A manifold three-step synthetic route to polycyclic annulated hydantoins via cyclic imines

Article abstract of DOI:10.1002/hlca.201200441

A new three-step synthetic pathway to generate polycyclic annulated hydantoins via rarely investigated heterocyclic imines is described. This procedure includes a one-pot reaction forming imines as precursor structures (e.g., Asinger reaction), followed by an Ugi reaction to build up a bisamide structure that allows a ring-closing reaction to the targeted hydantoins via substitution. This pathway leads to a multiplicity of substances with a potential pharmacological activity. Copyright

Full text of DOI:10.1002/hlca.201200441

Helvetica Chimica Acta – Vol. 95 (2012)
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A Manifold Three-Step Synthetic Route to Polycyclic Annulated Hydantoins
via Cyclic Imines
by Fabian Brockmeyer, Denis Krçger, Timo Stalling, Pasqual Ullrich, and Jꢀrgen Martens*
Institut fꢀr Reine und Angewandte Chemie der Carl von Ossietzky Universitꢁt Oldenburg, Carl-von-
Ossietzky-Str. 9 – 11, D-26129 Oldenburg
(phone: þ 49-441-798-3837; fax: þ 49-441-798 3329; e-mail: juergen.martens@uni-oldenburg.de)
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
A new three-step synthetic pathway to generate polycyclic annulated hydantoins via rarely
investigated heterocyclic imines is described. This procedure includes a one-pot reaction forming imines
as precursor structures (e.g., Asinger reaction), followed by an Ugi reaction to build up a bisamide
structure that allows a ring-closing reaction to the targeted hydantoins via substitution. This pathway
leads to a multiplicity of substances with a potential pharmacological activity.
Introduction. – Hydantoins (¼ imidazolidine-2,4-diones) are a very interesting and
well-known substance class [1]. A plenty of this cyclic ureides are important
compounds because of their industrial relevance as intermediates in the production
of a-amino acids [2] and their frequent use in a plethora of pharmaceutical products
[3][4]. Those derivatives with an annulated five-membered thiazolidine ring show
activities against neurodegenerative diseases, such as morbus Alzheimer [5]. Also
anticancer activity was reported [6]. Therefore, we focused our attention to the
synthesis of polycyclic hydantoins. For this purpose, we developed a sequential
combination of reactions which involves the utilization of the rarely investigated
heterocyclic imines 2,5-dihydro-1,3-oxazole [7] and 1,4-benzothiazine [8], in addition
to the known 2,5-dihydro-1,3-thiazole [9][10]. The cyclic amine parts of these species
are also privileged scaffolds in an array of different biologically and pharmaceutically
active compounds [10][11][12]. For example linezolid, which is a famous antibacterial
[12a], is a 1,3-oxazolidine derivative. The 3,4-dihydrobenzothiazine substructure builds
the skeleton of some antibiotica and potent potassium and calcium channel openers
[11b – e][13]. The biological and pharmacological activities of the hydantoins and the
mentioned heterocycles, respectively, suggests that the combination of both structures
would lead to compounds with interesting properties. Therefore, we developed a
sequential three-step synthetic route to the target structures depicted in the Figure.
On the basis of the retrosynthetic consideration outlined in Scheme 1, the target
annulated hydantoins can be synthesized from bisamides [14]. The required bisamides
starting from the cyclic imines can be obtained by an Ugi three-component reaction (U-
3CR) [15]. Leading to our research on cyclic imines, the above mentioned imines are
accessible by one-pot conversion of a-halo aldehydes [8][16]. In the case of the thia-
and oxazoles, this strategy results in the combination of two multicomponent reactions.
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Helvetica Chimica Acta – Vol. 95 (2012)
Figure. The target structures
Displaying a high substrate tolerance, the developed synthetic sequence provides
products that are characterized by a high diversity.
Scheme 1. Retrosynthetic Consideration of the Target Structure
Results and Discussion. – Synthesis of the Cyclic Imines. The first of the three-step
synthesis sequence to polycyclic hydantoines was the preparation of the cyclic imines.
To investigate the diversity of our route, three different types of cyclic imines were
prepared as precursors for the further reaction steps. Two of them, i.e., the five-
membered 2,5-dihydro-1,3-thiazoles 1 and 2,5-dihydro-1,3-oxazole 2, were prepared by
a modified Asinger reaction [7][16]. This multicomponent reaction is well-known for
its efficient manifold synthesis of cyclic imines [17]. Following the prevalent procedure
[16], an a-chloro aldehyde was treated with a second variable carbonyl compound,
NH3, and NaHS or H2O in CH2Cl2 to generate the imines 1 and 2 (Scheme 2).
