatives are associated with a
wide range of biological properties including anticonvul-
sant,1 antidepressant,2,3 antiviral2,3 and platelet inhibitory
activities.4
Various synthetic methods exist to afford hydantoins from
diverse starting materials. Classical routes include reaction
of ureas with carbonyl compounds5 and the Bucherer-Bergs
route involving inorganic cyanide with carbonyl com-
pounds.6 A variety of additional methods utilize both
To overcome this problem, higher temperatures, longer
reaction times, other solvents, and a variety of bases were
studied (Table 3).22 The critical variable was the choice of
base. Entry 10 shows the optimized conditions utilizing DBU
(10) Talaty, E. R.; Yusoff, M. M.; Ismail, S. A.; Gomez, J. A.; Keller, C.
E.; Younger, J. M. Synlett 1997, 683–684.
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McElwee-White, L. J. Org. Chem. 2000, 65, 5216–5222.
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Kokka, M.; McElwee-White, L. J. Org. Chem. 2002, 67, 4086–4092.
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8862 J. Org. Chem. 2009, 74, 8862–8865
Published on Web 10/28/2009
DOI: 10.1021/jo9016138
r
2009 American Chemical Society

Dumbris et al.
JOCNote
TABLE 1. Substitution Patterns of 1-8 and 1a-8a
SCHEME 2. Synthesis of 6-9
compound
R1
R2
R3
R4
1
2
3
4
5
6
7
8
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2OH
CH2Ph
Ph
H
H
H
H
H
H
Ph
Ph
H
H
H
H
H
CH2Ph
H
H
CH3
CH2CH3
(CH3)2CH
CH2Ph
CH2Ph
H
CH2Ph
H
Ph
TABLE 2. Yields of 1-4 from the Amino Acid Methyl Ester
compound
yield (%)
1
2
3
4
90
82
74
84
TABLE 3. Optimization of Conditions for W(CO)6/I2 Carbonylation of
R-Amino Amide 1
time
(h)
CO
(atm)
temp
(°C)
base/
equiv
yield
(%)
entry
solventa
CH2Cl2
CH2Cl2
1
2
3
4
5
6
7
8
9
10
24
36
45
36
42
36
36
36
48
36
80
90
80
90
90
85
85
85
85
80
45
55
25
50
50
45
45
45
45
45
Py/2
Py/2
Py/2
K2CO3
DMAP/2
DMAP/3
DMAP/3
DMAP/4
DMAP/4
DBU/4
0
40
0
20
0
TABLE 4. Yields of Hydantoins 1a-8a from W(CO)6/I2 Carbonyla-
tion of 1-8
CH2Cl2
R-amino amide
product
yield (%)
CH2Cl2/H2O
CH2Cl2
toluene
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
DCE
1
2
3
4
1a
2a
3a
4a
5a
6a
7a
8a
73
61
trace
75
50
41
11
64
0
50
50
trace
72
5
6a
7a
8a
aThe solution concentration of entry 1 was 4 M (0.87 mL of solvent);
all others were conducted at 0.031 M (35 mL of solvent).22
aConditions for carbonylation were 1.1 equiv of DBU, 35 °C, 24 h
with CH2Cl2 as solvent. Other conditions are as reported for optimiza-
tion of 1 to 1a.
SCHEME 1. Synthesis of 5
use 7 as a precursor to 8 failed as we could not find conditions
to remove the benzyl unit by hydrogenation. Amino amide 8
was instead synthesized by treatment of the Boc-protected
amino acid 9 with SOCl2 followed by addition of a saturated
solution of ammonia in THF. This procedure proved for-
tuitous as it also resulted in the removal of the Boc protecting
group to afford 8 in an overall yield of 88%.
as the base and 36 h reaction time. Product decomposition
was observed at longer reaction times.
Amino amides 5-9 could not be obtained in acceptable
quantities via the route in eq 2, so alternative methods were
employed for their synthesis. Substrate 5 was prepared using
a mixed anhydride coupling procedure23 (Scheme 1), afford-
ing a yield of 71% from the amino acid.
The secondary amino amide 6 (Scheme 2) was synthesized
in an overall yield of 72% according to literature precedent
by condensation of L-phenylalanamide with benzaldehyde
followed by reduction with NaBH4.24 Compounds 7 and 8
were both synthesized from the N-Boc-protected amino acid
9. Conversion of 9 to 7 was then realized in 81% yield
utilizing a benzotriazole-mediated coupling.25 Attempts to
Substrates 1-8 were then carbonylated using the condi-
tions optimized for the conversion of 1 to 1a (Table 4).
