Acid-catalysed formation of tricyclic N,S-acetals in imidazolinone series based on the use of the unprecedented N-acyliminium ion cascade reaction involving transposition, heterocyclisation and π-cyclisation

Article abstract of DOI:10.1039/b508214e

4-Hydroxy-5,5-dimethylimidazolines tethered at N-1 to an aryl sulfide undergo an unprecedented acid-catalysed domino reaction, involving double methyl transposition, heterocyclisation, isomerisation of thiazetidinium ion and, finally, π-cyclisation. In th

Full text of DOI:10.1039/b508214e

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A R T I C L E
Acid-catalysed formation of tricyclic N,S-acetals in imidazolinone
series based on the use of the unprecedented N-acyliminium ion
cascade reaction involving transposition, heterocyclisation and
p-cyclisation†
Anthony Pesquet,a Adam Da¨ıch,*a Bernard Decroixa and Luc Van Hijfteb
a URCOM, EA 3221, UFRST de lꢀUniversite´ du Havre, B.P: 540, 25 rue Philippe Lebon,
F-76058, Le Havre, France. E-mail: adam.daich@univ-lehavre.fr;
Fax: (+033) 02-32-74-44-03; Tel: (+033) 02-32-74-44-03
b Johnson & Johnson, Pharmaceutical Research & Development, Division of Janssen-Cilag,
Campus de Maigremont, B.P: 615, F-27106, Val-de-Reuil, France
Received 10th July 2005, Accepted 5th September 2005
First published as an Advance Article on the web 4th October 2005
4-Hydroxy-5,5-dimethylimidazolines tethered at N-1 to an aryl sulfide undergo an unprecedented acid-catalysed
domino reaction, involving double methyl transposition, heterocyclisation, isomerisation of thiazetidinium ion and,
finally, p-cyclisation. In this way a one-pot synthesis of original tricyclic N,S-acetals was developed. The same
triheterocyclic products can be prepared also starting from the corresponding 5-hydroxy isomers (in this case the
cascade of reactions does not involve methyl transposition).
Introduction
Sequential processes that enable the easy access to complex
structures from simple building blocks in a single preparative
step are of high interest in organic synthesis, especially if they
allow the generation of biologically active compounds.1,2
While the importance of N-acyliminium chemistry involving
olefinic and aromatic cationic cyclisations has been widely
demonstrated and reviewed extensively,3 useful synthetic reac-
tions of the construction of carbon–heteroatom bonds mediated
by N-acyliminium ion species has been by far less explored,
but constitutes a novel and powerful strategy to access new
compounds as cyclic N,O-, N,N-, and N,S-acetals.4
Because we are interested in developing new reactions for
Fig. 1 All plausible targets structures via the cascade N-acyliminium
accessing libraries of original N,S-heterocyclic systems contain-
ion rearrangement–heterocyclisation–p-cationic cyclisation.
ing imidazolinone and benzothiazine skeletons with promis-
ing pharmaceutical activities, we have continued to explore
p-cationic cyclisation, a new mechanistic pathway to access
cyclic thiolactams. A cascade reaction is proposed, relying
on chemical and spectroscopic considerations, including X-ray
crystallography.
synthetic opportunities based on our recent reports dealing
with intramolecular heteroamidoalkylation.4j,l,m,5 Although the
cationic cyclisation using a nitrogen and oxygen atom as internal
nucleophile has been mentioned,4 the intramolecular use of a
sulfur nucleophile for trapping an N-acyliminium cation was
unprecedented before our previous work.5 The association of
this process in tandem with N-acyliminium isomerisation–p-
cationic cyclisation was reported, and led conveniently to sub-
stituted benzothiazoles and thiazines fused to an isoindolinone
nucleus.6,7 To the best of our knowledge the present application
of this cascade process, which would produce the central six-
membered and/or bridged ring systems as cyclic N,S-acetals
(types II–V: Fig. 1) starting from hydroxyimidazolidinone of
type I, represents a novel illustration of this chemistry. In fact,
the selection of the functionality N–CH2–S in an imidazolinone
ring allows consideration of both endocyclic and/or exocyclic
N-acyliminium intermediates, which, if containing a moder-
ately activated aromatic ring and a sulfur atom, would acts
as effective p-aromatic and/or sulfur nucleophile scavenger.
Herein, we present the preliminary results of our finding on
this combination of double transposition–heterocyclisation–
Results and discussion
The synthesis of the required hydroxyimidazolidinones of type
I (5) was accomplished in a four/five-step sequence as outlined
in Scheme 1. The commercially available 1-hydroxymethyl
derivative 1 was chlorinated quantitatively with thionyl chloride
and the resulting halide 2 was S-alkylated with slight excess of
aryl mercaptan in alkaline medium (41 to 86%).8 Regioselective
reduction of the resulting imide (3a: R3 = H), chosen as a
model substrate, was performed with a large excess of NaBH4
(6 mole equiv.) in analogy to reports by Hough et al.9 To
avoid the poor solubility of the imide 3a, in addition to the
laborious work-up encountered during this process, we have
anticipated that the conversion of 3a to the N-Boc protected
imide 4a could offer a better result by increasing the solubility of
hydroxyimidazolidinone substrate. So, treatment of 4a, obtained
by standard N-protection with the tandem Boc2O–DMAP
(quantitative yield),10 under our reduction protocol (conditions
(v)) gave 5-hydroxyimidazolidinone 5a (R3 = H, R4 = Boc) in
89% yield.
† Electronic supplementary information (ESI) available: detailed spec-
troscopic (1H and 13C NMR and DEPT) data of all compounds in
Schemes 1 and 2. See DOI: 10.1039/b508214e
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7
3 9 3 7
©

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Scheme 1 Reagents and conditions: (i) SOCl2 (3.0 mole equiv.),
CH2Cl2, 0 to 20 ◦C, 12 h, 100%; (ii) Ar–SH (1.2 mole equiv.), MeONa
(1.2 mole equiv.), DMF, 20 ◦C, 12 to 24 h, 41 to 86%; (iii) Boc2O,
DMAPcat, CH3CN or THF, 20 ◦C, 12 to 24 h, 54 to 100%; (iv) R4–X
(1.2 mole equiv.), K2CO3 (1.2 mole equiv.), 18-C-6 (1% molar), KI
(0.1 mole equiv.), toluene, reflux, 24 h, 91% (R4 = Me) and 97%
(R4 = Bn); (v) NaBH4 (6 mole equiv.), EtOH, 20 ◦C, 12 to 48 h, 70
to 100%; (vi) TFA (1.5 mL for 1 mmol of 5-hydroxyimidazolidinone 5),
24 h, 21 to 92%; (vii) R4–X (1.2 mole equiv.), NaH (1.2 mole equiv.),
THF, 20 ◦C, 60 h, 62% (R4 = Me) and 58% (R4 = Bn).
Scheme 2 Reagents and conditions: (i) 7x,y (see ref. 6) (1.2 mole equiv.),
K2CO3 (1.2 mole equiv.), 18-C-6 (1% molar), KI (0.1 mole equiv.),
toluene, reflux, 48 h, 63% (R5 = Et) and 73% (R5 = Bn); (ii) NaBH4
(6 mole equiv.), EtOH, 20 ◦C, 24 h, 94% (R5 = Et) and 84% (R5 = Bn);
(iii) TFA (1.5 mL for 1 mmol of 4-hydroxyimidazolidinones 10), 24 h, 67
and 52%, respectively; (iv) PTSAcat, toluene, reflux, 48 h, 58%. (v) neat
TFA, reflux, 48 h, 67%.
Analogous procedures (3 → 4 → 5) were used successfully
to afford elegantly 5c–i (R4 = Boc), with other substituents
on different positions of the aromatic ring (see Table 1). In
addition, to measure the effect of the R4 group, on both
reduction and cyclisation steps and to establish the generality
and versatility of our proposed cascade process, the N3-alkylated
imides 4j,k were elaborated successfully with high yields (91
and 97% yields, respectively) under PTC conditions.4j Their
reduction led to corresponding 5-hydroxyimidazolidinones 5j
and 5k in 89 and 84% yields, respectively. On the other hand, 4-
hydroxyimidazolidinones 10x (R5 = Et) and 10y (R5 = Bn) were
easily obtained in two steps from bromides 7x and 7y,6 by N-
alkylation (63% and 73% yields, respectively (see Scheme 2))
and a sodium borohydride regioselective reduction (94 and
84% yields, respectively). Similarly, as shown in Scheme 3, 4-
hydroxyimidazolidinones 15j,l–n were obtained in two steps and
very good yields by S-alkylation of halide 1311 and sodium
borohydride reduction.
Scheme 3 Reagents and conditions: (i) 13 (1.0 mole equiv.) Ar–SH
(1.2 mole equiv.), MeONa (1.2 mole equiv.), DMF, 20 ◦C, 12 to 24 h,
66 to 85% (R3 = H (12j), R3 = o–Br (12l), R3 = o-MeO (12m), R3 =
m.p-MeO (12n)); (ii) NaBH4 (6 mole equiv.), EtOH, 20 ◦C, 12 to 48 h, 69
to 95%; (vi) PTSAcat, toluene, reflux, 48 h, 58%. (vii) neat TFA, reflux,
48 h, 67%; (iii) TFA (1.5 mL for 1 mmol of 4-hydroxyimidazolidinones
15), 24 h, 44 to 100%.
In these acid conditions, the cyclised product, identified as the
unexpected imidazolo[1,3]benzothiazine 6a, was isolated as a
crystalline material in 56% yield. From this result, its seems
that the reaction did not occur by direct cyclisation but by a
cascade process in one-pot procedure. This tricyclic product was
obtained also in 92% of yield from 5b (R3 = R4 = H) under the
same conditions. These preliminary attempts revealed also that
In the outset of our investigations, the 5-hydroxyimida-
zolidinone 5a, as an N-acyliminium generator model, was
subjected to different acid conditions (entries 1–4). The obtained
results allowed us to select neat trifluoroacetic acid (TFA)
in precise proportion to substrate (1.5 mL for 1 mmol of
5) as the best cyclisation protocol (conditions D in Table 1).
Table 1 Cascade N-acyliminium isomerisation–p-cyclisationa
Entry
Reactantb
R3
R4
Method
Productb (R4)
Yield (%)c
d
d
e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5a
5a
5a
5a
5c
5d
5ef
5f
5g
5h
5i
5j
5k
H
H
H
H
H
o.Br
o-MeO
m-MeO
p-MeO
p-Cl
b-Naphth
m,p-MeO
H
Boc
Boc
Boc
Boc
H
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Me
Bn
A
B
6a (H)
6a (H)
6a (H)
6a (H)
6a (H)
6c (H)
6d (H)
6e (H)
6f (H)
6g (H)
6h (H)
6i (H)
6j (Me)
6k (Bn)
C
D
D
D
D
D
D
D
D
D
D
D
56
92
21
29
77
d
d
61
55
87
95
H
a Reagents and conditions: Method A: PTSAcat, toluene, reflux, 24 h; Method B: BF3.Et2O (2.0 mole equiv.), CH2Cl2, 20 ◦C, 24 h; Method C: TFA
(2.0 mole equiv.), CH2Cl2, 20 ◦C, 24 h; Method D: (see conditions (vi) in Scheme 1) TFA, 24 h. b The substrates 5a and 5c–i have group R4
=
Boc. Importantly, it should be noted that the Boc group is lost during the cyclisation process and consequently when R4 = Boc in substrate 5 it
becomes H in product 6 after the cyclisation reaction. c Chromatographically pure compounds. d Only the thiophenol was isolated. e The unprotected
starting material as 5-hydroxyimidazolidinone (5b) was recovered and was accompanied with the disulfur namely, 4-phenylthio-1-phenylthiomethyl-
5,5-dimethylimidazolidin-2-one. f In the case of the m-methoxy derivative 6e (entry 8), the reaction was performed with total regioselectivity in favor
of the 2-position of the benzene ring.
3 9 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7

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only the thiophenol (entries 1, 2) or the 4-phenylthio-1-phenyl-
thiomethyl-5,5-dimethylimidazolidin-2-one (entry 3) resulting
from the cleavage of the thioether linkage, followed by its attack
or not of the iminium intermediate, were isolated in protocols
A, B and C, respectively.
Having established the capacity of 5-hydroxyimidazolidin-
ones 5a,b to provide a cascade process in forming unusual
six-membered N,S-heterocyclic complex systems, we sought to
determine if this novel mechanistic paradigm might be extended
to other aromatic substituents. Significant structural variation
in the p-aromatic system can also be realized. Importantly, the
reaction appears quite tolerant with respect to the substituent at
the benzene ring o-, m- and m,p-positions (entries 6–8, 11, 12).
While reasonable yields (55 to 77%) are obtained with the m-
and m,p-positions (entries 8, 11, 12), the o-substitution (entries
6, 8), was characterized with low yields which do not exceed
whatever the attempts, 29%.12 This yield dramatically falls to
0% (entries 9, 10) when the benzene ring was para-substituted.
This clearly demonstrates the impact of electronic influence of
the benzene moiety on the kinetic of the reaction. Unexpectedly,
the introduction of alkyl substituent at N3 on the imidazolidine
moiety proved to have a beneficial effect on the yield of the
reaction, which may be attributed to an increased nucleophilic
character of the sulfur atom (Table 1, entries 13, 14).
Fig. 3 A molecular structure of imidazobenzothiazine 6j derived
from X-ray crystallographic data. Arbitrary numbering of atoms, 50%
probability ellipsoids.
carbon in their 5-hydroxyimidazolidinones 5 congeners) which is
due to the proximity of the sulfur atom instead of the oxygen one.
These observations were also corroborated with similar results
outlined by us in recent reports for related structures. Finally,
the structures of products 6a,j were unequivocally confirmed by
single X-ray crystallographic analysis as shown by the ORTEP
drawing in Fig. 2 for imidazo[1,3]benzothiazine 6a and Fig. 3
for imidazo[1,3]benzothiazine 6j.