Scheme 2. Four-Component Reaction to Form the 2,5-Dihydro-1,3-thiazoles [16] 1 and 2,5-Dihydro-1,3-
oxazole [7] 2
By means of the modified Asinger reaction, three different 2,5-dihydro-1,3-
thiazoles 1 and one 2,5-dihydro-1,3-oxazole 2 were prepared as precursors (Table 1).
The common cyclic imines 1a [9], 1b [18], and 2 [7], as well as the cyclic imine 1c, which
is reported for the first time, were obtained in moderate-to-good yields (up to 67%).
The annulated six-membered 2H-1,4-benzothiazine 3 [19] was synthesized from an
a-bromo aldehyde, 2-aminothiophenol, and NaH in anhydrous THF (Scheme 3).

Helvetica Chimica Acta – Vol. 95 (2012)
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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3. Synthesis of the 2H-1,4-Benzothiazines 3 [19]
All three types of cyclic imines, 1 – 3, are known for their reactivity, and they have
been successfully utilized in the synthesis of different amides [7][20] and polycyclic
structures [9][19][21].
Synthesis of the Bisamides. Adequate precursors for the final ring closure to the
polycyclic hydantoins are a-bisamides containing at least one secondary amide,
whereas the second amide group has to be affected by its electrophilicity and the
presence of a leaving group [14]. An appropriate and efficient way to such structures is
the Ugi reaction [14][22][23], which is one of the most efficient multicomponent
reactions. In 1959, this reaction was described as a four-component reaction (U-4CR)
to prepare bisamides from an amine, a carbonyl compound, a carboxylic acid, and an
isocyanide [22]. Later, the U-3CR was developed to reduce the by-products [15][23].
Instead of the amine and the carbonyl compound, which were used in the U-4CR for the
in situ formation of an imine compound, a pre-built imine was treated with a carboxylic
acid and an isocyanide. The U-3CR was applied to the cyclic imines 1 – 3 in the recent
past, too [8][18]. Following this strategy, the cyclic imines 1 – 3, respectively, were
reacted with Cl3CCOOH and several isocyanides, which were commercially available
or readily accessible, in anhydrous MeOH (Scheme 4). To amplify the scope of
isocyanides, 2-(isocyanomethyl)naphthalene, which has never been reported before,
was prepared from naphthalene-2-carbaldehyde.
Scheme 4. Ugi Three-Component Reaction [23] of the Imines 1 – 3 to Prepare the Desired Bisamides 4 – 6,
Respectively
As disclosed in Table 1, the imines 1 and 2 could be converted to the desired
bisamides 4 and 5, respectively, in moderate-to-good yields. Even when sterically
hindered substrates, such as the imines 1b and 1c, or cyclohexyl isocyanide, were used in
the reaction, the corresponding bisamides were obtained in moderate yields (i.e.,
compounds 4c, 4e, 4f, 4g, 4h, and 5c). The U-3CR of the annulated six-membered
imines 6 did not proceed in such high yields, but the expected bisamides 6a – 6c were
obtained in all cases (Table 2). It is noteworthy to mention that the use of the new
2-(isocyanomethyl)naphthalene resulted in the highest yields (i.e., compounds 4d and
5d).
Cyclization to the Polycyclic Hydantoins. The synthetic route to the polycyclic
hydantoins was finalized by a ring closure of the bisamides 4 – 6. A deprotonation of the
secondary amide group is prerequisite for the desired cyclization. Treatment of the

Helvetica Chimica Acta – Vol. 95 (2012)
1861
Table 2. Preparation of Hydantoins 9 via Annulated Six-Membered Cyclic Imines 3
Entry
R
Imine Yielda) [%] Bisamide Yielda) [%] Hydantoin Yielda) [%]
13
14
15
CH2¼CHCH2
4-MeOꢀC6H4CH2
PhCH2CH2
3
3
3
57
57
57
6a
6b
6c
12
6
7
9a
9b
9c
67
78
63
a) Isolated yields.
bisamides 4 – 6 with freshly prepared EtONa is a suitable procedure to realize this
initiation step of the ring closure (Scheme 5). As a result of this deprotonation, the
hydantoins 7 – 9 were generated via a replacement of the leaving group Cl3Cꢀ.
Scheme 5. Final Cyclization of the Bisamides 4 – 6 to the Polycyclic Hydantoins 7 – 9, Respectively
Starting from the bisamides 4 and 5, the aimed products 7 and 8, respectively, were
obtained in good-to-excellent yields as compiled in Table 1. The cyclization of the
bisamides 6 occurred in good yields, too (Table 2). Surprisingly, the best result for the
final cyclization was accomplished starting from the bisamide 4e (Table 1, Entry 5;
94%).
