Palladium Catalyzed C-Arylation of Amino Acid Derived Hydantoins

Article abstract of DOI:10.1021/acs.orglett.5b01803

Palladium(II) trifluoroacetate (5 mol %) catalyzes the C-arylation of N,N-disubstituted hydantoins by aryl iodides in good yield. The reaction proceeds through base-promoted enolization of the amino acid derived hydantoins, and the resulting 5,5-disubstituted hydantoins may be deprotected at one or both N atoms to yield biologically active structures or alternatively hydrolyzed to the parent α-aryl α-amino acids. The reaction is successful with a variety of parent amino acids and a range of electron-rich and electron-poor aryl iodides.

Full text of DOI:10.1021/acs.orglett.5b01803

Letter
pubs.acs.org/OrgLett
Palladium Catalyzed C‑Arylation of Amino Acid Derived Hydantoins
Fernando Fernandez-Nieto,† Josep Mas Rosello,† Simone Lenoir,† Simon Hardy,‡
́
́
and Jonathan Clayden*,†
†School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
‡Syngenta Ltd., Jealott’s Hill Research Centre, Bracknell, Berkshire, RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: Palladium(II) trifluoroacetate (5 mol %)
catalyzes the C-arylation of N,N-disubstituted hydantoins by
aryl iodides in good yield. The reaction proceeds through base-
promoted enolization of the amino acid derived hydantoins,
and the resulting 5,5-disubstituted hydantoins may be
deprotected at one or both N atoms to yield biologically
active structures or alternatively hydrolyzed to the parent α-
aryl α-amino acids. The reaction is successful with a variety of
parent amino acids and a range of electron-rich and electron-
poor aryl iodides.
Scheme 1. General Approach to Quaternary 5-Arylated
Hydantoins and Quaternary α-Aryl α-Amino Acids
he hydantoin motif is found in numerous drugs and
bioactive natural products.1,2 Its value in organic chemistry
T
is further enhanced by its utility as an intermediate in the
synthesis of natural and unnatural α-amino acids,3 particularly by
Bucherer−Bergs chemistry.4 Of the many possible nonproteino-
genic α-amino acids, α,α-disubstituted quaternary amino acids
are of particular importance in both medicinal and structural
biological chemistry.5,6 Many methods exist for the α-alkylation
of α-amino acids, but α-arylation remains challenging.
Because of the specific challenges of reactivity evident in the
coupling of an enolate nucleophile with an aryl electrophile, the
α-arylation of carbonyl compounds in general is an important
transformation that has received considerable attention in recent
years.7 Arylation of amino acid enolates may be achieved using
rearrangement chemistry,8 but the direct C-arylation of a tertiary
amino acid would constitute a particularly efficient method for
the preparation of α-arylated quaternary amino acids. The use of
a transition metal catalyst9 has led to a small selection of methods
allowing the coupling of an sp2 carbon with an amino acid derived
enolate, but to date these are far from general with regard to
amino acid and aryl coupling partners.10 α-Arylations have been
carried out with a limited number of amino acids using
palladium11 or iron12 catalysis, and with stoichiometric amounts
of aryl metal13 or diaryliodonium14 species, or with more toxic
arenechromium tricarbonyl complexes.15
In this work we show that direct α-arylation of the hydantoin
derivatives of readily available amino acids provides a short,
general route to 5,5-disubstituted hydantoins, and hence also to
quaternary α-aryl amino acids in racemic form. Our general
synthetic approach to the quaternary amino acids is detailed in
Scheme 1 and entails the construction of hydantoins 5 carrying
suitable base-stable N-protecting groups from amino esters 1 by
reductive amination with p-anisaldehyde,16 urea formation with
tert-butyl isocyanate, and base-promoted ring closure.17 C-
Arylation of hydantoins 5 yields 8, from which acid-catalyzed
deprotection and base-catalyzed ring cleavage provide the
quaternary amino acids 2.
