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.
(32) Lazarus, R. A. J. Org. Chem. 1990, 15, 4755–4757.
(33) Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem.
2005, 16, 6369–6377.
(26) Mills, J. E.; Maryanoff, C. A.; Cosgrove, R. M.; Scott, L.; McCom-
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