1
The structures of the products were verified by IR, H- and 13C-NMR, and mass
spectra. The shift of the signal arising from the methine group in the imine ring strongly
evidenced the formation of the hydantoins. For example, the 1H-NMR spectrum of the
bisamide 4d exhibited one signal of the methine group at 5.16 ppm, whereas the
spectrum of the corresponding hydantoin 7d displayed that signal at 4.43 ppm.
Moreover, the presence of the hydantoins is substantiated by the finding that the signals
1
arising from the NH and the CCl3 moiety were missing in the H- and 13C-NMR
spectrum, respectively.
The obtained results (Tables 1 and 2) indicate the variability of the three-step
synthesis sequence leading to polycyclic hydantoins. The cyclic imines, prepared in the
first step, as well as the isocyanide compound, used in the second step, are variable in a
wide range. It could be established that both five-membered cyclic imines containing S
or O, i.e., (1 and 2, resp.) and the six-membered annulated 2H-1,4-benzothiazine 3
could be converted to the desired hydantoins 7 – 9. In addition to that, the applicability
of five different isocyanides in the reaction sequence was also successfully examined.

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Conclusions. – In summary, we developed a new three-step synthetic route to
polycyclic hydantoins containing S or O in the annulated heterocycles. Starting from
commercially available simple starting materials, the heterocyclic imines 1 – 3 were
prepared in one-pot reactions. By functionalizing the highly reactive C¼N bond of
these precursors in the Ugi three-component reaction, we obtained the bisamides 4 – 6
characterized by a leaving group for a ring-closing reaction. In the final cyclization,
initiated by treatment with EtONa, the annulated hydantoins 7 – 9 were synthesized. By
following this synthetic route, it is possible to prepare a great number of products with
high diversity.
Experimental Part
General. Synthetic procedures under Ar: vacuum line using standard Schlenk techniques. TLC:
Merck SiO2 F254 plates on aluminium sheets. Column chromatography (CC): Grace SiO2 (0.035 –
0.070 mm, type KG 60). M.p.: Laboratory Devices; uncorrected. IR Spectra: Bruker Tensor 27
spectrometer, ꢃGolden Gateꢄ diamond-ATR (attenuated total reflection) unit; in cmꢀ1. 1H- and 13C-NMR
spectra: Bruker AMX R 500 instrument (at 500.1 and 125.8 MHz, resp.) or Bruker Avance III 500
instrument (at 499.9 and 125.7 MHz, resp.), in CDCl3, (D6)DMSO, or CD3OD; multiplicity of C-atoms
from DEPT spectra; assignments from COSY techniques; d in ppm rel. to the solvent signal (CDCl3: 7.26
and 77.16 ppm, resp.; (D6)DMSO: 2.50 and 39.52 ppm, resp.; CD3OD: 3.31 and 49.00 ppm, resp.) [24], J
in Hz; in case of phenylene compounds, the assignments (o-, m-) refer to the methylene group. MS:
Finnigan MAT 95 (EI, 70 eV, or CI (isobutane or NH3)) or Waters Q-TOF Premier (ESI, pos.-ion mode)
instrument; in m/z (rel. %).
2-Chloro-2-methylpropanal [7], 1-chlorocyclohexane-1-carbaldehyde [25], 2-bromo-2-methylpro-
panal [26], allyl isocyanide [27][28], 1-(isocyanomethyl)-4-methoxybenzene [29][30], cyclohexyl
isocyanide [31][32], and (2-isocyanoethyl)benzene [33] were prepared according to published
procedures. All other chemicals were commercially available (Aldrich and Merck) and used without
further purification. MeOH was refluxed with Mg and freshly distilled prior to use. EtOH was refluxed
with Na and freshly distilled prior to use.
2-(Isocyanomethyl)naphthalene. A soln. of naphthalene-2-carbaldehyde (675 mg, 4.3 mmol) and
HCOOH (1.66 g, 36.1 mmol) in HCONH2 (30 ml) was heated at 140 – 1508 for 5 h. The mixture was
poured into 35 ml of ice-water and basified with 2n NaOH soln. to pH 9. The soln. was extracted with
CH2Cl2 (2 ꢁ 25 ml). The org. layer was washed with H2O, dried (MgSO4), and the solvent was removed at
a rotary evaporator to afford a yellow solid. The crude N-(naphthalen-2-ylmethyl)formamide was used in
the next step without further purification.