Additionally, structure confirmation of these thiazacyclic sys-
tems was performed by two approaches as highlight in Schemes 2
and 3. So, subjection of 4-hydroxyimidazolidinone 10y prepared
as outlined above (see also Scheme 2) to our established acid-
protocol, furnished the desired heterocyclic thiolactam 6a (52%
yield) by successive intramolecular thioamidoalkylation of the
acyliminium ion into the intermediate thiazinium salt I and
debenzylation (Scheme 2). In parallel experiments from 4-
hydroxyimidazolidinone 10x (R5 = Et), the reaction occurred
only when PTSA in catalytic amount was used (i.e. toluene,
reflux, 48 h). The product isolated in 58% of yield was identified
as imidazolone 11x which is the consequence of the simple
transposition of one methyl group.13
Taking into account that an enamidone function could
generate an N-acyliminium ion under acidic conditions,14 the
cyclisation of 11x into 6a was achieved under drastic conditions
in 67% yield (i.e. TFA, reflux, 48 h). This result showed that the
transformation of the imidazolone 11x into the azasulfonium
salt I and vice versa was accomplished in acid medium.
In the second pathway, the good nucleophilicity of the
sulfur atom was again explored. So, upon treatment with TFA
(conditions (iii), Scheme 3), 4-hydroxyimidazolidinone 15j gave
the desired cyclised product 6j (89% yield) via the p-cationic
cyclisation of the intermediate exocyclic N-acyliminium ion
J, which was obtained from the endocyclic one generated
under influence of acid via the cyclic azasulfonium ion.6 This
sequence was generalized successfully and led to other new
cyclic thioactams as 6l–n (Scheme 3). Additionally as illustrated
in Fig. 1, structures of 6b (R4 = Boc), 6j (R4 = Me) and 6k
(R4 = Bn) were confirmed chemically by N-protection using
classical protocols with respectively Boc, methyl and benzyl
groups starting from 6a. Finally, structures of 6a and 6j were
proved by single X-ray crystallographic analysis, which are
identical to that in the ORTEP drawing in Fig. 2 and 3.
The assignment of all structures reported herein was made on
the basis on their IR, NMR (1H and 13C experiments including
NOE difference and DEPT programs, respectively), and GC-
MS spectra. In the case of solids, their elemental analyses were
1
also performed. So, the H NMR spectra of imides 3 and 4
showed a methylene groups as a singlet with the chemical shifts
values of about d = 4.73–5.00 ppm for 3 and from d = 4.45–
4.94 ppm for 4, respectively. The same methylene protons in
N–CH2–S functionalities of the 5-hydroxyimidazolidinones 5
and the cyclic N,S-acetals 6 appear as an AB system due to the
diastereotopic effect with a coupling constant of J = 13–15 Hz
for 5 and J = 12–17 Hz for benzothiazines 6 characteristic of gem
protons. Interestingly in the latter case we found that coupling
constant J = 17 Hz for the majority of the tricyclic N,S-acetals
6 excepted for compounds 6e (8-MeO benzene substituent), 6h
(naphthalene derivative) and 6i (6,7-MeO benzene substituent)
in which J = 12–13 Hz. This result is in corroboration with
the chemical displacement values of the angular carbon “C10
in the ORTEP drawing, see Fig. 3 for example” (d = 61.2–
65.0 ppm) in the 13C NMR spectra compared to the same
one in the N,S-acetal derivatives 6 bearing other substituents
(d = 67.5–69.3 ppm).
Fig. 2 A molecular structure of imidazobenzothiazine 6a derived
from X-ray crystallographic data. Arbitrary numbering of atoms, 50%
probability ellipsoids.
Scheme 4 represents a plausible mechanistic rationale for
the cascade process reported herein. Formation of the inter-
mediate C from 5-hydroxyimidazolidinones 5, by transposition
of one methyl group under acid, accounts for the literature
observations.9 This intermediate, isolated when R3 = H and
R4 = Bn, is in equilibrium via the intermediacy of D with the
corresponding cation E which could also obtained directly when
15 was used as starting material. This cation E by successive
stepwise S-alkylation (F), isomerisation (J) and p-cyclisation
would ultimately lead to unusual cyclic N,S-acetals 6.
Likewise, the 13C NMR spectra of the cyclic N,S-acetal
products 6 reveled the presence of an additional quaternary
carbon in the aromatic region as the consequence of the
cyclisation process. Furthermore an important shielding of the
angular carbon of components 6 was observed (d = 61.2–
69.3 ppm instead of the range 83.4 to 84.8 ppm for the same
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7
3 9 3 9

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dichloromethane was added thionyl chloride (32.8 mL, 0.45 mol)
at 0 ◦C. After stirring for 12 h at room temperature, the solution
was concentrated under reduced pressure. The white solid was
filtered off and washed several times with dry cyclohexane to give
the suitable halide derivative 2 as a white solid in quantitative
yield; mp 123–125 ◦C (decomposition, see ref. 15); Found: C,
40.67; H, 5.21; N, 15.66. Calc. for C6H9ClN2O2: C, 40.81; H,
5.14; N, 15.86%; IR mmax (KBr)/cm−1 3305 (NH), 1786 (C O),
=
1
=
1727 (C O); H NMR (300 MHz, CDCl3) d 1.45 (s, 6H, 2 ×
CH3), 5.26 (s, 2H, CH2), 6.86 (s broad, 1H, NH);13C NMR
(75 MHz, CDCl3) d 24.8 (2 × CH3), 45.5 (CH2), 59,3 (C), 154.3
+
=
=
(C2 O), 175.6 (C4 O); MS (m/z: EI) 176–178 (M ).
General procedure for S-alkylation of 1-chloromethyl-5,5-
dimethylhydantoin (2). To a stirred solution under an atmo-
sphere of dry nitrogen or argon of aryl mercaptan derivative
(6a, 0.024 mol) in 45 mL of dry DMF was added 1.3 g
(0.024 mol) of sodium methoxide. After stirring for 1 h at
room temperature, 1-chloromethyl-5,5-dimethylhydantoin (2,
3.52 g, 0.02 mol) in 15 mL of the same solvent was added
slowly dropwise over a period of 20 min. The mixture was
then allowed to react at ambient temperature for 12 to 24 h.
After cooling, the solution was poured onto cold water and the
precipitate formed was filtered off and air dried. The resultant
solid was then recrystallized from the solvent indicated to give
the hydantoin derivative 3 in moderate to good yields (41 to
86%). In the case of no solid was obtained, the aqueous solution
was extracted three times with diethyl ether (3 × 100 mL).
The combined organic layers was washed successively with
water, brine and dried over MgSO4. The organic phase was
concentrated under reduced pressure and the crude resulting
solid was purified by flash chromatography on silica gel with
a mixture of cyclohexane–AcOEt (4 : 1) as eluent to give
S-alkylated imide 3. Recrystallization from suitable solvent
afforded pure imide 3 in moderate to good yields (41 to 86%).
Scheme 4 Proposed mechanisms to access thiazines 6 from 5 and 15.
Conclusion
In summary, a one-pot synthesis of complexes heterocyclic N,S-
acetals 6 was initiated by acid-catalysed rearrangement of 5-
hydroxyimidazolidinones 5 and 4-hydroxyimidazolidinones 10
and 15, respectively. During these transformations, it seems that
in the case of 4-hydroxyimidazolidinones 10 it is difficult to
introduce substituents in the aryl ring, while for 4-hydroxy-
imidazolidinones 15 it is difficult to prepare compounds with
R4 = H. As a consequence, the pathway using 5-hydroxy-
imidazolidinones 5 as a cation source appears to be general,
easy to apply and gives moderate to good yields. In this work,
a cascade process including alkyl transposition, heterocyclisa-
tion, N-acyliminium isomerisation, and finally a p-cyclisation
was also established. Finally, the mechanistic aspect of these
transformations was also addressed.
5,5-Dimethyl-1-phenylthiomethylhydantoin (3a). This prod-
uct was obtained as a white solid in 79% yield; mp 106 ◦C
(ethanol–diethyl ether); Found: C, 57.29; H, 5.38; N, 11.05.
Calc. for C12H14N2O2S: C, 57.58; H, 5.64; N. 11,19%; IR mmax
Elsewhere, we are currently investigating rational design of
new hydroxyimidazolidinones as N-acyliminium ion precursors
bearing other C5-substituents and heteroatoms than sulfur and
the application to multi-step synthesis, the results of which will
be published in due course.
1
(KBr)/cm−1 3293 (NH), 1770 (C O), 1720 (C O); H NMR
(300 MHz, CDCl3) d 1.27 (s, 6H, 2 × CH3), 4.76 (s, 2H, CH2),
6.48 (s broad, 1H, NH), 7.21–7.28 (m, 3H, Haro), 7.43–7.48 (m,
2H, Haro);13C NMR (75 MHz, CDCl3) d 25.0 (2 × CH3), 42.8
(CH2), 58.9 (C), 128.3 (CHaro), 129.1 (2 × CHaro), 132.6 (Caro–S),
=
=
=
=
133.3 (2 × CHaro), 155.3 (C2 O), 176.2 (C4 O); MS (m/z: EI)
250 (M+).
Experimental
General remarks
1-(o-Bromophenyl)thiomethyl-5,5-dimethylhydantoin
(3c).
This product was obtained as a white solid in 71% yield; mp
Melting points are uncorrected. IR spectra of solids (potassium
bromide) were recorded on a Perkin Elmer FTIR paragon 1000
spectrophotometer. 1H and 13C NMR spectra were measured on
a Bruker AC-200 and Bruker 300 instruments (200 and 300 MHz
respectively) and chemical shifts are reported relative to CDCl3
at d 7.24 ppm (or to DMSO-d6 at d 2.49 ppm) and tetram-
ethylsilane as an internal standard. MS spectral measurements
were carried out on a AEI MS 902 S spectrometer (70 eV,
electron impact). Reagents were obtained from commercial
suppliers and used without further purification. Solvents were
dried and purified by standard methods. A Merck silica gel
60 was used for both column chromatography (70–230 mesh)
and flash chromatography (230–400 mesh). Ascending TLC was
performed on precoated plates of silica gel 60 F 254 (Merck)
and the spots visualized using an ultraviolet lamp or iodine
vapor. Elemental analyses (C, H, N) were performed by the
microanalysis laboratory of INSA at Rouen, F-76130 Mt-St-
Aignan, France.
91 ◦C (ethanol); Found: C, 43.60; H, 3.77; N, 8.53. Calc.
for C12H13BrN2O2S: C, 43.78; H, 3.98; N, 8.51%; IR mmax
1
(KBr)/cm−1 3264 (NH), 1765 (C O), 1714 (C O); H NMR
(300 MHz, CDCl3) d 1.26 (s, 6H, 2 × CH3), 2.59 (s broad, 1H,
NH), 4.80 (s, 2H, CH2), 7.03–7.20 (m, 2H, Haro), 7.49–7.60 (m,
2H, Haro); 13C NMR (75 MHz, CDCl3) d 24.7 (2 × CH3), 41.8
(CH2), 58.7 (C), 127.9 (CHaro), 128.0 (Caro–Br), 129.6 (CHaro),
=
=
=
133.2 (CHaro), 133.7 (Caro–S), 134.4 (CHaro), 155.0 (C2 O),
+
=
176.4 (C4 O); MS (m/z: EI) 328–329 (M ).
1-(o-Methoxyphenyl)thiomethyl-5,5-dimethylhydantoin (3d).
This product was isolated as a white solid in 41% yield; mp
126 ◦C (ethanol); Found: C, 55.45; H, 5.68; N, 10.05. Calc. for
C13H16N2O3S: C, 55.70; H, 5.75; N, 9.99%; IR mmax (KBr)/cm−1
1
=
=
3301 (NH), 1778 (C O), 1720 (C O); H NMR (300 MHz,
CDCl3) d 1.25 (s, 6H, 2 × CH3), 3.92 (s, 3H, OCH3), 4.83 (s, 2H,
CH2), 6.16 (s broad, 1H, NH), 6.77–6.88 (m, 2H, Haro), 7.29–7.41
(m, 2H, Haro); 13C NMR (75 MHz, CDCl3) d 24.9 (2 × CH3),
40.4 (CH2), 55.9 (OCH3), 58.7 (C), 111.0 (CHaro), 119.3 (Caro–S),
1-Chloromethyl-5,5-dimethylhydantoin15 (2). To a stirred
solution, at room temperature, of 1-hydroxymethyl-5,5-
dimethylhydantoin (1, 23.7 g, 0.15 mol) in 50 mL of dry
120.6 (CHaro), 130.7 (CHaro), 135.9 (CHaro), 155.5 (Caro–O), 159.8
+
=
=
(C2 O), 176.4 (C4 O); MS (m/z: EI) 280 (M ).
3 9 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7

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1-(m-Methoxyphenyl)thiomethyl-5,5-dimethylhydantoin (3e).
This product was isolated as a white solid in 47% yield; mp
93 ◦C (diethyl ether); Found: C, 55.39; H, 5.61; N, 9.82. Calc. for
of cyclohexane–AcOEt (1 : 4) as eluent to give N-protected
imides 4 in quantitative yields.
t
3- Butyloxycarbonyl-5,5-dimethyl-1-phenylthiomethylhydantoin
C13H16N2O3S: C, 55.70; H, 5.75; N, 9.99%; IR mmax (KBr)/cm−1
(4b). This product was obtained as a white solid in 100%
1
=
=
3270 (NH), 1772 (C O), 1720 (C O); H NMR (300 MHz,
CDCl3) d 1.50 (s, 6H, 2 × CH3), 3.94 (s, 3H, OCH3), 5.00 (s, 2H,
CH2), 6.07 (s broad, 1H, NH), 6.95 (dd, 1H, J = 2 and 8 Hz,
Haro), 7.20–7.40 (m, 3H, Haro); 13C NMR (75 MHz, CDCl3) d 24.9
(2 × CH3), 42.4 (CH2), 55.4 (OCH3), 58.9 (C), 114.2 (CHaro),
yield; mp 144 ◦C (cyclohexane); Found: C, 58.09; H, 6.08; N,
7.77. Calc. for C17H22N2O4S: C, 58.27; H, 6.33; N, 7.99%; IR
1
mmax (KBr)/cm−1 1751 (C O), 1742 (C O), 1735 (C O); H
NMR (300 MHz, CDCl3) d 1.49 (s, 6H, 2 × CH3), 1.53 (s, 9H,
3 × CH3), 4.85 (s, 2H, CH2), 7.27–7.30 (m, 3H, Haro), 7.48–7.53
(m, 2H, Haro); 13C NMR (75 MHz, CDCl3) d 23.1 (2 × CH3),
28.2 (3 × CH3), 43.2 (CH2), 63.2 (C), 84.4 (C(tBu)), 128.5
=
=
=
117.5 (CHaro), 124.7 (CHaro), 129.9 (CHaro), 133.9 (Caro–S), 155.3
+
=
=
(Caro–O), 159.8 (C2 O), 176.2 (C4 O); MS (m/z: EI) 280 (M ).
