β-Lactam-synthon-interceded facile synthesis of functionally decorated thiohydantoins

Article abstract of DOI:10.1055/s-0033-1341049

Base-promoted facile synthesis of thiohydantoins has been described via intramolecular amidolysis of C-3 functionalized 2-azetidinones. This approach provides a convenient and rapid access to diversely functionalized thiohydantoins compared to conventional protocols. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0033-1341049

1124▌
LETTER
letter
β-Lactam-Synthon-Interceded Facile Synthesis of Functionally Decorated
Thiohydantoins
Facile Synthesis of Functionally Decorated Thiohydantoins
Vishu Mehra,a Parvesh Singh,b Neha Manhas,b Vipan Kumar*a
a
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Fax +91(183)225881920; E-mail: vipan_org@yahoo.com
b
School of Chemistry, University of Kwazulu Natal, Durban 4000, South Africa
Received: 31.01.2014; Accepted after revision: 02.03.2014
nessed a remarkable growth in the field of β-lactam chem-
Abstract: Base-promoted facile synthesis of thiohydantoins has
istry.19,20 The use of β-lactams as synthetic intermediates
been described via intramolecular amidolysis of C-3 functionalized
is well documented21 and has resulted in an impressive va-
2-azetidinones. This approach provides a convenient and rapid ac-
cess to diversely functionalized thiohydantoins compared to con-
riety of stereocontrolled transformations,19b,22 affording
ventional protocols.
highly efficient routes to a variety of non-protein amino
acids, functionalized piperazines, 1,4-diazepanes, enan-
tiopure succinimides, oligopeptides and peptidomimetics,
indolizidine alkaloids, taxol derivatives, cryptophycins
and lankacidins.23
Key words: β-lactam synthon, thiohydantoin, intramolecular ami-
dolysis
Thiohydantoin-based heterocycles represent an interest-
ing class of compounds in medicinal and agricultural
chemistry with a wide array of biological properties1 with
applications as cardioprotective agents for the prevention
of atherosclerosis,2 gelatinase inhibitors, desmutagens
and herbicides.3–5 In particular, 2-thiohydantoins have
found extensive applications as hypolipidemic,6 anticar-
cinogenic,7 antimutagenic,4 antiviral (e.g., against herpes
simplex virus HSV8 and human immunodeficiency
virus9,10), antituberculosis,11 antimicrobial,12 antiulcer and
anti-inflammatory agents.13 Great efforts have been de-
voted to introduce thiohydantoin derivatives into pharma-
cophores and synthetic intermediates such as
leucettamine B, the tetracyclic core of styloguanidine,
(Z)-hymenialdisine, (Z)-2-debromohymenialdisine, bio-
active heterocycles possessing a glycociamidine ring and
aplysinopsin analogues.14
A recent report from our laboratory has described the syn-
thesis of hydantoins and their dimers via methoxide-pro-
moted intramolecular amidolysis of C-3 functionalized
azetidin-2-ones.24 In an extension to the above protocol
and continuation with our recent exposure to the prospect
of a β-lactam synthon approach for the diastereoselective
synthesis of functionally decorated novel heterocyclic
compounds,25 the present work details a facile and conve-
nient synthesis of functionalized 2-thiohydantoins via am-
idolysis of C-3 functionalized 2-azetidinones.
Thus, the treatment of racemic cis-2-isothiocyanateazeti-
din-2-ones 1, prepared via Staudinger reaction of racemic
cis-3-azidoazetidin-2-ones with triphenylphosphine fol-
lowed by treatment with CS2,25b with different amines re-
sulted in the isolation of the corresponding racemic cis-
thioureas 2 in quantitative yields.26 Subsequent room tem-
perature stirring of 2 with sodium methoxide in anhydrous
methanol for 50–55 minutes led to the formation of 3-al-
kyl/aryl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-
ones 4 in good to excellent yields (Scheme 1).27
The classical method for thiohydantoin synthesis involves
the reaction of isothiocyanates with N-substituted α-ami-
no acids or their esters,2,15 while other approaches include
one-pot three-component reaction of an α-amino acid es-
ter, aromatic aldehyde, and isothiocyanate in the presence
of sodium triacetoxyborohydride,16 solid-phase synthesis
of novel thiohydantoin-containing heterocycles17 and a
potassium carbonate supported solvent-less approach via
cyclization of diarylthioureas with chloroacetyl chloride
under microwave irradiation.18 However, current synthet-
ic protocols often suffer from synthetic limitations such as
lack of versatility, use of expensive and corrosive starting
materials and reagents, long reaction times, poor yields
and tedious workup procedures.
A plausible mechanism for the formation of 4 is shown in
Scheme 2 and may involve either methoxide-assisted tan-
dem intermolecular amidolysis–intramolecular cycliza-
tion (path A) or the generation of the thiouriedo anion
(path B), leading to the intermediate 3 with subsequent β-
elimination.
To discriminate between the proposed mechanistic path-
ways for the formation of 4, racemic cis-thiourea 2c was
treated with potassium tert-butoxide in anhydrous THF at
room temperature to act as a good base and poor nucleo-
phile (path B), resulting in the isolation of 4c (Scheme 3),
as confirmed by comparison with a sample of 4c prepared
previously.
After the discovery of penicillins and cephalosporins as
clinically useful agents, the past few decades have wit-
In conclusion, the present manuscript describes a conve-
nient approach towards the synthesis of functionally en-
riched thiohydantoins via base-promoted intramolecular
amidolysis of C-3 functionalized β-lactams.
SYNLETT 2014, 25, 1124–1126
Advanced online publication: 27.03.2014
DOI: 10.1055/s-0033-1341049; Art ID: ST-2014-D0087-L
© Georg Thieme Verlag Stuttgart · New York
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3
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-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Facile Synthesis of Functionally Decorated Thiohydantoins
1125
R1
O
R1
R1
O
NH
O
R2NH2
N
H1
N
S
MeONa
H3
H3
N
R3
H2
N
N
R3
MeOH (anhyd)
N=C=S
H2 H1
H4
acetone
(anhyd)
H2 H1
H4
H
H
HN
S
3
1
2
R1 = 4-MeC6H4
O
N
R3
HN
S
4
Product
R3
% yield
4a
4b
4c
4d
4e
4f
Ph
85
82
88
87
90
81
84
89
4-ClC6H4
4-MeC6H4
4-FC6H4
C6H11
Bn
i-Bu
Bu
4g
4h
Scheme 1 Sodium methoxide mediated synthesis of C-3 functionalized 2-thiohydantoins 4
R1
NH
O
path A
OMe
NHR2
R1
HN
NH
O
R1
O
H1
N
S
NaOMe
NH R2
MeOH
S
R2
H2
N
5
HN
N
H
R1
O
S
N
S
3
4
N
H
N
R2
path B
2
O
N
R2
HN
6
S
Scheme 2 Plausible mechanistic pathways for the formation of 4
O
O
N
S
N
S
t-BuOK
N
H
NH
HN
THF (anhyd)
2c
4c
Scheme 3 Potassium tert-butoxide mediated intermolecular amidolysis
01(2407)/10/EMR-II (VK) is also acknowledged. P.S. expresses his
acknowledgment to the Centre for High Performance Computing
(CHPC), an initiative supported by the Department of Science and
Technology of South Africa.
Acknowledgment
V.M. gratefully acknowledges a Senior Research Fellowship gran-
ted under the CSIR open Scheme No. 09/254(0244)/2012-EMR-I.
Financial support from the CSIR, New Delhi under Scheme No.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1124–1126