Hydantoins 1a-8a were obtained in moderate to good
yields. The yields of 1a-4a from amino amides 1-4 show
the effects of steric variation in the amide N-alkyl group on
the ring closure. The yields were highest from substrates 1, 2,
and 4 (R4 = Me, Et, Bn), which have no branching at the
R-carbon of the substituent. The effect of a secondary alkyl
substituent is seen with 3 (R4 = iPr), for which the hydantoin
product 3a was produced in only trace quantities. Similar
effects have been observed previously in the carbonylation of
secondary diamines containing these N-alkyl substituents.17
Compound 6, the constitutional isomer of 4, afforded
hydantoin 6a in 41% yield under slightly different condi-
tions. Although 6 is more nucleophilic than 4, it illustrates
the effect that steric bulk at the amine nitrogen has on this
system as 6a could only be obtained in about half the yield of
4a. Hydantoin 8a is the pharmaceutical phenytoin, which is
(23) Andurkar, S. V.; Stables, J. P.; Kohn, H. Tetrahedron: Asymmetry
1998, 9, 3841–3854.
(24) Bailey, P. D.; Bannister, N.; Bernad, M.; Blanchard, S.; Boa, A. N.
J. Chem. Soc., Perkin Trans. 1 2001, 3245–3251.
(25) Wolin, R. L.; Venkatesan, H.; Tang, L.; Santillan, A., Jr.; Barclay,
T.; Wilson, S.; Lee, D. H.; Lovenberg, T. W. Bioorg. Med. Chem. 2004, 12,
4477–4492.
J. Org. Chem. Vol. 74, No. 22, 2009 8863

Dumbris et al.
JOCNote
an anticonvulsant used in the treatment of seizures. It was
obtained in an optimized yield of 64% but required a switch
to DCM as the solvent as an unidentified oligomerization
occurred in DCE. Although amines are known to react with
chlorinated solvents,26 no products of reaction with DCE
were observed, and we attribute the higher yields of hydan-
toins in DCM to higher solubility of the substrate. Unfortu-
nately, decomposition of 8 to produce benzophenone is
competitive with product formation, even when milder con-
ditions using less base and much shorter reaction times are
employed. Hydantoin 7a could be obtained in 11% yield, but
decomposition of 7 to benzophenone appears to be faster
than carbonylation. One possible explanation for the lower
yields of hydantoins from primary amides as compared to
their secondary counterparts is that decomposition of the
starting material is competitive with product formation.
Despite the lower nucleophilicity of the amide nitrogen
compared to that of the amine, no symmetrical acyclic ureas
were detected in reaction mixtures from any of the sub-
strates. The mechanism for carbonylation of R-amino
amides 1-8 has not been elucidated. Our previous studies
of higher valent tungsten catalysts suggest the intermediacy
of either free or coordinated isocyanates,27 a mechanism that
is also precedented in other literature.28 This mechanism is
possible for most of the R-amino amides studied here.
However, the secondary amino amide 6 cannot form an
isocyanate intermediate but still yields hydantoin 6a, ruling
out the intermediacy of an isocyanate for that particular
substrate.
Other group VI metal carbonyls such as chromium hexa-
carbonyl and molybdenum carbonyl have been previously
investigated as catalysts for the oxidative carbonylation of
amines.17 However, tungsten hexacarbonyl afforded higher
yields of ureas from primary and secondary aliphatic amines.
Similar experiments were carried out for the amino amide
substrate 1 using Mo(CO)6 and Cr(CO)6 as catalysts. How-
ever, the yield obtained for the hydantoin 1a was 20% in the
case of Mo, while the Cr catalyst produced an inseparable
mixture.
In summary, we have shown that W(CO)6-catalyzed oxi-
dative carbonylation of amino amides results in moderate-
to-good yields of hydantoins. Steric hindrance at the amine
nitrogen has an effect on the yield, and decomposition of the
substrate is competitive with product formation in a few
cases. The use of our catalytic oxidative carbonylation reac-
tion provides an alternative to other existing methodologies
for hydantoin synthesis and can successfully yield hydan-
toins from primary-amino-secondary amides in good yields.
N-Benzyl-r,r-diphenylglycamide (7). The Boc-protected ami-
no acid 9 was converted to the amide via benzotriazole-mediated
coupling.25 After workup, the mixture was then deprotected
using 5 molar equiv of 4.0 M HCl in dioxane and stirred
overnight. The resulting mixture was purified on silica using a
solvent gradient from DCM to 90:10 DCM/MeOH to afford 7
in 72% yield. The product was identified by comparison to
literature data.29
r,r-Diphenylglycamide (8). The Boc-protected amino acid 9
(1.00 g, 3.18 mmol) was dissolved in 20 mL of DCM and brought
to reflux under Ar, according to a procedure adapted from the
literature.30 Then SOCl2 (1.13 g, 9.54 mmol) was added, and the
mixture continued to reflux for 3 h. After cooling, the acid
chloride solution was evaporated in vacuo, and 50 mL of THF
saturated in ammonia was slowly added. The reaction mixture
was stirred overnight. The excess ammonia was removed by
sparging with N2, and the concentrate was dissolved in DCM
and washed once with H2O. The organics were separated and
dried over MgSO4. The reaction mixture was purified by column
chromatography (95:5 DCM/MeOH) on silica to afford 8 in
95% yield. The compound was identified by comparison to
literature data.31
N-Boc-r,r-Diphenylglycine (9). The commercially available
R,R-diphenylglycine (2.26 g, 10 mmol) was slurried in 80 mL of
acetonitrile and dissolved in a minimum amount of 25% (w/w)
tetramethylammonium hydroxide in water. Di-tert-butyldicar-
bonate (5.00 g, 25 mmol) was added over a 3 day period and
allowed to stir for a total of 4 days until TLC indicated that the
reaction was complete. The mixture was then concentrated
under reduced pressure and dissolved in 150 mL of EtOAc
and acidified to pH 3-4 using 1.0 M HCl. The organics were
separated, and the aqueous material was extracted twice with
EtOAc. The organics were combined, washed with brine, and
then dried over MgSO4. The product was obtained in 92% yield
following column chromatography (97:3 DCM/MeOH) on
silica, and the pure compound was identified by comparison
to literature data.25 Yield, 92%.