A soln. of the crude product, Ph3P (1.36 g, 5.2 mmol), CCl4 (664 mg, 4.3 mmol), and Et3N (437 mg,
4.3 mmol) in 1,2-dichloroethane (5 ml) was heated at 608 for 3 h. The solvent was removed at a rotary
evaporator. The residue was taken up in MeCN, cooled to ꢀ 308 for 5 h, and filtered. The filtrate was
concentrated at a rotary evaporator. The crude product was purified by CC (CH2Cl2/hexane 1:1). Yield:
328 mg (45%). Brown solid. M.p. 678. Rf (CH2Cl2/hexane 1:2) 0.31. IR (ATR): 3057, 3024, 2966, 2919,
2850. 1H-NMR (500.1 MHz, CDCl3): 4.79 (s, CH2); 7.40 – 7.42 (m, 1 arom. H); 7.51 – 7.55 (m, 2 arom. H);
7.83 – 7.89 (m, 4 arom. H). 13C-NMR (125.8 MHz, CDCl3): 45.81 (CH2); 124.16, 125.74, 126.69, 126.85,
127.87, 128.01, 129.05 (7 arom. CH); 129.72, 133.10, 133.28 (3 arom. C); 158.02 (NC). CI-MS: 185 (5,
[M þ H þ NH3]þ). HR-CI-MS: 185.1077 ([M þ H þ NH3]þ, C12H13Nþ2 ; calc. 185.1079).
2,5-Dihydro-2,2,5,5-tetramethylthiazole (1a) [9]. Acetone (22.54 g, 0.388 mol) was added dropwise to
a soln. of NaHS · H2O (14.37 g, 0.194 mol) and aq. NH3 soln. (26.43 g, 0.388 mol, 25%). To this soln., 2-
chloro-2-methylpropanal (20.67 g, 0.194 mol) was added dropwise at 5 – 108. After diluting with CH2Cl2
(20 ml), the soln. was stirred overnight at r.t. The phases were separated, and the aq. phase was extracted
with CH2Cl2 (2 ꢁ 20 ml). The recombined org. phases were dried (MgSO4), and the solvent was removed
at a rotary evaporator. The crude product was purified by recrystallization from hexane. Yield: 17.78 g
(64%). Colorless solid.

Helvetica Chimica Acta – Vol. 95 (2012)
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7-Thia-14-azadispiro[5.1.5.2]pentadec-14-ene (1b) [18]. Cylohexanone (8.19 g, 83.4 mol) was added
dropwise to a soln. of NaHS · H2O (3.07 g, 41.4 mmol) and aq. NH3 soln. (5.68 g, 83.4 mmol, 25%). To this
soln., 1-chlorocyclohexane-1-carbaldehyde (6.07 g, 41.4 mol) was added dropwise at 5 – 108. After
diluting with CH2Cl2 (20 ml), the soln. was stirred overnight at r.t. The phases were separated, and the aq.
phase was extracted with CH2Cl2 (2 ꢁ 20 ml). The recombined org. phases were dried (MgSO4), and the
solvent was removed at a rotary evaporator. The crude product was purified by distillation (1108/
0.067 mbar). Yield: 6.20 g (67%). Colorless oil.
2,2-Dimethyl-8-oxa-1-thia-4-azaspiro[4.5]dec-3-ene (1c). Oxan-4-one (2.50 g, 25.0 mmol) was added
dropwise to a soln. of NaHS · H2O (926 mg, 12.5 mmol) and aq. NH3 soln. (426 mg, 25.0 mmol, 25%). To
this soln., 2-chloro-2-methylpropanal (1.33 g, 12.5 mmol) was added dropwise at 5 – 108. After diluting
with CH2Cl2 (20 ml), the soln. was stirred overnight at r.t. The phases were separated, and the aq. phase
was extracted with CH2Cl2 (2 ꢁ 20 ml). The recombined org. phases were dried (MgSO4), and the solvent
was removed at a rotary evaporator. The crude product was purified by distillation (95 – 1008/1.0 mbar).
1
Yield: 960 mg (45%). Colorless solid. M.p. 45 – 468. IR (ATR): 2962, 2944, 2917, 2847, 1651. H-NMR
(500.1 MHz, CDCl3): 1.78 (s, 2 Me); 2.03 – 2.06, 2.43 – 2.49 (2m, CH2CCH2); 3.82 – 3.86, 4.19 – 4.25 (2m,
CH2OCH2); 7.49 (s, CH). 13C-NMR (125.8 MHz, CDCl3): 30.26 (2 Me); 42.36 (CH2CCH2); 63.72
(SCMe2); 66.06 (CH2OCH2); 92.10 (SC(CH2)2N); 166.85 (CH). CI-MS: 186 (100, [M þ H]þ). HR-CI-
MS: 186.0955 ([M þ H]þ, C9H16NOSþ; calc. 186.0953).