1126
V. Mehra et al.
LETTER
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(26) Typical Procedure for the Preparation of Thiourea 2: To
a stirred solution of 2-isothiocyanateazetidin-2-one 1 (1
mmol) was added a solution of the amine (1 mmol) in anhyd
acetone (20 mL). The reaction mixture was allowed to stir at
r.t. for 15–20 min and the reaction progress was monitored
by TLC. The solvent was removed in vacuo resulting in a
solid that was recrystallized from Et2O to yield the desired
product 2.
1-(2-Oxo-4-styryl-1-p-tolylazetidin-3-yl)-3-
phenylthiourea (2a): white solid; mp 156–157 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.35 (s, 3 H, Me), 4.64 (dd, J = 4.8,
6.4 Hz, 1 H, H2), 4.92 (dd, J = 4.8, 7.2 Hz, 1 H, H1), 6.08
(dd, J = 6.4, 15.6 Hz, 1 H, H3), 6.61 (d, J = 15.6 Hz, 1 H,
H4), 6.80–7.02 (m, 5 H, ArH), 7.06 (d, J = 8.1 Hz, 2 H, ArH),
7.12 (d, J = 8.1 Hz, 2 H, ArH), 7.16–7.32 (m, 5 H, ArH), 7.82
(d, J = 7.2 Hz, 1 H, NH, D2O exch.). 13C NMR (75 MHz,
CDCl3): δ = 20.6, 59.0, 63.4, 120.0, 123.3, 124.8, 125.5,
126.2, 127.3, 127.8, 128.1, 128.8, 129.6, 133.1, 134.9,
137.4, 139.4, 170.5, 178.1. MS: m/z = 414 [M+]. Anal. Calcd
for C25H23N3OS: C, 72.61; H, 5.61; N, 10.16. Found: C,
72.51; H, 5.57; N, 10.22.
(27) Typical Procedure for the Sodium Methoxide Mediated
Synthesis of 3-Aryl/Alkyl-5-(3-phenylallylidene)-2-
thioxoimidazolidin-4-ones 4: To a stirred solution of
thiourea 2 (1 mmol) in anhyd MeOH was added a solution of
sodium methoxide (1 mmol) in anhyd MeOH. The reaction
mixture was allowed to stir at r.t. for 50–60 min and the
progress of the reaction was monitored by TLC. On
completion, the precipitated crude product was filtered and
recrystallized from EtOAc–hexane (60:40) to yield 3-
aryl/alkyl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-
one 4 as yellow crystals.
3-Phenyl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-
one (4a): yellow solid; mp >220 °C. 1H NMR (300 MHz,
CDCl3): δ = 6.54 (d, J = 11.7 Hz, 1 H, H1), 7.00 (dd, J = 11.7,
15.0 Hz, 1 H, H2), 7.18 (d, J = 15.0 Hz, 1 H, H3), 7.32–7.80
(m, 10 H, ArH), 12.63 (s, 1 H, NH, D2O exch.). 13C NMR (75
MHz, CDCl3): δ = 112.5, 113.9, 114.2, 120.8, 125.6, 125.9,
127.2, 127.4, 128.9, 129.0, 134.8, 138.6, 161.3, 175.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H14N2OS:
307.0827; found: 307.0838. Anal. Calcd for C18H14N2OS: C,
70.56; H, 4.61; N, 9.14. Found: C, 70.50; H, 4.56; N, 9.19
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Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med.
Synlett 2014, 25, 1124–1126
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