(CHaro), 129.2 (2 × CHaro), 132.5 (Caro–S), 133.1 (2 × CHaro),
1-(p-Methoxyphenyl)thiomethyl-5,5-dimethylhydantoin (3f).
This product was isolated as a white solid in 70% yield; mp
120 ◦C (ethanol–diethyl ether); Found: C, 55.41; H, 5.67; N,
t
=
=
148.4 (CO2 Bu), 155.9 (C2 O), 173.9 (C4 O).
1-(o-Bromophenyl)thiomethyl-3-tbutyloxycarbonyl-5,5-di-
methylhydantoin (4c). This product was obtained as a white
solid in 98% yield; mp 89 ◦C (cyclohexane); Found: C, 47.39;
H, 4.76; N, 6.39. Calc. for C17H21BrN2O4S: C, 47.56; H, 4.93;
9.86. Calc. for C13H16N2O3S: C, 55.70; H, 5.75; N, 9.99%; IR mmax
1
(KBr)/cm−1 3287 (NH), 1762 (C O), 1715 (C O); H NMR
(300 MHz, CDCl3) d 1.32 (s, 6H, 2 × CH3), 3.76 (s, 3H, OCH3),
4.70 (s, 2H, CH2), 6.39 (s broad, 1H, NH), 6.80 (d, 2H, J = 9 Hz,
Haro), 7.42 (d, 2H, J = 9 Hz, Haro); 13C NMR (75 MHz, CDCl3)
d 24.8 (2 × CH3), 43.5 (CH2), 55.2 (OCH3), 58.7 (C), 114.5 (2 ×
=
=
N, 6.52%; IR mmax (KBr)/cm−1 1755 (C O), 1736 (C O), 1732
=
=
1
=
(C O); H NMR (300 MHz, CDCl3) d 1.51 (s, 6H, 2 × CH3),
1.53 (s, 9H, 3 × CH3), 4.89 (s, 2H, CH2), 7.09–7.28 (m, 2H,
Haro), 7.56–7.65 (m, 2H, Haro); 13C NMR (75 MHz, CDCl3) d
23.0 (2 × CH3), 28.0 (3 × CH3), 42.3 (CH2), 63.0 (C), 84.3
(C(tBu)), 128.0 (CHaro), 128.2 (Caro–Br), 129.9 (CHaro), 133.4
CHaro), 122.7 (Caro–S), 136.1 (2 × CHaro), 155.4 (Caro–O), 160.1
+
=
=
(C2 O), 176.2 (C4 O); MS (m/z: EI) 280 (M ).
1-(p-Chlorophenyl)thiomethyl-5,5-dimethylhydantoin
(3g).
t
(CHaro), 133.5 (Caro–S), 134.6 (CHaro), 148.3 (CO2 Bu), 150.6
This product was isolated as a white solid in 86% yield; mp
135 ◦C (ethanol); Found: C, 50.33; H, 4.50; N, 9.88. Calc.
=
=
(C2 O), 173.7 (C4 O).
3-tButyloxycarbonyl- 1 - ( o - methoxyphenyl )thiomethyl - 5,5 -
dimethylhydantoin (4d). This product was obtained as a white
solid in 96% yield; mp 79 ◦C (diethyl ether–cyclohexane);
Found: C, 56.77; H, 6.12; N, 7.20. Calc. for C18H24N2O5S: C,
for C12H13ClN2O2S: C, 50.61; H, 4.60; N, 9.84%; IR mmax
1
(KBr)/cm−1 3292 (NH), 1770 (C O), 1721 (C O); H NMR
(300 MHz, CDCl3) d 1.34 (s, 6H, 2 × CH3), 4.80 (s, 2H, CH2),
5.87 (s broad, 1H, NH), 7.25 (d, 2H, J = 9 Hz, Haro), 7.44 (d,
2H, J = 9 Hz, Haro); 13C NMR (75 MHz, CDCl3) d 25.0 (2 ×
CH3), 42.8 (CH2), 59.0 (C), 129.3 (2 × CHaro), 131.2 (Caro–Cl),
=
=
56.82; H, 6.36; N, 7.36%; IR mmax (KBr)/cm−1 1751 (C O), 1736
=
1
=
=
(C O), 1722 (C O); H NMR (300 MHz, CDCl3) d 1.42 (s,
6H, 2 × CH3), 1.52 (s, 9H, 3 × CH3), 3.92 (s, 3H, OCH3), 4.86
(s, 2H, CH2), 6.77–6.88 (m, 2H, Haro), 7.26–7.43 (m, 2H, Haro);
13C NMR (75 MHz, CDCl3) d 23.0 (2 × CH3), 28.2 (3 × CH3),
41.0 (CH2), 55.9 (OCH3), 63.0 (C), 84.2 (C(tBu)), 111.2 (CHaro),
=
=
134.4 (2 × CHaro), 134.5 (Caro–S), 155.2 (C2 O), 176.2 (C4 O);
MS (m/z: EI) 284 (M+).
5,5-Dimethyl-1-(b-naphthyl)thiomethylhydantoin (3h). This
◦
product was isolated as a white solid in 61% yield; mp 115 C
119.1 (Caro–S), 120.7 (CHaro), 131.0 (CHaro), 136.0 (CHaro), 148.5
(ethanol–diethyl ether–cyclohexane); Found: C, 63.80; H, 5.41;
(CO2 Bu), 150.8 (Cqaro–O), 159.9 (C2 O), 174.0 (C4 O).
t
=
=
N, 9.21. Calc. for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33%;
1
IR mmax (KBr)/cm−1 3287 (NH), 1786 (C O), 1721 (C O); H
3-tButyloxycarbonyl-1-(m-methoxyphenyl)thiomethyl-5,5-
dimethylhydantoin (4e). This product was obtained as a white
solid in 100% yield; mp 82 C (ethanol–diethyl ether); Found:
=
=
NMR (300 MHz, CDCl3) d 1.23 (s, 6H, 2 × CH3), 4.90 (s,
2H, CH2), 6.50 (s broad, 1H, NH), 7.40–7.97 (m, 7H, Haro); 13
C
◦
NMR (75 MHz, CDCl3) d 24.9 (2 × CH3), 42.5 (CH2), 58.9
(C), 126.6 (CHaro), 126.7 (CHaro), 127.6 (CHaro), 127.9 (CHaro),
128.8 (CHaro), 129.8 (CHaro), 129.9 (Caro–C), 132.0 (CHaro), 132.7
C, 56.69; H, 6.09; N, 7.17. Calc. for C18H24N2O5S: C, 56.82; H,
6.36; N, 7.36%; IR mmax (KBr)/cm−1 1753 (C O), 1737 (C O),
=
=
1
=
1725 (C O); H NMR (300 MHz, CDCl3) d 1.51 (s, 6H, 2 ×
=
=
(Caro–S), 133.6 (Caro–C), 155.2 (C2 O), 176.2 (C4 O); MS (m/z:
CH3), 1.53 (s, 9H, 3 × CH3), 3.78 (s, 3H, OCH3), 4.87 (s, 2H,
CH2), 6.80 (dd, 1H, J = 2 and 8 Hz, Haro), 7.04–7.08 (m, 2H,
Haro), 7.17 (dd, 1H, J = 2 and 8 Hz, Haro); 13C NMR (75 MHz,
CDCl3) d 23.0 (2 × CH3), 28.1 (3 × CH3), 42.8 (CH2), 55.4
(OCH3), 63.1 (C), 84.3 (C(tBu)), 114.4 (CHaro), 117.3 (CHaro),
EI) 300 (M+).
1-(m,p-Dimethoxyphenyl)thiomethyl-5,5-dimethylhydantoin
(3i). This product was obtained as a white solid in 76% yield;
mp 99 ◦C (ethanol–cyclohexane); Found: C, 54.11; H, 5.69;
t
124.6 (CHaro), 129.9 (CHaro), 133.7 (Caro–S), 148.4 (CO2 Bu),
N, 9.00. Calc. for C14H18N2O4S: C, 54.18; H, 5.85; N, 9.03%;
=
=
150.7 (Caro–O), 159.9 (C2 O), 173.8 (C4 O).
1
IR mmax (KBr)/cm−1 3337 (NH), 1781 (C O), 1720 (C O); H
NMR (300 MHz, CDCl3) d 1.29 (s, 6H, 2 × CH3), 3.80 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 4.73 (s, 2H, CH2), 6.65 (s broad,
=
=
3-tButyloxycarbonyl-1- ( p - methoxyphenyl )thiomethyl - 5,5 -
dimethylhydantoin (4f). This product was obtained as a white
solid in 100% yield; mp 123 ◦C (ethanol–diethyl ether); Found:
C, 56.71; H, 6.13; N, 7.19. Calc. for C18H24N2O5S: C, 56.82; H,
1H, NH), 6.70–6.75 (m, 1H, Haro), 7.01–7.04 (m, 2H, Haro); 13
C
NMR (75 MHz, CDCl3) d 24.8 (2 × CH3), 43.3 (CH2), 55.8
6.36; N, 7.36%; IR mmax (KBr)/cm−1 1753 (C O), 1736 (C O),
(OCH3), 56.0 (OCH3), 58.7 (C), 111.2 (CHaro), 116.8 (CHaro),
=
=
1
123.2 (Caro–S), 126.9 (CHaro), 148.9 (Caro–O), 149.5 (Caro–O),
=
1725 (C O); H NMR (300 MHz, CDCl3) d 1.49 (s, 6H, 2 ×
+
=
=
155.3 (C2 O), 176.2 (C4 O); MS (m/z: EI) 310 (M ).
CH3), 1.53 (s, 9H, 3 × CH3), 3.76 (s, 3H, OCH3), 4.73 (s, 2H,
CH2), 6.81 (d, 2H, J = 9 Hz, Haro), 7.41 (d, 2H, J = 9 Hz, Haro);
13C NMR (75 MHz, CDCl3) d 23.1 (2 × CH3), 28.2 (3 × CH3),
44.2 (CH2), 55.4 (OCH3), 63.1 (C), 84.3 (C(tBu)), 114.8 (2 ×
General procedure for N-protection of 1-arylthiomethyl-5,5-
dimethylhydantoin (3). To a stirred solution of dry acetonitrile
or THF (40 mL) under an atmosphere of dry argon containing 1-
arylthiomethyl-5,5-dimethylhydantoin (3, 0.012 mol) was added
in one portion Boc2O (3.14 g, 0.014 mol) and a catalytic amount
of DMAP. After being stirred at room temperature for 12 to
24 h (the reaction was monitored by TLC using precoated
plate of silica gel and CH2Cl2 as eluent), the reaction mixture
was concentrated in vacuo. The crude resulting viscous oil was
purified by column chromatography on silica gel with a mixture
t
CHaro), 122.7 (Caro–S), 136.1 (2 × CHaro), 148.5 (CO2 Bu), 150.7
=
=
(Caro–O), 160.4 (C2 O), 173.8 (C4 O).
3-tButyloxycarbonyl-1-(p-chlorophenyl)thiomethyl-5,5-di-
methylhydantoin (4g). This product was obtained as a white
solid in 100% yield; mp 114 ◦C (diethyl ether); Found: C, 52.86;
H, 5.35; N, 7.11. Calc. for C17H21ClN2O4S: C, 53.05; H, 5.50;
N, 7.28%; IR mmax (KBr)/cm−1 1752 (C O), 1745 (C O), 1737
=
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7
3 9 4 1

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1
=
(C O); H NMR (300 MHz, CDCl3) d 1.50 (s, 6H, 2 × CH3),
1.52 (s, 9H, 3 × CH3), 4.82 (s, 2H, CH2), 7.24 (d, 2H, J = 9 Hz,
Haro), 7.42 (d, 2H, J = 9 Hz, Haro); 13C NMR (75 MHz, CDCl3)
d 23.1 (2 × CH3), 28.1 (3 × CH3), 43.2 (CH2), 63.2 (C), 84.5
General procedure for regioselective reduction of N-protected-
N-arylthiomethylhydantoin (3a = 4a and 4b–k). To a well
stirred solution of N-protected-N-arylthiomethylhydantoin (4,
6 mmol) in dry ethanol (60 mL) was added in portions at
ambient temperature sodium borohydride (1.37 g, 36 mmol)
over a period of 5 min. After complete reaction (12 to 48 h; the
reaction was monitored by TLC using precoated plate of silica
gel and CH2Cl2 as eluent), the excess of sodium borohydride
was decomposed by careful addition of 10% HCl solution to
pH = 3. After removal of the solvent under reduced pressure,
the residue was diluted with H2O (40 mL) and extracted with
2 × 30 mL of CH2Cl2. The organic phase was separated, dried
with MgSO4, filtered and concentrated under reduced pressure,
to give a solid, which was recrystallized from suitable solvent
to give corresponding 5-hydroxyimidazolidinone 5 in good
yields.
(C(tBu)), 129.4 (2 × CHaro), 131.0 (Caro–Cl), 134.2 (2 × CHaro),
t
=
=
134.7 (Caro–S), 148.3 (CO2 Bu), 150.7 (C2 O), 173.9 (C4 O).