Hartwig had previously reported the arylation in moderate to
good yield of azlactone derivatives of unfunctionalized/branched
amino acids,11b but we were first alerted to the susceptibility of
hydantoins to C-arylation during the attempted N-arylation of
urea 9 during a related project (Scheme 2).8a,b Rather than the
desired N-pyridyl urea 10, the C-arylated hydantoin 11a was
formed. Stepwise arylation, under similar conditions, of the
hydantoin 12 (presumably an intermediate in the formation of
11a) with bromobenzene gave a good yield of 11b.
Trial couplings of related alanine-derived hydantoins 3 and 4
(Scheme 1) with bromobenzene gave the products 6 (Ar = Ph)
in 65% yield and 7 (Ar = Ph) in 80% yield, suggesting the
Received: June 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. A Hydantoin Arylation
Scheme 3. Arylation of α-Amino Acid Derived Hydantoins
hydantoin arylation might turn out to be a general method for
quaternary amino acid synthesis.
Encouraged by this preliminary work, we proceeded to
develop a more versatile approach to both hydantoins and
quaternary amino acids, by replacing the various less easily
removable N-substituents of 3, 4, and 12 by the simple acid-labile
protecting groups of 5 (Scheme 1). Initial explorations of the α-
arylation of the enolate derivatives of hydantoins 5 were carried
out using the alanine-derived substrate 5a (R1 = Me) in the
presence of halobenzenes and a palladium catalyst. A range of
conditions were screened, as shown in Table 1.
Initially, several bases were tested (Table 1, entries 1−6), and
under typical enolate arylation conditions,11 using Xantphos as a
ligand, only NaHMDS or KHMDS gave the desired arylated
hydantoin 8a, in moderate yield. Aiming to improve upon these
results, we next screened a range of palladium catalysts,
maintaining NaHMDS as the base (entries 7−10). We found
that the yield was increased markedly, to 82%, with Pd(TFA)2 as
the source of Pd(II). No benefit was obtained either by changing
to KHMDS (entry 11) or by varying the bulky phosphine ligand
(entries 12, 13). Using bromobenzene as an arylating agent still
a
Reactions were conducted with PhI (1.5 equiv), Pd(TFA)2 (5 mol
%), Xantphos (10 mol %), ZnF2 (1.5 equiv), NaHMDS (2 equiv).
gave product, but in lower yield (entry 14). Other solvents (1,4-
dioxane and DMF) were as effective as toluene (entries 15, 16),
but the best results were obtained by adding 1.5 equiv of ZnF2 to
a
Table 1. Optimization of Reaction Conditions for the Arylation of 5a
b
c
entry
base
[Pd]
L
solvent
Ar−X
yield 8a/%
d
1
K3PO4
NaOtBu
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(acac)2
Pd(hacac)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L1
L1
L1
L1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−I
Ph−Br
Ph−I
Ph−I
Ph−I
−
d
2
−
d
3
LDA
−
d
4
LiHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
−
5
38
52
25
32
48
84
61
6
7
8
9
10
11
12
13
14
15
16
17
de
,
−
−
d
e
37
81
86
92
1,4-dioxane
DMF
toluene + Ph−I of ZnF2
a
b
Reactions were conducted with [Pd] (5 mol %), L (10 mol %), base (200 mol %), and Ph−X (150 mol %). Ligand L1, Xantphos; L2,
c
d
e
NiXantphos; L3, P(tBu)3. Isolated yield. 5a recovered unchanged. No reaction with chlorobenzene.
B
DOI: 10.1021/acs.orglett.5b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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a
Scheme 4. Scope of the Aryl Coupling Partner
Scheme 6. Cleavage to Quaternary α-Aryl Amino Acids
products 8ea and 8fa. Proline and pipecolic acid provided the
quaternary bicyclic compounds 8ga and 8ha also in remarkably
good yield. All chiral products formed from the couplings were
racemic.
The coupling partner was also varied, with a number of
different iodoarenes carrying electron-rich and electron-poor
groups in different positions on the aromatic ring screened for
successful coupling with acyclic (Ala) and cyclic (Pro) amino
acid derived hydantoins 5a and 5g (Scheme 4).