2,5-Dihydro-2,2,5,5-tetramethyloxazole (2) [7]. 2-Chloro-2-methylpropanal (21.31 g, 0.200 mol) was
added dropwise to a soln. of H2O (14.23 g, 0.790 mol), aq. NH3 soln. (53.81 g, 0.790 mol, 25%), and
acetone (45.88 g, 0.790 mol) at 0 – 58. After stirring for 1 h at 58, the soln. was stirred overnight at r.t. The
phases were separated, and the aq. phase was extracted with CH2Cl2 (2 ꢁ 30 ml). The recombined org.
phases were dried (MgSO4), and the solvent was removed at a rotary evaporator. The crude product was
purified by distillation (47 – 558/150 mbar). Yield: 10.17 g (40%). Colorless oil.
2,2-Dimethyl-2H-1,4-benzothiazine (3) [19]. Under Ar, a soln. of 2-aminothiophenol (6.00 g,
48.0 mmol) in 20 ml anh. THF was added to a suspension of NaH (2.00 g, 50.0 mmol, 60% in oil) in 70 ml
anh. THF at 08. The resulting foamy white/violet colored mixture was stirred for 2 h at r.t. 2-Bromo-2-
methylpropanal (7.63 g, 50.5 mmol), dissolved in 15 ml anh. THF, was added dropwise. After stirring
overnight at r.t., molecular sieves were added, and the mixture was stirred for 3 h. After filtration, the
solvent was removed at a rotary evaporator. The crude product was purified by recrystallization from
petroleum ether 40 – 608. Yield: 4.84 g (57%). Colorless solid. M.p. 56 – 588.
General Procedure (GP 1) for the Synthesis of the Bisamides 4, 5, and 6. A soln. of 1 equiv. of the
respective isocyanide and 1 equiv. of Cl3CCOOH in anh. MeOH (3 ml per mmol imine) was added to a
soln. of 1 equiv. of the respective cyclic imine 1, 2, or 3 in anh. MeOH (3 ml per mmol imine). The
progress of the reaction was monitored by TLC. The solvent was removed at the rotary evaporator. The
purification of the crude product is described in the experiments.
(RS)-2,2,5,5-Tetramethyl-N-(prop-2-en-1-yl)-3-(trichloroacetyl)-1,3-thiazolidine-4-carboxamide
(4a). According to GP 1: 1a (286 mg, 2.00 mmol), allyl isocyanide (134 mg, 2.00 mmol), and Cl3CCOOH
i
(327 mg, 2.00 mmol); 2 d. Purification by washing with Pr2O and pentane. Yield: 395 mg (53%).
1
Colorless solid. M.p. 1228. IR (ATR): 3363, 2993, 2973, 2941, 2859, 1687, 1650. H-NMR (499.9 MHz,
CDCl3): 1.45, 1.71, 2.01, 2.07 (4s, 4 Me); 3.80 – 3.85, 3.95 – 4.00 (2m, NHCH2); 5.11 (s, NCH); 5.14 – 5.17,
5.23 – 5.27 (2m, CH¼CH2); 5.77 – 5.85 (m, CH¼CH2); 5.96 – 5.97 (m, NH). 13C-NMR (125.7 MHz,
CDCl3): 25.87, 29.72, 31.26, 33.01 (4 Me); 42.30 (CH2); 51.77 (SCMe2CH); 76.96 (SCMe2N); 77.16
(NCH); 94.22 (CCl3); 117.64 (CH¼CH2); 133.43 (CH¼CH2); 158.51 (NCO); 168.46 (NHCO). CI-MS:
373 (100, [M þ H]þ). HR-CI-MS: 372.0229 ([M þ H]þ, C13H19Cl3N2O2Sþ; calc. 372.0233).
(RS)-N-(4-Methoxybenzyl)-2,2,5,5-tetramethyl-3-(trichloroacetyl)-1,3-thiazolidine-4-carboxamide
(4b). According to GP 1: 1a (286 mg, 2.00 mmol), 1-(isocyanomethyl)-4-methoxybenzene (294 mg,
2.00 mmol), and Cl3CCOOH (327 mg, 2.00 mmol); 5 d. Purification by CC (tBuOMe/hexane 3 :7).