3-tButyloxycarbonyl-5,5-dimethyl-1-(b-naphthyl)thiomethyl-
hydantoin (4h). This product was obtained as a white solid in
95% yield; mp 135 ◦C (diethyl ether–cyclohexane); Found: C,
62.78; H, 6.00; N, 6.84. Calc. for C21H24N2O4S: C, 62.98; H,
6.04; N, 6.99%; IR mmax (KBr)/cm−1 1756 (C O), 1743 (C O),
=
=
1
=
1736 (C O); H NMR (300 MHz, CDCl3) d 1.44 (s, 6H, 2 ×
CH3), 1.51 (s, 9H, 3 × CH3), 4.94 (s, 2H, CH2), 7.41–7.97 (m,
7H, Haro); 13C NMR (75 MHz, CDCl3) d 23.0 (2 × CH3), 28.1
(3 × CH3), 42.8 (CH2), 63.1 (C), 84.3 (C(tBu)), 126.6 (CHaro),
126.7 (CHaro), 127.6 (CHaro), 127.8 (CHaro), 128.9 (CHaro), 129.7
4-Hydroxy-5,5-dimethyl-1-phenylthiomethylimidazolidin-2-
one (5a). This product was isolated as white crystals in 93%
yield; mp 166 ◦C (ethanol–water); Found: C, 57.01; H, 6.14; N,
(CHaro), 131.9 (CHaro), 132.7 (Caro–S), 133.5 (2 × Caro–C), 148.3
t
=
=
(CO2 Bu), 150.7 (C2 O), 173.8 (C4 O).
3-tButyloxycarbonyl-1-(m,p-dimethoxyphenyl)thiomethyl-5,5-
dimethylhydantoin (4i). This product was obtained as a white
10.98. Calc. for C12H16N2O2S: C, 57.12; H, 6.39; N, 11.10%; IR
1
mmax (KBr)/cm−1 3277 (NH and OH), 1698 (C O); H NMR
=
◦
solid in 94% yield; mp 125 C (ethanol–diethyl ether and then
(300 MHz, DMSO d6) d 0.90 (s, 3H, CH3), 1.05 (s, 3H, CH3),
4.32 (d, 1H, J = 13 Hz, CH2), 4.60 (d, 1H, J = 7 Hz, CH),
5.08 (d, 1H, J = 13 Hz, CH2), 6.07 (d, 1H, J = 7 Hz, CH),
6.79 (s broad, 1H, NH), 7.17–7.30 (m, 3H, Haro), 7.33–7.44 (m,
2H, Haro); 13C NMR (75 MHz, DMSO d6) d 21.9 (CH3), 27.7
(CH3), 43.9 (CH2), 55.3 (C), 84.0 (CH), 126.4 (CHaro), 129.0
cyclohexane); Found: C, 55.42; H, 6.22; N, 6.68. Calc. for
C19H26N2O6S: C, 55.59; H, 6.38; N, 6.82%; IR mmax (KBr)/cm−1
1
=
=
=
1752 (C O), 1745 (C O), 1736 (C O); H NMR (300 MHz,
CDCl3) d 1.48 (s, 6H, 2 × CH3), 1.52 (s, 9H, 3 × CH3), 3.82 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 4.78 (s, 2H, CH2), 6.72–6.76
(m, 1H, Haro), 7.02–7.07 (m, 2H, Haro); 13C NMR (75 MHz,
CDCl3) d 23.1 (2 × CH3), 28.1 (3 × CH3), 43.8 (CH2), 56.0
(OCH3), 56.1 (OCH3), 63.1 (C), 84.4 (C(tBu)), 111.4 (CHaro),
=
(2 × CHaro), 129.8 (2 × CHaro), 134.5 (Caro–S), 157.4 (C O).
3-tButyloxycarbonyl-4-hydroxy-5,5-dimethyl-1-phenylthiometh-
ylimidazolidin-2-one (5b). This product was isolated as white
crystals in 89% yield; mp 140 ◦C (ethanol); Found: C, 57.59;
H, 6.68; N, 7.80. Calc. for C17H24N2O4S: C, 57.93; H, 6.86;
116.7 (CHaro), 123.0 (Caro–S), 127.0 (CHaro), 148.4 (Caro–O),
t
=
=
149.1 (Caro–O), 149.8 (CO2 Bu), 150.7 (C2 O), 173.8 (C4 O).
N, 7.95%; IR mmax (KBr)/cm−1 3399 (OH), 1770 (C O), 1759
General procedure for N-alkylation of 5,5-dimethyl-1-
phenylthiomethylhydantoin (3a). To a stirred mixture of 5,5-
dimethyl-1-phenylthiomethylhydantoin (3a, 5 g, 20 mmol) and
18-C-6 (1% w/w) in 50 mL of dry toluene were added solid
potassium carbonate (2.92 g, 22 mmol) and 0.1 equiv. per mmol
of potassium iodide. After stirring for 25 min, 24 mmol of methyl
iodide or benzyl bromide in 50 mL of dry toluene was added
dropwise over a period of 20 min. The mixture was then refluxed
for 24 h and cooled. After filtration over a short column of celite,
the organic phase was concentrated under reduced pressure and
the crude resulting solid was purified by flash chromatography
on silica gel with dichloromethane as eluent to give N-alkylated
imide 4j or 4k. Recrystallization from ethanol afforded pure 4j
or 4k in 91 and 97%, respectively.
=
1
=
(C O); H NMR (300 MHz, CDCl3) d 1.09 (s, 3H, CH3), 1.46
(s, 3H, CH3), 1.48 (s, 9H, 3 × CH3), 3.64 (d, 1H, J = 11 Hz,
OH), 4.53 (d, 1H, J = 14 Hz, CH2), 4.64 (d, 1H, J = 11 Hz,
CH), 5.22 (d, 1H, J = 14 Hz, CH2), 7.18–7.42 (m, 5H, Haro);
13C NMR (75 MHz, CDCl3) d 20.6 (CH3), 24.9 (CH3), 28.3
(3 × CH3), 44.6 (CH2), 61.7 (C), 82.9 (C(tBu)), 83.8 (CH), 127.1
(CHaro), 129.3 (2 × CHaro), 130.2 (2 × CHaro), 133.7 (Caro–S),
t
=
150.3 (CO2 Bu), 153.1 (C O).
1-(o-Bromophenyl)thiomethyl-3-tbutyloxycarbonyl-4-hydroxy-
5,5-dimethylimidazolidin-2-one (5c). This product was isolated
as yellow crystals in 70% yield; mp < 40 ◦C (diethyl ether);
Found: C, 47.22; H, 5.19; N, 6.21. Calc. for C17H23BrN2O4S:
C, 47.34; H, 5.37; N, 6.49%; IR mmax (KBr)/cm−1 3400 (OH),
1
3,5,5-Trimethyl-1-phenylthiomethylhydantoin
(4j). This
=
=
1765 (C O), 1758 (C O); H NMR (300 MHz, CDCl3) d 1.11
(s, 3H, CH3), 1.48 (s, 12H, 4 × CH3), 3.81 (d, 1H, J = 11 Hz,
OH), 4.56 (d, 1H, J = 15 Hz, CH2), 4.67 (d, 1H, J = 11 Hz,
CH), 5.26 (d, 1H, J = 15 Hz, CH2), 6.98–7.07 (m, 1H, Haro),
7.23–7.30 (m, 1H, Haro), 7.44–7.52 (m, 2H, Haro); 13C NMR
(75 MHz, CDCl3) d 20.6 (CH3), 24.9 (CH3), 28.3 (3 × CH3),
43.8 (CH2), 61.8 (C), 83.1 (C(tBu)), 83.6 (CH), 124.3 (Caro–Br),
product was isolated as white prisms in 91% yield; mp 73 ◦C
(cyclohexane); Found: C, 58.87; H, 6.00; N, 10.45. Calc. for
C13H16N2O2S: C, 59.07; H, 6.10; N, 10.60%; IR mmax (KBr)/cm−1
1
=
=
1772 (C O), 1718 (C O); H NMR (300 MHz, CDCl3) d 1.26
(s, 6H, 2 × CH3), 2.83 (s, 3H, CH3), 4.84 (s, 2H, CH2), 7.25–7.33
(m, 3H, Haro), 7.46–7.52 (m, 2H, Haro); 13C NMR (75 MHz,
CDCl3) d 21.9 (2 × CH3), 24.4 (CH3), 42.8 (CH2), 61.2 (C),
127.8 (CHaro), 128.3 (CHaro), 129.9 (CHaro), 133.2 (CHaro), 135.2
t
(Cqaro–S), 150.4 (CO2 Bu), 153.3 (C O).
128.0 (CHaro), 128.2 (Caro–S), 129.0 (2 × CHaro), 132.8 (2 ×
=
+
=
=
CHaro), 153.8 (C2 O), 175.5 (C4 O); MS (m/z: EI) 264 (M ).
t
3- Butyloxycarbonyl-4-hydroxy-1-(o-methoxyphenyl)thiomethyl-
3-Benzyl-5,5-dimethyl-1-phenylthiomethylhydantoin
(4k).
5,5-dimethylimidazolidin-2-one (5d). This product was isolated
as yellow crystals in 86% yield; mp 144 ◦C (ethanol–diethyl
ether); Found: C, 56.41; H, 6.77; N, 7.18. Calc. for C18H26N2O5S:
This product was isolated as white crystal in 97% yield; mp
97 ◦C (cyclohexane–diethyl ether); Found: C, 66.94; H, 5.81; N,
8.16. Calc. for C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23%; IR mmax
C, 56.52; H, 6.85; N, 7.32%; IR mmax (KBr)/cm−1 3406 (OH),
1
1
(KBr)/cm−1 1772 (C O), 1716 (C O); H NMR (300 MHz,
1765 (C O), 1758 (C O); H NMR (300 MHz, CDCl3) d 1.13
(s, 3H, CH3), 1.46 (s, 12H, 4 × CH3), 3.85 (d, 1H, J = 11 Hz,
OH), 3.88 (s, 3H, OCH3), 4.52 (d, 1H, J = 14 Hz, CH2), 4.65 (d,
1H, J = 11 Hz, CH), 5.18 (d, 1H, J = 14 Hz, CH2), 6.82–6.70
(m, 2H, Haro), 7.17–7.26 (m, 1H, Haro), 7.36–7.40 (m, 1H, Haro);
13C NMR (75 MHz, CDCl3) d 20.5 (CH3), 24.9 (CH3), 28.3
(3 × CH3), 43.4 (CH2), 55.9 (OCH3), 61.6 (C), 82.8 (C(tBu)),
84.0 (CH), 111.0 (CHaro), 120.9 (Caro–S), 121.2 (CHaro), 129.2
=
=
=
=
CDCl3) d 11.14 (s, 6H, 2 × CH3), 4.45 (s, 2H, CH2), 4.89 (s,
2H, CH2), 7.16–7.36 (m, 8H, Haro), 7.51–7.55 (m, 2H, Haro); 13
C
NMR (75 MHz, CDCl3) d 23.3 (2 × CH3), 43.0 (CH2), 43.2
(CH2), 62.2 (C), 127.8 (CHaro), 127.9 (2 × CHaro), 128.3 (CHaro),
128.7 (2 × CHaro), 129.1 (2 × CHaro), 132.5 (Caro–S), 133.4 (2 ×
=
=
CHaro), 137.7 (Caro–C), 154.5 (C2 O), 175.5 (C4 O); MS (m/z:
EI) 340 (M+).
3 9 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7

View Article Online
t
(CHaro), 132.8 (CHaro), 150.3 (CO2 Bu), 152.9 (Caro–O), 158.4
(s, 3H, CH3), 1.46 (s, 12H, 4 × CH3), 3.83 (d, 1H, J = 10 Hz,
OH), 3.84 (s, 6H, 2 × OCH3), 4.45 (d, 1H, J = 14 Hz, CH2),
4.62 (d, 1H, J = 10 Hz, CH), 5.10 (d, 1H, J = 14 Hz, CH2),
6.73–6.78 (m, 1H, Haro), 6.95–6.99 (m, 2H, Haro); 13C NMR
(75 MHz, CDCl3) d 20.5 (CH3), 25.0 (CH3), 28.3 (3 × CH3),
45.7 (CH2), 56.0 (OCH3), 56.1 (OCH3), 61.6 (C), 82.9 (C(tBu)),
83.8 (CH), 111.7 (CHaro), 114.6 (CHaro), 124.2 (Caro–S), 124.3
=
(C O).
t
3- Butyloxycarbonyl-4-hydroxy-1-(m-methoxyphenyl)thiomethyl-
5,5-dimethylimidazolidin-2-one (5e). This product was isolated
after a second chromatography purification as yellow crystals in
86% yield; mp 69 C (ethanol–diethyl ether); Found: C, 56.38;
◦
H, 6.79; N, 7.20. Calc. for C18H26N2O5S: C, 56.52; H, 6.85;
t
(CHaro), 148.8 (Caro–O), 149.3 (Caro–O), 150.3 (CO2 Bu), 153.0
N, 7.32%; IR mmax (KBr)/cm−1 3403 (OH), 1759 (C O), 1720
=
=
(C O).