Iodoarenes bearing electron-donating (methyl, methoxy)
substituents in ortho, meta, and para positions all coupled
reasonably well, providing the corresponding quaternary
hydantoins 8ab, 8ac, and 8gc in moderate yields. Rings carrying
electron-withdrawing groups such as a methyl ester, a
trifluoromethyl group, and a nitrile also proved to be compatible
with the reaction conditions, affording 8ad, 8ae, and 8gd in good
yields. A 2-naphthyl group was coupled successfully to give the
hindered product 8gb in good yield. Halogen atoms in different
positions, namely ortho-F, meta-Cl, and para-Br, were tolerated,
providing the hydantoins 8ge, 8gf, and 8af respectively. Even the
electron-deficient and electron-rich heteroaryl iodides 2-
iodopyridine and 3-iodothiophene produced satisfactory results
(8ag, 8gg) in a similar yield.
The products 8 are N-protected analogues of some important
biologically active hydantoins.19 Both the p-methoxybenzyl and
tert-butyl protecting groups could be removed simultaneously by
treatment with methanesulfonic acid in refluxing dichloro-
methane.20 As shown in Scheme 5, this allowed us to make the
anticonvulsant agents phenytoin 13 and, after selective
methylation of the more acidic 3-position, mephenytoin 14.
On the other hand, selective orthogonal cleavage of the PMB
group from the 1-position with ceric ammonium nitrate revealed
an N3-protected hydantoin that could be methylated at N1.
Acidic cleavage of the tert-butyl group resulted in compound 15,
a regioisomeric analogue of mephenytoin.
a
Reactions were conducted with Ar−I (1.5 equiv), Pd(TFA)2 (5 mol
%), Xantphos (10 mol %), ZnF2 (1.5 equiv), NaHMDS (2 equiv).
Scheme 5. Synthesis of Pharmaceutically Active Hydantoins
Further base-promoted hydrolysis of the fully deprotected
hydantoins led to the quaternary α-aryl amino acids 2 in racemic
form, as illustrated for two examples, α-phenylalanine and α-(3-
chlorophenyl)proline in Scheme 6.21 The route from 1 to 2, via 5
and 8 (illustrated in Scheme 1), thus constitutes a divergent
method for the racemic α-arylation of natural and unnatural
amino acids.
In summary, intermolecular palladium-catalyzed α-arylation of
the enolates of amino acid derived N-protected hydantoins has
been achieved for the first time, using readily available starting
materials. The optimized protocol provides a valuable tool for the
synthesis of 5-aryl hydantoins (including biologically active
compounds such as phenytoin or mephenytoin) and, after
deprotection and hydrolysis, α-arylated quaternary amino acids.
Previous methods for the direct intermolecular α-arylation of
amino acid derivatives required either electron-deficient aryl
the reaction mixture18 (entry 17) to act as a Lewis acid and
possibly to transmetallate to a zinc enolate.
Using these optimized conditions, α-phenylation was
successful with substrates carrying a range of different side
chains (Scheme 3). For example, phenylglycine-derived
hydantoin 5b gave 5,5-diphenyl hydantoin 8ba, and amino
acids with linear alkyl substituents, namely 2-aminobutyric acid
(butyrine) and methionine, led to 5-phenylated hydantoins 8ca
and 8da in 85% and 51% yield, respectively. The reaction was
also successful with bulkier aliphatic and aromatic side chains:
leucine and phenylalanine-derived hydantoins giving phenylated
C
DOI: 10.1021/acs.orglett.5b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
partners10d,e or stoichiometric reagents,13−15 or were limited to
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arylation.22
Reedijk, J., Ed.; Elsevier: Oxford, 2015 [doi:10.1016/B978-0-12-
409547-2.11043-1].
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Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01803.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clayden@man.ac.uk.
Notes
The authors declare no competing financial interest.
Kundig, E. P. Chem. Commun. 2008, 4040−4042.
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(12) Li, K.; Tan, G.; Huang, J.; Song, F.; You, J. Angew. Chem., Int. Ed.
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ACKNOWLEDGMENTS
■
This work was funded by the Xunta de Galicia (plan I2C,
postdoctoral fellowship to F.F.N.), the EPSRC (studentship to
J.M.R.), and Syngenta (CASE award to J.M.R.). Jonathan
Clayden is the recipient of a Royal Society Wolfson Research
Merit Award.
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