Yield: 470 mg (52%). Colorless solid. M.p. 163 – 1658. Rf (tBuOMe/hexane 3 :7) 0.18. IR (ATR): 3300,
3073, 2971, 2937, 2842, 1687, 1656, 1612, 1548, 1515. 1H-NMR (500.1 MHz, CDCl3): 1.45, 1.70, 1.99, 2.00
3
(4s, 2 Me2C); 3.79 (s, MeO); 4.25 (dd, 2J ¼ 14.4, J ¼ 5.0, 1 H, CH2); 4.48 (dd, 2J ¼ 14.4, 3J ¼ 6.0, 1 H,
CH2); 5.11 (s, NCH); 6.09 – 6.11 (m, NH); 6.84 – 6.86 (m, 2 m-CH); 7.17 – 7.19 (m, 2 o-CH). 13C-NMR
(125.8 MHz, CDCl3): 25.90, 29.46, 31.26, 32.96 (2 CMe2); 43.70 (CH2); 51.81 (SCMe2CH); 55.41 (MeO);

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Helvetica Chimica Acta – Vol. 95 (2012)
76.95 (NCH); 76.98 (SCMe2N); 94.15 (CCl3); 114.34 (2 m-CH); 129.22 (C(Ar)CH2); 129.48 (2 o-CH);
158.37 (NCO); 159.34 (C(Ar)OMe); 168.42 (NHCO). CI-MS: 453 (99, [M þ H]þ). HR-CI- MS:
453.0563 ([M þ H]þ, C18H24Cl3N2O3Sþ; calc. 453.0573).
(RS)-N-Cyclohexyl-2,2,5,5-tetramethyl-3-(trichloroacetyl)-1,3-thiazolidine-4-carboxamide (4c). Ac-
cording to GP 1: 1a (286 mg, 2.00 mmol), cyclohexyl isocyanide (218 mg, 2.00 mmol), and Cl3CCOOH
(327 mg, 2.00 mmol); 3 d. Purification by CC (AcOEt/hexane 3 :7). Yield: 246 mg (30%). Colorless
solid. M.p. 1268. Rf (AcOEt/hexane 3 :7) 0.62. IR (ATR): 3333, 2930, 2855, 1687, 1522. 1H-NMR
(499.9 MHz, CDCl3): 1.10 – 1.22 (m, 3 H, 2 CH2); 1.30 – 1.40 (m, CH2); 1.44 (s, Me); 1.57 – 1.62 (m, 1 H,
CH2); 1.66 – 1.69 (m, CH2); 1.69 (s, Me); 1.87 – 1.90 (m, CH2); 2.00, 2.08 (2s, 2 Me); 3.74 – 3.82 (m,
3
NHCH); 5.04 (s, NCH); 5.74 (d, J ¼ 7.8, NH). 13C-NMR (125.7 MHz, CDCl3): 23.81, 24.56 (3 CH2);
24.87, 28.72, 30.26 (3 Me); 31.89 (2 CH2); 32.06 (Me); 47.79 (NHCH); 50.75 (SCMe2CH); 75.82
(SCMe2N); 76.13 (NCH); 93.28 (CCl3); 157.51 (NCO); 166.48 (NHCO). CI-MS: 415 (98, [M þ H]þ).
HR-EI-MS: 414.0712 (Mþ, C16H25Cl3N2O2Sþ; calc. 414.0702).
(RS)-2,2,5,5-Tetramethyl-N-(naphthalen-2-ylmethyl)-3-(trichloroacetyl)-1,3-thiazolidine-4-carbox-
amide (4d). According to GP 1: 1a (286 mg, 2.00 mmol), 2-(isocyanomethyl)naphthalene (334 mg,
2.00 mmol) and Cl3CCOOH (327 mg, 2.00 mmol); 2 d. Purification by washing with iPr2O and pentane.
Yield: 545 mg (58%). Colorless solid. M.p. 1988. IR (ATR): 3304, 2971, 2938, 1685, 1657, 1543. 1H-NMR
(499.9 MHz, CDCl3): 1.48, 1.72, 2.01, 2.03 (4s, 4 Me); 4.49 (dd, 2J ¼ 14.7, 3J ¼ 5.1, 1 H, CH2); 4.74 (dd, 2J ¼
14.7, 3J ¼ 5.1, 1 H, CH2); 5.16 (s, NCH); 6.22 – 6.24 (m, NH); 7.36 – 7.38 (m, 1 arom. H); 7.46 – 7.51 (m, 2
arom. H); 7.73 – 7.74 (m, 1 arom. H); 7.79 – 7.83 (m, 3 arom. H). 13C-NMR (125.7 MHz, CDCl3): 25.95,
29.61, 31.30, 33.03 (4 Me); 44.32 (CH2); 51.87 (SCMe2CH); 77.05 (SCMe2N); 77.16 (NCH); 94.22 (CCl3);
125.90, 126.30, 126.59, 126.86, 127.86, 127.89, 128.92 (7 arom. CH); 132.99, 133.48, 134.74 (3 arom. C);
158.45 (NCO); 168.49 (NHCO). CI-MS: 473 (99, [M þ H]þ). HR-EI-MS: 472.0540 (Mþ,
C21H23Cl3N2O2Sþ; calc. 472.0546).