1
=
(C O); H NMR (300 MHz, CDCl3) d 1.12 (s, 3H, CH3), 1.46
4-Hydroxy-3,5,5-trimethyl-1-phenylthiomethylimidazolidin-2-
one (5j). This product was isolated as white crystals in 89%
yield; mp 98 ◦C (diethyl ether–pentane); Found: C, 58.39; H,
(s, 3H, CH3), 1.48 (s, 9H, 3 × CH3), 3.72 (d, 1H, J = 10 Hz,
OH), 3.76 (s, 3H, OCH3), 4.53 (d, 1H, J = 14 Hz, CH2), 4.65 (d,
1H, J = 10 Hz, CH), 5.21 (d, 1H, J = 14 Hz, CH2), 6.72 (dd,
1H, J = 2 and 8 Hz, Haro), 6.94–7.13 (m, 2H, Haro), 7.13–7.22
(m, 1H, Haro); 13C NMR (75 MHz, CDCl3) d 20.5 (CH3), 24.9
(CH3), 28.3 (3 × CH3), 44.4 (CH2), 55.5 (OCH3), 61.7 (C), 82.9
(C(tBu)), 83.8 (CH), 113.4 (CHaro), 114.7 (CHaro), 122.0 (CHaro),
6.69; N, 10.41. Calc. for C13H18N2O2S: C, 58.62; H, 6.81; N,
1
10.52%; IR mmax (KBr)/cm−1 3345 (OH), 1701 (C O); H NMR
=
(300 MHz, CDCl3) d 0.91 (s, 3H, CH3), 1.20 (s, 3H, CH3), 2.61
(s, 3H, CH3), 3.20 (d, 1H, J = 10 Hz, OH), 4.48 (d, 1H, J =
14 Hz, CH2), 4.74 (d, 1H, J = 10 Hz, CH), 5.17 (d, 1H, J =
14 Hz, CH2), 7.18–7.31 (m, 3H, Haro), 7.40–7.45 (m, 2H, Haro);
13C NMR (75 MHz, CDCl3) d 19.1 (CH3), 23.3 (CH3), 24.6
(CH3), 45.1 (CH2), 59.8 (C), 83.4 (CH), 127.0 (CHaro), 129.1
t
130.2 (CHaro), 135.0 (Caro–S), 150.3 (CO2 Bu), 153.0 (Caro–O),
=
160.0 (C O).
t
3- Butyloxycarbonyl-4-hydroxy-1-(p-methoxyphenyl)thiomethyl-
5,5-dimethylimidazolidin-2-one (5f). This product was isolated
as a white crystal in 93% yield; mp 66 ◦C (cyclohexane–diethyl
ether); Found: C, 56.40; H, 6.73; N, 7.16. Calc. for C18H26N2O5S:
C, 56.52; H, 6.85; N, 7.32%; IR mmax (KBr)/cm−1 3400 (OH),
=
(2 × CHaro), 130.6 (2 × CHaro), 134.1 (Caro–S), 157.1 (C O).
3-Benzyl-4-hydroxy-5,5-dimethyl-1-phenylthiomethylimida-
zolidin-2-one (5k). This product was isolated as white crystals
in 84% yield; mp 161 ◦C (diethyl ether–pentane); Found: C,
1768 (C O), 1758 (C O); 1H NMR (300 MHz, CDCl3) d
1.15 (s, 3H, CH3), 1.46 (s, 12H, 4 × CH3), 3.75 (s, 3H, OCH3),
4.41 (d, 1H, J = 14 Hz, CH2), 4.62 (s, 1H, CH), 5.04 (d, 1H,
J = 14 Hz, CH2), 6.50 (s broad, 1H, OH), 6.79 (d, 2H, J =
9 Hz, Haro), 7.35 (d, 2H, J = 9 Hz, Haro); 13C NMR (75 MHz,
CDCl3) d 20.6 (CH3), 25.0 (CH3), 28.2 (3 × CH3), 46.1 (CH2),
55.4 (OCH3), 61.6 (C), 82.8 (C(tBu)), 83.7 (CH), 114.8 (2 ×
=
=
66.49; H, 6.31; N, 8.02. Calc. for C19H22N2O2S: C, 66.64; H,
1
6.48; N, 8.18%; IR mmax (KBr)/cm−1 3280 (OH), 1679 (C O); H
=
NMR (300 MHz, CDCl3) d 0.72 (s, 3H, CH3), 1.07 (s, 3H, CH3),
2.71 (d, 1H, J = 9 Hz, OH), 4.12 (d, 1H, J = 16 Hz, CH2), 4.31
(d, 1H, J = 16 Hz, CH2), 4.44 (d, 1H, J = 14 Hz, CH2), 4.72 (d,
1H, J = 9 Hz, CH), 5.26 (d, 1H, J = 14 Hz, CH2), 7.07–7.31
(m, 8H, Haro), 7.40–7.44 (m, 2H, Haro); 13C NMR (75 MHz,
CDCl3) d 19.9 (CH3), 25.4 (CH3), 43.2 (CH2), 45.4 (CH2), 60.5
(C), 84.8 (CH), 127.1 (2 × CHaro), 127.7 (CHaro), 128.5 (CHaro),
128.7 (2 × CHaro), 129.2 (2 × CHaro), 130.6 (Caro–S), 131.1 (2 ×
t
CHaro), 123.8 (Caro–S), 133.6 (2 × CHaro), 150.3 (CO2 Bu), 153.1
=
(Caro–O), 159.4 (C O).
3-tButyloxycarbonyl-1-(p-chlorophenyl)thiomethyl-4-hydroxy-
5,5-dimethylimidazolidin-2-one (5g). This product was isolated
as white crystals in 92% yield; mp 139 ◦C (ethanol–diethyl ether);
Found: C, 52.56; H, 5.79; N, 7.05. Calc. for C17H23ClN2O4S: C,
=
CHaro), 139.4 (Caro–C), 157.1 (C2 O).
General procedure for cyclisation of 5-hydroxyimidazolidinones
5. To a stirred and cold solution of 5-hydroxyimidazolidinone
5 (2.5 mmol) was added neat TFA (4 mL). After 24 h of reaction
at room temperature under stirring, the reaction mixture was
diluted with water (5 mL) and CH2Cl2 (10 mL) and neutralized
with 10% NaOH aqueous solution. The solution was extracted
twice with CH2Cl2 (10 mL). The organic layer was washed
with water, separated, dried over MgSO4 and evaporated. The
resulting residue was purified by flash chromatography (SiO2,
CH2Cl2–hexane (9 : 1)) to give the tricyclic product 6 as white
crystals in 21 to 91% yields.
52.77; H, 5.99; N, 7.24%; IR mmax (KBr)/cm−1 3391 (OH), 1769
1
=
=
(C O), 1760 (C O); H NMR (300 MHz, CDCl3) d 1.10 (s,
3H, CH3), 1.46 (s, 3H, CH3), 1.47 (s, 9H, 3 × CH3), 4.11 (d, 1H,
J = 11 Hz, OH), 4.51 (d, 1H, J = 15 Hz, CH2), 4.62 (d, 1H, J =
11 Hz, CH), 5.19 (d, 1H, J = 15 Hz, CH2), 7.22 (d, 2H, J =
9 Hz, Haro), 7.33 (d, 2H, J = 9 Hz, Haro); 13C NMR (75 MHz,
CDCl3) d 20.6 (CH3), 24.9 (CH3), 28.3 (3 × CH3), 44.4 (CH2),
61.8 (C), 83.1 (C(tBu)), 83.6 (CH), 129.4 (2 × CHaro), 131.2 (2 ×
t
CHaro), 132.3 (Caro–Cl), 132.9 (Caro–S), 150.3 (CO2 Bu), 153.3
=
(C O).
3-tButyloxycarbonyl-4-hydroxy-5,5-dimethyl-1-(b-naphthyl)-
thiomethylimidazolidin-2-one (5h). This product was isolated
as white crystals in 90% yield; mp 125 ◦C (cyclohexane–diethyl
ether); Found: C, 62.53; H, 6.42; N, 6.79. Calc. for C21H26N2O4S:
2,3,3a,9-Tetrahydro-3,3-dimethylimidazo[5,1-b][1,3]benzothiazin-
1-one (6a). This product was isolated as white crystals in
56–92% yield; mp 162 ◦C (diethyl ether–pentane); Found: C,
61.35; H, 5.85; N, 11.79. Calc. for C12H14N2OS: C, 61.51; H,
6.02; N, 11.96%; IR mmax (KBr)/cm−1 3249 (NH), 1703 (C O);
=
C, 62.66; H, 6.51; N, 6.96%; IR mmax (KBr)/cm−1 3400 (OH),
1H NMR (300 MHz, CDCl3) d 1.40 (s, 3H, CH3), 1.43 (s, 3H,
CH3), 4.30 (d, 1H, J = 17 Hz, CH2), 4.81 (s, 1H, CH), 4.87 (d,
1H. J = 17 Hz, CH2), 5.13 (s broad, 1H, NH), 7.08–7.22 (m,
4H, Haro); 13C NMR (75 MHz, CDCl3) d 23.9 (CH3), 28.7 (CH3),
43.9 (CH2), 55.8 (C), 69.2 (CH), 125.8 (CHaro), 127.1 (CHaro),
1
=
=
1767 (C O), 1758 (C O); H NMR (300 MHz, CDCl3) d 1.07
(s, 3H, CH3), 1.45 (s, 12H, 4 × CH3), 3.82 (d, 1H, J = 11 Hz,
OH), 4.61 (d, 1H, J = 14 Hz, CH2), 4.67 (d, 1H, J = 11 Hz,
CH), 5.31 (d, 1H, J = 14 Hz, CH2), 7.38–7.51 (m, 3H, Haro),
7.70–7.87 (m, 4H, Haro); 13C NMR (75 MHz, CDCl3) d 20.6
(CH3), 24.9 (CH3), 28.2 (3 × CH3), 44.5 (CH2), 61.7 (C), 82.9
(C(tBu)), 83.7 (CH), 126.1 (CHaro), 126.6 (CHaro), 127.4 (CHaro),
127.6 (CHaro), 127.8 (CHaro), 128.9 (CHaro), 129.0 (CHaro), 131.0
127.9 (CHaro), 129.3 (CHaro), 130.6 (Caro–S), 131.8 (Caro–C),
+
=
159.7 (C O); MS (m/z: EI) 234 (M ).
X-Ray crystallographic analysis of benzothiazinone (6a)‡.
(Caro–S), 132.1 (Cqaro–C), 133.7 (Caro–C), 150.3 (CO2 Bu), 153.2
t
C12H14N2OS, Mr = 234.31, monoclinic, P21/c, a = 7.569(2),
◦
=
(C O).
˚
b = 18.652(2), c = 8.388(2) A, b = 103.69(3) , V = 1150.6(7)
−3
−3
˚
˚
A , Z = 4, Dx = 1.353 mg m , k (Mo Ka) = 0.71073 A, l =
2.61 cm−1, F(000) = 496, T = 293 K. The sample (0.45*0.32*0.32
mm) is studied on an automatic diffractometer CAD4 NONIUS
3-tButyloxycarbonyl-4-hydroxy-1-(m,p-dimethoxyphenyl)-
thiomethyl-5,5-dimethylimidazolidin-2-one (5i). This product
was isolated as white crystals in 100% yield; mp 130 ◦C (diethyl
ether); Found: C, 55.21; H, 6.70; N, 6.55. Calc. for C19H28N2O6S:
C, 55.32; H, 6.84; N, 6.79%; IR mmax (KBr)/cm−1 3392 (OH),
‡ CCDC reference numbers 266273–266274. For crystallographic data
in CIF format see DOI: 10.1039/b508214e
1
=
=
1770 (C O), 1757 (C O); H NMR (300 MHz, CDCl3) d 1.14
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7
3 9 4 3

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with graphite monochromatized Mo Ka radiation.16 The cell
parameters are obtained by fitting a set of 25 high-theta
reflections. The data collection (2hmax = 54◦, scan x/2h = 1,
tmax = 60 s, range HKL: H 0,9 K 0,23 L-10,10) gives 2687
unique reflections from which 1868 with I > 2.0r(I). After
Lorenz and polarization corrections17 the structure was solved
with SIR-9718 which reveals the non hydrogen atoms of the
compound. After anisotropic refinement a Fourier difference
reveals many hydrogen atoms. The whole structure was refined
with SHELXL97 by the full-matrix least-square techniques (use
of F square magnitude; x, y, z, bij for S, C, O and N atoms, x, y, z
in riding mode for H atoms; 149 variables and 2505 observations;
calc. w = 1/[r2(Fo2)+(0.057P)2] where P = (Fo2 + 2Fc2)/3 with
the resulting R = 0.035, Rw = 0.094 and Sw = 1.043 (residual
1H, J = 8 Hz, Haro), 8.04 (d, 1H, J = 8 Hz, Haro); 13C NMR
(75 MHz, DMSO-d6) d 25.1 (CH3), 29.8 (CH3), 43.5 (CH2), 59.2
(C), 61.2 (CH), 122.8 (CHaro), 125.3 (Caro–C), 125.4 (CHaro),
126.6 (CHaro), 127.2 (CHaro), 128.2 (CHaro), 128.9 (CHaro), 131.9
=
(Caro–C), 132.2 (Caro–C), 133.7 (Caro–S), 158.9 (C O); MS (m/z:
EI) 284 (M+).
2,3,3a,9-Tetrahydro-6,7-dimethoxy-3,3-dimethylimidazo[5,1-
b][1,3]benzothiazin-1-one (6i). This product was isolated as
white crystals in 55% yield; mp 207 ◦C (ethanol); Found: C,
57.01; H, 6.03; N, 9.36. Calc. for C14H18N2O3S: C, 57.12; H,
6.16; N, 9.52%; IR mmax (KBr)/cm−1 3234 (NH), 1704 (C O);
=
1H NMR (300 MHz, CDCl3) d 0.77 (s, 3H, CH3), 1.50 (s,
3H, CH3), 3.82 (s, 6H, 2 × OCH3), 4.09 (d, 1H, J = 13 Hz,
CH2), 4.74 (s, 1H, CH), 4.98 (d, 1H, J = 13 Hz, CH2), 5.47 (s
broad, 1H, NH), 6.51 (s, 1H, Haro), 6.68 (s, 1H, Haro); 13C NMR
(75 MHz, CDCl3) d 24.8 (CH3), 28.5 (CH3), 42.5 (CH2), 56.0
(OCH3), 56.2 (OCH3), 60.2 (C), 65.0 (CH), 110.8 (CHaro), 112.5
−3
˚
Dq ≤ 0.27 eA ).
Atomic scattering factors from International Tables for X-ray
Crystallography (1992). Ortep views realized with PLATON9820
and Ortep-3 for Windows.21 All the calculations were performed
on a Pentium NT Server computer. See the electronic supple-
mentary information for further data for compound 6a.