General Procedure A for Catalytic Carbonylation of 1-5.22 To
a 300 mL glass lined Parr high-pressure vessel containing 35 mL
of 1,2-dichloroethane were added R-amino amide 1 (400 mg,
2.2 mmol), W(CO)6 (56 mg, 0.16 mmol), I2 (396 mg, 1.56 mmol),
and DBU (1.34 mL, 8.96 mmol). The vessel was then charged
with 80 atm CO and heated to 45 °C for 36 h with constant
stirring. The pressure was released, and 15 mL of water was
added. The organics were then separated and washed separately
with Na2SO3 and with 0.1 N HCl. The aqueous layer was
extracted with EtOAc (20 mLÂ4). The combined organic layers
were dried with MgSO4, filtered, and concentrated. The result-
ing residue was purified via column chromatography on silica
using DCM/EtOAc (80:20) to afford hydantoin 1a in 72% yield.
The same procedure was applied to prepare hydantoins 2a-5a,
which were identified by comparison to literature data.12,32,33
General Procedure B for Catalytic Carbonylation of 6-8. To a
300 mL glass lined Parr high-pressure vessel containing 20 mL
of DCM were added R-amino amide 8 (250 mg, 1.1 mmol),
W(CO)6 (29 mg, 0.081 mmol), I2 (195 mg, 0.77 mmol), and DBU
(0.184 mL, 1.22 mmol). The vessel was then charged with 80 atm
CO and heated to 35 °C for 24 h with constant stirring. The
pressure was released, and 20 mL of 95:5 (DCM/MeOH) was
added. The organics were then immediately washed with
Na2SO3 and separated. The aqueous layer was then extracted
Experimental Section
General. All reactions were conducted under an inert argon
atmosphere using oven-dried glassware unless otherwise noted.
All column chromatography used Fisher brand 230-400 mesh
silica gel. Reagents and solvents were purchased and used
without further purification. Caution: Adequate ventilation
and shielding equipment are required when using high pres-
sure CO.
(29) Duschinsky, R. U.S. Patent 2642433, 1953.
(30) Zhao, M.-X. W. S.-M. Tetrahedron: Asymmetry 2002, 13, 1695–
1702.
(31) Edward, J. T.; Lantos, I. Can. J. Chem. 1967, 1925–1934.
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sey, D. F. Org. Prep. Proced. Int. 1984, 16, 97–114.
(27) McCusker, J. E.; Logan, J.; McElwee-White, L. Organometallics
1998, 17, 4037–4041.
(28) Jetz, W.; Angelici, R. J. J. Am. Chem. Soc. 1972, 94, 3799–3802.
8864 J. Org. Chem. Vol. 74, No. 22, 2009

Dumbris et al.
JOCNote
with ethyl acetate (2 Â 20 mL). The combined organic layers
were dried with MgSO4 and concentrated. The resulting residue
was purified via column chromatography on silica using DCM/
EtOAc (80:20) to afford hydantoin 8a in 64% yield. Identifica-
tion of 8a was made by comparison to a commercially available
sample. The same procedure was applied to prepare hydantoins
6a and 7a, which were identified by comparison to literature
data.34,35
Acknowledgment. We thank the donors of the American
Chemical Society Petroleum Research Fund for support of
this work through the Green Chemistry Institute. We would
also like to thank Jennifer Johns for her help in synthesis and
isolation of compounds.
Supporting Information Available: 1H NMR spectra of
compounds 7-9, 1a, 2a, and 4a-8a. Previously unreported
spectral data (1H NMR, 13C NMR and IR) for known com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(34) Sanders, M. L.; Donkor, I. O. Synth. Commun. 2002, 7, 1015–1021.
ꢀꢁ
ꢁ
ꢁ
(35) Banjac, N.; Uscumlic, G.; Valentic, N.; Mijin, D. J. Solution Chem.
2007, 36, 869–878.
J. Org. Chem. Vol. 74, No. 22, 2009 8865