(RS)-N-(Naphthalen-2-ylmethyl)-14-(trichloroacetyl)-7-thia-14-azadispiro[5.1.5.2]pentadecane-15-
carboxamide (4e). According to GP 1: 1b (670 mg, 3.00 mmol), 2-(isocyanomethyl)naphthalene
(502 mg, 3.00 mmol) and Cl3CCOOH (490 mg, 3.00 mmol); 3 d. Purification by crystallization from
hexane. Yield: 646 mg (39%). Colorless solid. M.p. 2208. IR (ATR): 3315, 3060, 2931, 2855, 1682, 1652.
1H-NMR (500.1 MHz, (D6)DMSO): 1.04 – 2.03 (m, 17 H, CH2, c-Hex); 2.57 – 2.63 (m, 1 H, CH2, c-Hex);
2.80 – 2.90 (m, 2 H, CH2, c-Hex); 4.28 (dd, 2J ¼ 14.4, 3J ¼ 4.9, 1 H, NHCH2); 4.53 (dd, 2J ¼ 14.4, 3J ¼ 6.4,
1 H, NHCH2); 5.28 (s, NCH); 7.37 – 7.39 (m, 1 arom. H); 7.47 – 7.53 (m, 2 arom. H); 7.75 – 7.76 (m, 1 arom.
H); 7.85 – 7.90 (3m, 3 arom. H); 8.69 – 8.72 (m, NH). 13C-NMR (125.8 MHz, (D6)DMSO): 21.95, 24.23,
24.27, 24.96, 25.12, 25.59, 34.35, 35.09, 35.46, 37.90 (10 CH2 , c-Hex); 42.99 (NHCH2); 57.44
(SC(CH2)5CH); 75.32 (NCH); 83.14 (SC(CH2)5N); 94.35 (CCl3); 125.88, 126.35, 126.63, 126.69,
127.53, 127.60, 127.96 (7 arom. CH); 132.13, 132.83, 136.25 (3 arom. C); 157.44 (NCO); 166.95 (NHCO).
CI-MS: 554 (98, [M þ H]þ). HR-CI-MS: 553.1242 ([M þ H]þ, C27H32Cl3N2O2Sþ; calc. 553.1245).
(RS)-2,2-Dimethyl-N-(prop-2-en-1-yl)-4-(trichloroacetyl)-8-oxa-1-thia-4-azaspiro[4.5]decane-3-car-
boxamide (4f). According to GP 1: 1c (278 mg, 1.50 mmol), allyl isocyanide (109 mg, 1.50 mmol), and
Cl3CCOOH (245 mg, 1.50 mmol); 4 d. Purification by CC (tBuOMe/hexane 3 :7). Yield: 282 mg (45%).
Colorless solid. M.p. 201 – 2028. Rf (tBuOMe/hexane 3 :7) 0.08. IR (ATR): 3317, 2967, 2913, 2856, 1687,
1
1660, 1537. H-NMR (499.9 MHz, CDCl3): 1.49 (s, Me); 1.59 – 1.62 (m, 1 H, CH2CCH2); 1.67 (s, Me);
2.28 – 2.30 (m, 1 H, CH2CCH2); 3.34 – 3.44 (m, 3 H, CH2CCH2, CH2OCH2); 3.71 – 3.76 (m, 1 H,
CH2OCH2); 3.81 – 3.86, 3.94 – 3.99 (2m, NHCH2); 4.03 – 4.09 (m, 2 H, CH2OCH2); 5.15 (s, NCH); 5.15 –
5.17, 5.22 – 5.25 (2m, CH¼CH2); 5.76 – 5.83 (m, 2 H, CH¼CH2, NH). 13C-NMR (125.7 MHz, CDCl3):
26.09, 33.11 (2 Me); 36.18 (CH2CCH2); 37.57 (CH2CCH2); 42.47 (NHCH2); 51.36 (SCMe2CH); 67.09
(CH2OCH2); 67.56 (CH2OCH2); 76.43 (NCH); 81.64 (SC(CH2)2N); 94.53 (CCl3); 117.97 (CH¼CH2);
133.33 (CH¼CH2); 158.43 (NCO); 167.96 (NHCO). CI-MS: 415 (96, [M þ H]þ). HR-CI-MS: 432.0674
([M þ H þ NH3]þ, C15H25Cl3N3O3Sþ; calc. 432.0682).