(CHaro), 121.3 (Caro–S), 125.3 (Caro–C), 147.4 (Caro–O), 148.3
+
=
(Caro–O), 159.6 (C O); MS (m/z: EI) 294 (M ).
Procedure for N-protection of N,S-acetal cyclic compound 6a
by Boc group; access to 2-tbutyloxycarbonyl-2,3,3a,9-tetrahydro-
2,3,3-trimethylimidazo[5,1-b][1,3]benzothiazin-1-one (6b). Ac-
cording to the typical procedure reported above for N-protected
imide 4, this product was obtained in quantitative yield as
a white–yellow solid by reaction of 2,3,3a,9-tetrahydro-3,3-
dimethylimidazo[5,1-b][1,3]benzothiazin-1-one 6a with Boc2O
and melted at 140 ◦C (diethyl ether–cyclohexane); Found: C,
61.00; H, 6.44; N, 8.25. Calc. for C17H22N2O3S: C, 61.05; H,
5-Bromo-2,3,3a,9-tetrahydro-3,3-dimethylimidazo[5,1-b]-
[1,3]benzothiazin-1-one (6c). This product was isolated as
white crystals in 21% yield; mp 184 ◦C (ethanol); Found: C,
45.87; H, 4.07; N, 8.84. Calc. for C12H13BrN2OS: C, 46.02; H,
4.18; N, 8.94%; IR mmax (KBr)/cm−1 3249 (NH), 1703 (C O);
=
1H NMR (300 MHz, CDCl3) d 1.41 (s, 3H, CH3), 1.49 (s, 3H,
CH3), 4.24 (d, 1H, J = 17 Hz, CH2), 4.82 (s, 1H, CH), 4.88 (d,
1H, J = 17 Hz, CH2), 5.03 (s broad, 1H, NH), 6.94–7.12 (m,
2H, Haro), 7.41–7.45 (m, 1H, Haro); 13C NMR (75 MHz, CDCl3)
d 23.7 (CH3), 28.6 (CH3), 43.9 (CH2), 55.9 (C), 69.3 (CH), 123.6
(Caro–Br), 126.1 (CHaro), 126.5 (CHaro), 131.1 (CHaro), 132.5
6.63; N, 8.38%; IR mmax (KBr)/cm−1 1706 (C O), 1698 (C O);
1H NMR (300 MHz, CDCl3) d 01.53 (s, 9H, 3 × CH3), 1.55 (s,
3H, CH3), 1.67 (s, 3H, CH3), 4.32 (d, 1H, J = 17 Hz, CH2), 4.78
(s, 1H, CH), 4.98 (d, 1H, J = 17 Hz, CH2), 7.11–7.16 (m, 4H,
Haro); 13C NMR (75 MHz, CDCl3) d 22.5 (CH3), 25.8 (CH3),
28.2 (3 × CH3), 43.9 (CH2), 60.3 (C), 67.5 (CH), 82.9 (C(tBu)),
=
=
+
=
(Caro–S), 133.1 (Caro–C), 159.1 (C O); MS (m/z: EI) 311 (M ).
2,3,3a,9-Tetrahydro-5-methoxy-3,3-dimethylimidazo[5,1-b]-
[1,3]benzothiazin-1-one (6d). This product was isolated as
yellow crystals in 29% yield; mp 182 ◦C (ethanol–diethyl ether);
Found: C, 58.91; H, 5.87; N, 10.36. Calc. for C13H16N2O2S: C,
126.0 (CHaro), 127.3 (CHaro), 127.8 (CHaro), 129.2 (CHaro), 129.6
t
=
=
(Caro), 131.2 (Caro), 149.7 (CO2 Bu), 150.4 (C O), 153.5 (C O).
59.07; H, 6.10; N, 10.60%; IR mmax (KBr)/cm−1 3260 (NH), 1698
1
General procedure for N-alkylation of 2,3,3a,9-tetrahydro-
3,3-dimethylimidazo[5,1-b][1,3]benzothiazin-1-one (6a); access
to tricyclic systems 6j and 6k. To a stirred solution un-
der an atmosphere of dry argon of 2,3,3a,9-tetrahydro-
3,3-dimethylimidazo[5,1-b][1,3]benzothiazin-1-one (6a, 702 mg,
3 mmol) in 30 mL of dry THF was added in three portions
(86.4 mg, 3.6 mmol) of sodium hydride (60% in mineral oil).
After stirring for 35 min at room temperature, methyl iodide
(3.6 mmol) or benzyl chloride (3.6 mmol) in 15 mL of the same
solvent was added slowly dropwise over a period of 15 min. The
mixture was then allowed to react at ambient temperature for
60 h. After cooling, the solution was poured onto water and the
precipitate formed was filtered and dried. The resultant solid
was recrystallized from ethanol to give the N-alkylated cyclic
derivative 6j (62% yield) and 6k (58% yield).
=
(C O); H NMR (300 MHz, CDCl3) d 1.38 (s, 3H, CH3), 1.47
(s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.30 (d, 1H, J = 17 Hz, CH2),
4.73 (s, 1H, CH), 4.87 (d, 1H, J = 17 Hz, CH2), 5.35 (s broad,
1H, NH), 6.66 (d, 1H, J = 7 Hz, Haro), 6.76 (d, 1H, J = 7 Hz,
Haro), 7.07 (t, 1H, J = 7 Hz, Haro); 13C NMR (75 MHz, CDCl3)
d 23.7 (CH3), 28.7 (CH3), 43.4 (CH2), 55.8 (C), 56.1 (OCH3),
67.8 (CH), 108.3 (CHaro), 120.1 (CHaro), 120.5 (Caro–S), 125.5
=
(CHaro), 130.9 (Caro–C), 155.9 (Caro–O), 159.5 (C O); MS (m/z:
EI) 264 (M+).
2,3,3a,9-Tetrahydro-8-methoxy-3,3-dimethylimidazo[5,1-b]-
[1,3]benzothiazin-1-one (6e). This ◦product was isolated as
white prisms in 77% yield; mp 176 C (ethanol–diethyl ether);
Found: C, 58.88; H, 5.95; N, 10.50. Calc. for C13H16N2O2S: C,
59.07; H, 6.10; N, 10.60%; IR mmax (KBr)/cm−1 3425 (NH), 1709
1
=
(C O); H NMR (300 MHz, CDCl3) d 0.76 (s, 3H, CH3), 1.48
2,3,3a,9-Tetrahydro-2,3,3-trimethylimidazo[5,1-b][1,3]benzo-
thiazin-1-one (6j). This product was isolated as white crystals
in 62% yield; mp 98 ◦C (diethyl ether); Found: C, 62.66; H, 6.25;
(s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.15 (d, 1H, J = 12 Hz, CH2),
4.67 (s broad, 1H, NH), 4.80 (s, 1H, CH), 5.01 (d, 1H, J =
12 Hz, CH2), 6.69–6.77 (m, 2H, Haro), 6.98 (d, 1H, J = 8 Hz,
Haro); 13C NMR (75 MHz, CDCl3) d 24.9 (CH3), 28.4 (CH3),
42.2 (CH2), 55.4 (OCH3), 60.2 (C), 64.8 (CH), 112.8 (CHaro),
N, 11.09. Calc. for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28%;
1
IR mmax (KBr)/cm−1 1694 (C O); H NMR (300 MHz, CDCl3)
=
d 1.28 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.74 (s, 3H, CH3), 4.28 (d,
1H, J = 17 Hz, CH2), 4.82 (s, 1H, CH), 4.88 (d, 1H, J = 17 Hz.
CH2), 7.07–7.18 (m, 4H, Haro); 13C NMR (75 MHz, CDCl3) d
21.5 (CH3), 23.6 (CH3), 24.8 (CH3), 44.4 (CH2), 58.8 (C), 68.5
(CH), 125.8 (CHaro), 127.1 (CHaro), 127.9 (CHaro), 129.3 (CHaro),
114.2 (CHaro), 121.6 (Caro–S), 128.9 (CHaro), 135.1 (Caro–C),
+
=
158.3 (Caro–O), 159.6 (C O); MS (m/z: EI) 264 (M ).
2,3,3a,9-Tetrahydro-3,3-dimethylimidazo[5,1-b][1,3]naphthen-
1-one (6h). This product was isolated as white crystals in 61%
yield; mp 260 ◦C (ethanol–DMF); Found: C, 67.33; H, 5.54; N,
=
130.9 (Caro–S), 131.9 (Caro–C), 158.5 (C O); MS (m/z: EI) 248
9.77. Calc. for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85%; IR
(M+).
1
mmax (KBr)/cm−1 3199 (NH), 1727 (C O); H NMR (300 MHz,
=
DMSO-d6) d 0.42 (s, 3H, CH3), 1.52 (s, 3H, CH3), 4.19 (d, 1H,
J = 12 Hz, CH2), 4.94 (d, 1H, J = 12 Hz, CH2), 5.83 (s, 1H,
CH), 7.24 (s broad, 1H, NH), 7.32 (d, 1H, J = 9 Hz, Haro),
7.45–7.60 (m, 2H, Haro), 7.76 (d, 1H, J = 9 Hz, Haro), 7.91 (d,
2-Benzyl-2,3,3a,9-tetrahydro-3,3-dimethylimidazo[5,1-b][1,3]-
benzothiazin-1-one (6k). This product was isolated as white
crystals in 58% yield; mp 112 ◦C (cyclohexane); Found: C,
70.20; H, 6.08; N, 8.51. Calc. for C19H20N2OS: C, 70.34; H,
3 9 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7

View Article Online
1
6.21; N, 8.63%; IR mmax (KBr)/cm−1 1694 (C O); H NMR
(300 MHz, CDCl3) d 1.24 (s, 3H, CH3), 1.27 (s, 3H, CH3), 4.23
(d, 1H, J = 16 Hz, CH2), 4.36 (d, 1H, J = 16 Hz, CH2), 4.61 (d,
1H, J = 16 Hz, CH2), 4.81 (s, 1H, CH), 5.01 (d, 1H, J = 16 Hz,
CH2), 7.11–7.30 (m, 9H, Haro); 13C NMR (75 MHz, CDCl3) d
22.2 (CH3), 25.1 (CH3), 43.1 (CH2), 44.4 (CH2), 59.6 (C), 68.7
(CH), 125.8 (CHaro), 127.0 (CHaro), 127.1 (CHaro), 127.2 (2 ×
CHaro), 127.8 (CHaro), 128.5 (2 × CHaro), 129.3 (CHaro), 130.6
3-(o-Benzylthiobenzyl)-4-hydroxy-5,5-dimethylimidazolidin-2-
one (10y). According to the typical procedure reported
above for reduction of N-protected imide 4, this product was
obtained in 84% yield as a white–yellow solid by reduction
of 3-(o-ethylthiobenzyl)-5,5-dimethylhydantoin (9y) with
6 mole equiv. of NaBH4 at 20 ◦C for 24 h in ethanol and melted
at 150 ◦C (ethanol); Found: C, 66.54; H, 6.21; N, 8.03. Calc. for
C19H22N2O2S: C, 66.64; H, 6.48; N, 8.18%; IR mmax (KBr)/cm−1
=
(Caro–S), 131.7 (Caro–C), 139.2 (Caro–C), 158.8 (C O); MS (m/z:
3363 (NH and OH), 1680 (C O); 1H NMR (300 MHz,
=
=
EI) 324 (M+).
DMSO-d6) d 1.10 (s, 3H, CH3), 1.12 (s, 3H, CH3), 4.15 (d, 1H,
J = 15 Hz, CH2), 4.23 (s, 2H, CH2), 4.33 (d, 1H, J = 7 Hz,
CH), 4.41 (d, 1H, J = 15 Hz, CH2), 5.91 (d, 1H, J = 7 Hz, OH),
6.73 (s broad, 1H, NH), 7.19–7.39 (m, 9H, Haro); 13C NMR
(75 MHz, DMSO-d6) d 22.1 (CH3), 27.9 (CH3), 36.5 (CH2),
40.6 (CH2), 55.6 (C), 85.7 (CH), 125.7 (CHaro), 127.2 (CHaro),
127.4 (CHaro), 127.5 (CHaro), 128.1 (CHaro), 128.5 (2 × CHaro),
129.0 (2 × CHaro), 134.9 (Caro–S), 136.9 (Caro–C), 137.2 (Caro–C),
General procedure for N-alkylation of 5,5-dimethylhydantoin
(8). To a stirred mixture of 5,5-dimethylhydantoin (8, 2.56 g,
20 mmol) and 18-C-6 (1% w/w) in 50 mL of dry toluene
were added solid potassium carbonate (2.92 g, 24 mmol) and
0.1 equiv. per mmol of 5,5-dimethylhydantoin (8) of potassium
iodide. After stirring for 25 min, o-ethylthiobenzyl bromide (7x,
5.52 g, 24 mmol) or o-benzylthiobenzyl bromide (7y, 7.04 g,
24 mmol)5a,6 in 50 mL of dry toluene was added dropwise over a
period of 20 min. The mixture was then refluxed for 48 h under
stirring and cooled. After filtration over a short column of celite,
the organic phase was concentrated under reduced pressure and
the crude resulting solid was purified by flash chromatography
on silica gel with dichloromethane as eluent to give 3-alkylated-
5,5-dimethylhydantoin derivative 9x or 9y. All data for these
products are as follows.
=
158.9 (C O).
1-(o-Ethylthiobenzyl)-4,5-dimethylimidazol-2(3H)-one (11x)
by simple transposition of 4-hydroxyimidazolidinone 10x in acid
medium. To a stirred solution of 4-hydroxyimidazolidinone
(10x, 560 mg, 2 mmol) in dry toluene was added a catalytic
amount of PTSA. After 48 h of reaction at reflux under
stirring, the reaction mixture was cooled, concentrated under
reduced pressure, diluted with water (10 mL) and CH2Cl2
(15 mL) and neutralized slowly on cooling with 5% NaOH
aqueous solution. The solution was extracted twice with CH2Cl2
(15 mL). The organic layer was washed with water, brine,
dried over MgSO4 and evaporated. The resulting oily residue
was purified by flash chromatography using a mixture of
cyclohexane–AcOEt (1 : 1) as eluent to give the imidazolone
derivative 11x as yellow oil in 58% yield; Found: C, 64.00;
3-(o-Ethylthiobenzyl)-5,5-dimethylhydantoin (9x). This
product was isolated as an uncolored oil in 63% yield; Found:
C, 60.18; H, 6.35; N, 9.87. Calc. for C14H18N2O2S: C, 60.40; H,
6.52; N, 10.06%; IR mmax (KBr)/cm−1 3294 (NH), 1761 (C O),
=
1
=
1712 (C O); H NMR (300 MHz, CDCl3) d 1.29 (t, 3H, J =
7 Hz, CH3), 1.44 (s, 6H, 2 × CH3), 2.95 (q, 2H, J = 7 Hz, CH2),
4.83 (s, 2H, CH2), 6.20 (s broad, 1H, NH), 7.00–7.21 (m, 3H,
Haro), 7.33–7.38 (m, 1H, Haro); 13C NMR (75 MHz, CDCl3) d
14.5 (CH3), 25.2 (2 × CH3), 28.4 (CH2), 40.1 (CH2), 59.0 (C),
126.5 (CHaro), 126.6 (CHaro), 128.0 (CHaro), 130.4 (CHaro), 134.9
H, 6.76; N, 10.45. Calc. for C14H18N2OS: C, 64.09; H, 6.91;
1
N, 10.68%; IR mmax (KBr)/cm−1 3332 (NH), 1692 (C O); H
=
NMR (300 MHz, CDCl3) d 1.30 (t, 3H, J = 7 Hz, CH3),
1.74 (s, 3H, CH3), 1.96 (s, 3H, CH3), 2.92 (q, 2H, J = 7 Hz,
CH2), 4.91 (s, 2H, CH2), 7.11–7.21 (m, 3H, Haro), 7.31–7.34
(m, 1H, Haro), 9.79 (s broad, 1H, NH); MS (m/z: EI) 262
(M+).
=
=
(Caro–S), 135.8 (Caro–C), 156.6 (C2 O), 177.3 (C4 O); MS (m/z:
EI) 278 (M+).
3-(o-Benzylthiobenzyl)-5,5-dimethylhydantoin
(9y). This
product was isolated as a white–yellow solid in 73% yield; mp
General procedure for S-alkylation of 3-bromomethyl-5,5-
dimethylhydantoin (13). By using same protocol described
above for S-alkylation of 3-bromomethyl-5,5-dimethylhy-
dantoin (2), reaction of 3-bromomethyl-5,5-dimethylhydantoin
(13)14 with 1.2 mole equiv. of substituted thiophenol 12j,l–n in
the presence of MeONa (1.2 mole equiv.) in dry DMF at ambient
temperature for 12 to 24 h give suitable S-alkylated products
14j,l–n in good yields.
88 ◦C (ethanol–cyclohexane); Found: C, 66.86; H, 5.78; N, 8.02.
Calc. for C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23%; IR mmax
1
(KBr)/cm−1 3300 (NH), 1774 (C O), 1714 (C O); H NMR
(300 MHz, CDCl3) d 1.44 (s, 6H, 2 × CH3), 4.09 (s, 2H, CH2),
4.78 (s, 2H, CH2), 6.00 (s broad, 1H, NH), 7.02–7.07 (m, 1H,
Haro), 7.13–7.33 (m, 8H, Haro); 13C NMR (75 MHz, CDCl3) d
25.3 (2 × CH3), 39.9 (CH2), 40.0 (CH2), 59.0 (C), 126.7 (CHaro),
127.3 (CHaro), 127.6 (CHaro), 128.1 (CHaro), 128.6 (2 × CHaro),
129.1 (2 × CHaro), 132.6 (CHaro), 134.3 (Caro–S), 137.0 (Caro–C),
=
=
1,5,5-Trimethyl-3-phenylthiomethylhydantoin (14j). This
=
=
137.4 (Caro–C), 156.4 (C2 O), 177.2 (C4 O); MS (m/z: EI) 340
product was isolated as a white solid in 85% yield; mp
◦
(M+).
77 C (ethanol); Found: C, 59.07; H, 6.10; N, 10.60. Calc. for
C13H16N2O2S: C, 58.81; H, 6.02; N, 10.45%; IR mmax (KBr)/cm−1
1
3-(o-Ethylthiobenzyl)-4-hydroxy-5,5-dimethylimidazolidin-2-
one (10x). According to the typical procedure reported above
for sodium borohydride reduction of N-protected imide 4,
this product was obtained in 94% yield as a white solid by
reduction of 3-(o-ethylthiobenzyl)-5,5-dimethylhydantoin (9x)
with 6 mole equiv. of NaBH4 at 20 ◦C for 24 h in ethanol
and melted at 129 ◦C (ethanol); Found: C, 59.77; H, 7.05; N,
=
=
1776 (C O), 1713 (C O); H NMR (300 MHz, CDCl3) d 1.26
(s, 6H, 2 × CH3), 2.83 (s, 3H, CH3), 4.84 (s, 2H, CH2), 7.25–
7.31 (m, 3H, Haro), 7.48–7.52 (m, 2H, Haro); 13C NMR (75 MHz,
CDCl3) d 21.8 (2 × CH3), 24.3 (CH3), 42.6 (CH2), 61.1 (C),
127.9 (CHaro), 128.9 (2 × CHaro), 132.6 (2 × CHaro), 132.7 (Caro
–
+
=
=
S), 153.6 (C2 O), 175.3 (C4 O); MS (m/z: EI) 264 (M ).
9.81. Calc. for C14H20N2O2S: C, 59.97; H, 7.19; N, 9.99%; IR
3-(o-Bromophenyl)thiomethyl-1,5,5-trimethylhydantoin (14l).
This product was isolated after a second chromatography
purification as a white–yellow solid in 85% yield; mp 110 ◦C
(ethanol–cyclohexane); Found: C, 45.31; H, 4.29; N, 8.00.
1
mmax (KBr)/cm−1 3299 (NH and OH), 1693 (C O); H NMR
=
(300 MHz, CDCl3) d 1.19 (s, 3H, CH3), 1.26 (s, 3H, CH3), 1.29
(t, 3H, J = 7 Hz, CH3), 2.92 (q, 2H, J = 7 Hz, CH2), 4.06 (d,
1H, J = 10 Hz, OH), 4.39 (d, 1H, J = 10 Hz, CH), 4.41 (d, 1H,
J = 15 Hz, CH2), 4.75 (d, 1H, J = 15 Hz, CH2), 4.80 (s broad,
1H, NH), 7.12–7.35 (m, 4H, Haro); 13C NMR (75 MHz, CDCl3)
d 14.3 (CH3), 22.2 (CH3), 27.8 (CH2). 28.2 (CH3), 41.7 (CH2),
56.5 (C), 86.7 (CH), 126.2 (CHaro), 128.1 (CHaro), 128.9 (CHaro),
Calc. for C13H15BrN2O2S: C, 45.49; H, 4.40; N, 8.16%; IR mmax
1
(KBr)/cm−1 1775 (C O), 1715 (C O); H NMR (300 MHz,
CDCl3) d 1.28 (s, 6H, 2 × CH3), 2.83 (s, 3H, CH3), 4.88 (s, 2H,
CH2), 7.08–7.28 (m, 2H, Haro), 7.56–7.67 (m, 2H, Haro); 13C NMR
(75 MHz, CDCl3) d 21.9 (2 × CH3), 24.4 (CH3), 42.1 (CH2), 61.2
(C), 127.9 (Caro–Br), 127.9 (CHaro), 129.5 (CHaro), 133.3 (CHaro),
=
=
=
129.5 (CHaro), 135.7 (Caro–S), 136.7 (Caro–C), 159.7 (C O).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7
3 9 4 5

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=
=
134.1 (Caro–S), 134.2 (CHaro), 153.7 (C2 O), 175.5 (C4 O); MS
d 19.1 (CH3), 23.3 (CH3), 24.6 (CH3), 43.8 (CH2), 55.9 (OCH3),
59.7 (C), 84.6 (CH), 110.9 (CHaro), 121.0 (CHaro), 121.3 (Caro–S),
(m/z: EI) 342 (M+).
=
129.1 (CHaro), 133.2 (CHaro), 157.1 (Caro–O), 158.5 (C O).
3-(o-Methoxyphenyl)thiomethyl-1,5,5-trimethylhydantoin
(14m). This product was isolated as an uncolored oil in 75%
yield; Found: C, 57.00; H, 6.02; N, 9.37. Calc. for C14H18N2O3S:
4-Hydroxy-3-(m,p-dimethoxyphenyl)thiomethyl-1,5,5-tri-
methylimidazolidin-2-one (15n). This product was isolated as
a white–yellow solid in 95% yield; mp 92 ◦C (ethanol); Found:
C, 55.03; H, 6.56; N, 8.40. Calc. for C15H22N2O4S: C, 55.19; H,
C, 57.12; H, 6.16; N, 9.52%; IR mmax (KBr)/cm−1 1781 (C O),
=
1
=
1714 (C O); H NMR (300 MHz, CDCl3) d 1.19 (s, 6H, 2 ×
6.79; N, 8.58%; IR mmax (KBr)/cm−1 3308 (OH), 1687 (C O);
=
CH3), 2.79 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 4.85 (s, 2H, CH2),
6.76–6.88 (m, 2H, Haro), 7.29–7.42 (m, 2H, Haro); 13C NMR
(75 MHz, CDCl3) d 21.9 (2 × CH3), 24.4 (CH3), 40.6 (CH2),
55.9 (OCH3), 62.1 (C), 111.0 (CHaro), 119.5 (Caro–S), 120.5
1H NMR (300 MHz, CDCl3) d 0.90 (s, 3H, CH3), 1.20 (s,
3H, CH3), 2.57 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 4.09 (d, 1H, J = 10 Hz, OH), 4.38 (d, 1H, J = 14 Hz,
CH2), 4.70 (d, 1H, J = 10 Hz, CH), 5.06 (d, 1H, J = 14 Hz,
(CHaro), 130.6 (CHaro), 135.7 (CHaro), 154.0 (Caro–O), 159.8
(C2 O), 175.7 (C4 O); MS (m/z: EI) 294 (M ).
+
CH2), 6.73 (d, 1H, J = 8 Hz, Haro), 6.94–6.99 (m, 2H, Haro); 13
C
=
=
NMR (75 MHz, CDCl3) d 19.0 (CH3), 23.4 (CH3), 24.6 (CH3),
45.9 (CH2), 56.0 (OCH3), 56.1 (OCH3), 59.8 (C), 84.4 (CH),
111.6 (CHaro), 114.7 (CHaro), 124.4 (CHaro), 124.6 (Caro–S), 148.7
3-(m,p-Dimethoxyphenyl)thiomethyl-1,5,5-trimethylhydantoin
(14n). This product was isolated as an uncolored oil in 66%
yield; Found: C, 55.39; H, 6.02; N, 8.51. Calc. for C15H20N2O4S:
=
(Caro–O), 149.2 (Caro–O), 157.1 (C O).
C, 55.54; H, 6.21; N, 8.64%; IR mmax (KBr)/cm−1 1770 (C O),
=
1714 (C O); 1H NMR (300 MHz, CDCl3) d 1.25 (s, 6H,
General procedure for cyclisation of 4-hydroxyimidazolidinones
10x,y and 15j,l–n; access to tricyclic N,S-acetals 6a and 6j,l–
n. By using the well-established acid protocol described above
for cyclisation of 4-hydroxyimidazolidinones 5, N-acyliminium
ions precursors 10x,y and 15j,l–n after treatment with TFA at
ambient temperature for 24 h led to suitable cyclised products
6a and 6j,l–n, respectively, in appreciable to good yields.
=
2 × CH3), 2.82 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 4.77 (s, 2H, CH2), 6.74 (d, 1H, J = 8 Hz, Haro),
7.01–7.06 (m, 2H, Haro); 13C NMR (75 MHz, CDCl3) d 22.0 (2 ×
CH3), 24.5 (CH3), 43.5 (CH2), 56.0 (OCH3), 56.1 (OCH3), 61.3
(C), 111.3 (CHaro), 116.6 (CHaro), 123.6 (Caro–S), 126.7 (CHaro),
=
=
149.1 (Caro–O), 149.5 (Caro–O), 154.0 (C2 O), 175.6 (C4 O);
MS (m/z: EI) 324 (M+).
2,3,3a,9-Tetrahydro-3,3-dimethylimidazo[5,1-b][1,3]benzothiazin-
1-one (6a).
Method A. This product, which was identical to that de-
scribed above, was obtained from hydroxylactam 10y and TFA
at reflux for 48 h in 52% yields.
Method B. Product 6a was also obtained in 67% yield from
imidazolone 11x by refluxing in TFA for 48 h.
General procedure for regioselective reduction of 1,5,5-
trimethylhydantoin derivatives 14j,l–n. By using same protocol
described above for reduction of the positional isomers N-
protected imides 4, treatment of imides 14j,l–n with NaBH4
(6 mole equiv.) in dry ethanol at 20 ◦C for 12 to 46 h
(monitored by TLC using CH2Cl2 as eluent) gives suitable 4-
hydroxyimidazolidinones 15j,l–n in good yields.
2,3,3a,9-Tetrahydro-2,3,3-trimethylimidazo[5,1-b][1,3]benzo-
thiazin-1-one (6j). This product, which was identical to that
described above, was obtained from 4-hydroxyimidazolidinone
15j and neat TFA at room temperature for 48 h in 89% yield.
4-Hydroxy-1,5,5-trimethyl-3-phenylthiomethylimidazolidin-2-
one (15j). This product was isolated as a white solid in 82%
yield; mp 105 ◦C (ethanol); Found: C, 58.33; H, 6.65; N, 10.22.
Calc. for C13H18N2O2S: C, 58.62; H, 6.81; N, 10.52%; IR mmax
X-Ray crystallographic analysis of benzothiazinone (6j)‡.
(KBr)/cm−1 3311 (OH), 1682 (C O); 1H NMR (300 MHz,
=
C13H16N2OS, Mr = 248.34, orthorhombic, Pna21, a = 19.225(8),
CDCl3) d 0.90 (s, 3H, CH3), 1.21 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 3.58 (s broad, 1H, OH), 4.46 (d, 1H, J = 14 Hz, CH2),
4.72 (d, 1H, J = 10 Hz, CH), 5.15 (d, 1H, J = 14 Hz, CH2),
7.13–7.30 (m, 3H, Haro), 7.40–7.44 (m, 2H, Haro); 13C NMR
(75 MHz, CDCl3) d 19.1 (CH3), 23.2 (CH3), 24.6 (CH3), 45.0
(CH2), 59.8 (C), 84.3 (CH), 127.0 (CHaro), 129.1 (2 × CHaro),
−3
˚
˚
b = 10.950(4), c = 6.047(9) A, V = 1273(2) A , Z = 4, Dx =
−3
−1
˚
1.296 Mg.m , k(Mo Ka) = 0.71073 A, l = 2.40 cm , F(000) =
528, T = 293 K. The sample (0.36*0.32*0.30 mm) is studied
on an automatic diffractometer CAD4 NONIUS with graphite
monochromatized Mo Ka radiation.16 The cell parameters are
obtained by fitting a set of 25 high-theta reflections. The data
collection (2hmax = 54◦, scan x/2h = 1, tmax = 60 s, range HKL: H
0,24 K 0,13 L 0,7) gives 1511 unique reflections from which 1209
with I > 2.0r(I). After Lorenz and polarization corrections17
the structure was solved with SIR-9718 which reveals the non
hydrogen atoms of the compound. After anisotropic refinement
a Fourier difference reveals many hydrogen atoms. The whole
structure was refined with SHELXL9719 by the full-matrix least-
square techniques (use of F square magnitude; x, y, z, bij for S, C,
O and N atoms, x, y, z in riding mode for H atoms; 155 variables
and 1209 observations; calc. w = 1/[r2(Fo2) +(0.109P)2] where
P = (Fo2 + 2Fc2)/3 with the resulting R = 0.048, Rw = 0.145
=
130.6 (2 × CHaro), 134.0 (Caro–S), 157.2 (C O).
3-(o-Bromophenyl)thiomethyl-4-hydroxy-1,5,5-trimethylimida-
zolidin-2-one (15l). This product was isolated as a white solid
in 90% yield; mp 110 ◦C (ethanol–diethyl ether); Found: C,
45.04; H, 4.69; N, 8.02. Calc. for C13H17BrN2O2S: C, 45.22; H,
4.96; N, 8.11%; IR mmax (KBr)/cm−1 3309 (OH), 1685 (C O);
=
1H NMR (300 MHz, CDCl3) d 0.90 (s, 3H, CH3), 1.21 (s, 3H,
CH3), 2.60 (s, 3H, CH3), 3.58 (s broad, 1H, OH), 4.46 (d, 1H,
J = 14 Hz, CH2), 4.72 (d, 1H, J = 10 Hz, CH), 5.15 (d, 1H,
J = 14 Hz, CH2), 7.13–7.30 (m, 3H, Haro), 7.40–7.44 (m, 2H,
Haro); 13C NMR (75 MHz, CDCl3) d 19.0 (CH3), 23.2 (CH3),
24.6 (CH3), 44.2 (CH2), 59.8 (C), 84.1 (CH), 124.7 (Caro–Br),
127.7 (CHaro), 128.0 (CHaro), 130.4 (CHaro), 133.1 (CHaro), 135.4
−3
˚
and Sw = 1.057 (residual Dq ≤ 0.40 eA ).
Atomic scattering factors from International Tables for X-ray
Crystallography (1992). Ortep views realized with PLATON9820
and Ortep-3 for windows.21 All the calculations were performed
on a Pentium NT Server computer. See the electronic supple-
mentary information for further data on compound 6j.
=
(Caro–S), 157.1 (C O).
4-Hydroxy-3-(o-methoxyphenyl)thiomethyl-1,5,5-trimethyl-
imidazolidin-2-one (15m). This product was isolated as a white
solid in 69% yield; mp 117 C (ethanol–ethyl acetate); Found:
◦
C, 56.57; H, 6.65; N, 9.23. Calc. for C14H20N2O3S: C, 56.73; H,
5-Bromo-2,3,3a,9-tetrahydro-2,3,3-trimethylimidazo[5,1-b]
[1,3]benzothiazin-1-one (6l). This product was isolated as an
uncolored oil in 100% yield; Found: C, 47.58; H, 4.41; N, 8.34.
6.80; N, 9.45%; IR mmax (KBr)/cm−1 3305 (OH), 1687 (C O);
=
1H NMR (300 MHz, CDCl3) d 0.92 (s, 3H, CH3), 1.20 (s, 3H,
CH3), 2.57 (s, 3H, CH3), 3.90 (s, 4H, OH and OCH3), 4.47 (d,
1H, J = 13 Hz, CH2), 4.73 (d, 1H, J = 10 Hz, CH), 5.11 (d,
1H, J = 13 Hz, CH2), 6.81–6.88 (m, 2H, Haro), 7.18–7.21 (m,
1H, Haro), 7.38–7.42 (m, 1H, Haro); 13C NMR (75 MHz, CDCl3)
Calc. for C13H15BrN2OS: C, 47.71; H, 4.62; N, 8.56%; IR mmax
1
(KBr)/cm−1 1703 (C O); H NMR (300 MHz, CDCl3) d 1.29
=
(s, 3H, CH3), 1.47 (s, 3H, CH3), 2.74 (s, 3H, CH3), 4.23 (d, 1H,
J = 16 Hz, CH2), 4.84 (s, 1H, CH), 4.89 (d, 1H, J = 16 Hz,
3 9 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 9 3 7 – 3 9 4 7

View Article Online
CH2), 6.96 (dd, 1H, J = 2 and 7 Hz, Haro), 7.09 (d, 1H, J = 7 Hz,
Haro), 7.41 (dd, 1H, J = 2 and 7 Hz, Haro); 13C NMR (75 MHz,
CDCl3) d 21.1 (CH3), 23.3 (CH3), 24.6 (CH3), 44.1 (CH2), 58.8
(C), 68.4 (CH), 123.2 (Caro–Br), 125.8 (CHaro), 126.3 (CHaro),
(e) W. N. Speckamp and M. J. Moolenaar, Tetrahedron, 2000, 56,
3817.
4 (a) For C–N bonds forming via the N-acyliminium chemistry, see:
P. Aeberli and W. J. Houlihan, J. Org. Chem., 1968, 33, 2402;
(b) J. B. P. A. Wijnberg and W. N. Speckamp, Tetrahedron, 1978, 34,
2399; (c) H. H. Wasserman, S. L. Henke, P. Luce and E. Nakanishi,
J. Org. Chem., 1990, 55, 5821; (d) H. H. Wasserman, S. L. Henke
and E. Nakanishi, J. Org. Chem., 1992, 57, 2641; (e) O. Surygina,
M. Ehwald and J. Liebscher, Tetrahedron Lett., 2000, 41, 5479; (f) H.
Sun and K. D. Moeller, Org. Lett., 2002, 4, 1547; (g) A. R. Katritzky,
Y.-J. Xu, H.-Y. He and P. J. Steel, J. Chem. Soc., Perkin Trans. 1, 2001,
1767; (h) A. R. Katritzky, H.-Y. He and A. K. Verma, Tetrahedron:
Asymmetry, 2002, 13, 933; (i) A. Fogain-Ninkam, A. Da¨ıch, B.
Decroix and P. Netchita¨ılo, Eur. J. Org. Chem., 2003, 4273; (j) A.
Cul, A. Da¨ıch, B. Decroix, G. Sanz and L. Van Hijfte, Tetrahedron,
2004, 60, 11029. For C–O linkages forming via the N-acyliminium
species see: (k) H. W. Moore, L. Hernandez, Jr., D. M. Kunert, F.
Mercer and A. Sing, J. Am. Chem. Soc., 1981, 103, 1769; (l) A.
ˇ
=
130.9 (CHaro), 132.5 (Caro–S), 133.0 (Caro–C), 157.9 (C O); MS
(m/z: EI) 326–328 (M+).
2,3,3a,9-Tetrahydro-5-methoxy-2,3,3-trimethylimidazo[5,1-
b][1,3]benzothiazin-1-one (6m). This product was isolated as a
white solid in 100% yield; mp 124 ◦C (ethanol–hexane); Found:
C, 60.18; H, 6.34; N, 9.87. Calc. for C14H18N2O2S: C, 60.40; H,
1
6.52; N, 10.06%; IR mmax (KBr)/cm−1 1694 (C O); H NMR
=
(300 MHz, CDCl3) d 1.28 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.75
(s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.31 (d, 1H, J = 17 Hz, CH2),
4.75 (s, 1H, CH), 4.91 (d, 1H, J = 17 Hz, CH2), 6.68–6.79 (m,
2H, Haro), 7.02–7.11 (m, 1H, Haro); 13C NMR (75 MHz, CDCl3)
d 21.2 (CH3), 23.5 (CH3), 24.7 (CH3), 43.8 (CH2), 56.0 (OCH3),
58.9 (C), 67.1 (CH), 108.3 (CHaro), 120.2 (CHaro), 120.5 (Caro–S),
Mamouni, A. Da
¨ıch, S. Marchal´ın and B. Decroix, Heterocycles,
2001, 54, 275; (m) P. Pigeon, J. Sikoraiova´, S. Marchal´ın and B.
Decroix, Heterocycles, 2002, 56, 129; (n) J. Sikoraiova´, A. Chihab-
ˇ
=
125.4 (CHaro), 131.1 (Caro–C), 155.9 (Caro–O), 158.3 (C O); MS
(m/z: EI) 278 (M+).
ˇ
Eddine, S. Marchal´ın and A. Da¨ıch, J. Heterocycl. Chem., 2002,
ˇ
39, 383; (o) J. Sikoraiova´, S. Marchal´ın, A. Da¨ıch and B. Decroix,
2,3,3a,9-Tetrahydro-6,7-dimethoxy-2,3,3-trimethylimidazo[5,1-
b][1,3]benzothiazin-1-one (6n). This product was isolated as a
white solid in 44% yield; mp 183 ◦C (ethanol); Found: C, 58.23;
Tetrahedron Lett., 2002, 43, 4747; (p) A. Cul, A. Chihab-Eddine, A.
ˇ
Pesquet, S. Marchal´ın and A. Da¨ıch, J. Heterocycl. Chem., 2003,
40, 499; (q) A. S. Kende, J. I. M. Hernando and J. B. J. Milbank,
Tetrahedron, 2002, 58, 61; (r) C. Agami, A. Beauseigneur, S. Comesse
and L. Dechoux, Tetrahedron Lett., 2002, 43, 4747. For C–O/C–N
and/or C–S linkages forming, via the N-acyliminium species see:
(s) N. Mizutani, W.-H. Chiou and I. Ojima, Org. Lett., 2002, 4, 4575;
(t) H. H. Wasserman, Y. O. Long, R. Zhang, A. J. Carr and J. Parr,
Tetrahedron Lett., 2002, 43, 3347.
5 (a) N. Hucher, A. Da¨ıch, P. Netchita¨ılo and B. Decroix, Tetrahedron
Lett., 1999, 40, 3363; (b) Another example of this process was
reported recently during their synthesis of azabicyclo[4.4.0]alkane
amino acids by Rh-catalyzed cyclocarbonylation of amide-olefins.
For this end, see ref. 4s, above.
6 (a) N. Hucher, B. Decroix and A. Da¨ıch, J. Org. Chem., 2001, 66, 4695;
(b) N. Hucher, A. Pesquet, P. Netchita¨ılo and A. Da¨ıch, Eur. J. Org.
Chem., 2005, 2758.
7 Only one report concerning similar phenomenon using a tandem
aza-Cope isomerisation/O-cyclisation was pointed in the literature.
See H. Ent, H. De Koning and W. N. Speckamp, Heterocycles, 1990,
30, 501.
H, 6.31; N, 8.82. Calc. for C15H20N2O3S: C, 58.42; H, 6.54; N,
1
9.08%; IR mmax (KBr)/cm−1 1690 (C O); H NMR (300 MHz,
=
CDCl3) d 0.68 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.72 (s, 3H,
CH3), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.13 (d, 1H, J =
12 Hz, CH2), 4.66 (s, 1H, CH), 5.05 (d, 1H, J = 12 Hz, CH2),
6.55 (s, 1H, Haro), 6.70 (s, 1H, Haro); 13C NMR (75 MHz, CDCl3)
d 19.5 (CH3), 25.2 (CH3), 26.1 (CH3), 43.4 (CH2), 56.0 (OCH3),
56.2 (OCH3), 63.3 (C), 64.0 (CH), 111.3 (CHaro), 112.7 (CHaro),
121.5 (Caro–S), 125.8 (Caro–C), 147.4 (Caro–O), 148.2 (Caro–O),
+
=
158.4 (C O); MS (m/z: EI) 308 (M ).
Acknowledgements
We are grateful to Johnson & Johnson, Pharmaceutical R. &
D., Division of Janssen-Cilag, for support of this research. We
thank also the Region of “Haute Normandie” for a Regional-
Industrial Graduate Fellowship, (BRI/2000–2003), attributed
to A. P. We are grateful also to Dr Lo¨ıc Toupet (University of
Rennes) and Dr Samuel Petit (University of Rouen) for X-ray
crystallographic analysis.
8 N. Hucher, A. Da¨ıch and B. Decroix, Org. Lett., 2000, 2, 1201.
9 T. L. Hough, J. Heterocycl. Chem., 1989, 26, 1523.
10 A. Guzma´n and M. Romero, Can. J. Chem., 1990, 68, 791.
11 H. Hilpert, Tetrahedron, 2001, 57, 7675.
12 Under these conditions the substituted thiophenol, which resulted
from the N–CH2–S functionality cleavage, was recovered in appre-
ciable quantity.
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