(RS)-N-(4-Methoxybenzyl)-2,2-dimethyl-4-(trichloroacetyl)-8-oxa-1-thia-4-azaspiro[4.5]decane-3-
carboxamide (4g). According to GP 1: 1c (278 mg, 1.50 mmol), 1-(isocyanomethyl)-4-methoxybenzene
(221 mg, 1.50 mmol), and Cl3CCOOH (245 mg, 1.50 mmol); 6 d. Purification by CC (tBuOMe/hexane
3 :7). Yield: 237 mg (32%). Colorless solid. M.p. 218 – 2198. Rf (tBuOMe/hexane 3 :7) 0.05. IR (ATR):
1
3299, 2962, 2932, 2856, 2839, 1689, 1656, 1612, 1544, 1513. H-NMR (500.1 MHz, CDCl3): 1.49 (s, 3 H,

Helvetica Chimica Acta – Vol. 95 (2012)
1865
Me2C); 1.58 – 1.61 (m, 1 H, CH2CCH2); 1.65 (s, 3 H, Me2C); 2.30 – 2.32 (m, 1 H, CH2CCH2); 3.33 – 3.35
(m, CH2CCH2, CH2O); 3.37 – 3.40 (m, 1 H, CH2CCH2); 3.70 – 3.74 (m, 1 H, CH2O); 3.80 (s, MeO);
3.99 – 4.00, 4.05 – 4.09 (2m, CH2O); 4.24 (dd, 2J ¼ 14.3, 3J ¼ 4.9, 1 H, NHCH2); 4.50 (dd, 2J ¼ 14.3, 3J ¼ 6.2,
1 H, NHCH2); 5.12 (s, NCH); 5.85 – 5.87 (m, NH); 6.84 – 6.86 (m, 2 m-CH); 7.17 – 7.18 (m, 2 o-CH).
13C-NMR (125.8 MHz, CDCl3): 26.17, 33.08 (CMe2); 36.24 (CH2CCH2); 37.29 (CH2CCH2); 43.78
(NHCH2); 51.36 (SCMe2CH); 55.46 (MeO); 67.10, 67.58 (CH2OCH2); 76.29 (NCH); 81.68
(SC(CH2)2N); 94.48 (CCl3); 114.39 (2 m-CH); 129.24 (C(Ar)CH2); 129.65 (2 o-CH); 158.30 (NCO);
159.44 (C(Ar)OMe); 167.72 (NHCO). CI-MS: 496 (100, [M þ H]þ). HR-CI-MS: 495.0690 ([M þ H]þ,
C20H26Cl3N2O4Sþ; calc. 495.0679).
(RS)-2,2-Dimethyl-N-(2-phenylethyl)-4-(trichloroacetyl)-8-oxa-1-thia-4-azaspiro[4.5]decane-3-carb-
oxamide (4h). According to GP 1: 1c (278 mg, 1.50 mmol), (2-isocyanoethyl)benzene (197 mg,
1.50 mmol), and Cl3CCOOH (245 mg, 1.50 mmol); 8 d. Purification by CC (tBuOMe/hexane 2 :3).
Yield: 390 mg (56%). Colorless solid. M.p. 179 – 1818. Rf (tBuOMe/hexane 2 :3) 0.16. IR (ATR): 3323,
3030, 2966, 2858, 1686, 1654, 1538. 1H-NMR (500.1 MHz, CDCl3): 1.43 (s, Me); 1.49 – 1.55 (m, 2 H,
CH2CCH2); 1.62 (s, Me); 2.80 – 2.83 (m, PhCH2); 3.10 – 3.21 (m, 2 H, CCH2, CH2OCH2); 3.23 – 3.29 (m,
1 H, CCH2); 3.55 – 3.70 (m, 3 H, CH2OCH2, NHCH2); 3.81 – 3.84 (m, 1 H, CH2OCH2); 4.01 – 4.05 (m,
1 H, CH2OCH2); 5.07 (s, NCH); 5.72 – 5.74 (m, NH); 7.17 – 7.19 (m, 2 o-CH); 7.21 – 7.24 (m, 1 p-CH);
7.29 – 7.32 (m, 2 m-CH). 13C-NMR (125.8 MHz, CDCl3): 25.98, 33.04 (2 Me); 35.28 (PhCH2); 35.79, 37.32
(CH2CCH2); 40.48 (NHCH2); 51.34 (SCMe2CH); 66.99 (CH2OCH2); 67.41 (CH2OCH2); 76.47 (NCH);
81.29 (SC(CH2)2N); 94.43 (CCl3); 127.00 (p-CH); 128.94, 129.04 (4 arom. CH); 138.15 (1 arom. C);
158.47 (NCO); 168.14 (NHCO). CI-MS: 479 (98, [M þ H]þ). HR-CI-MS: 496.0999 ([M þ H þ NH3]þ,
C20H29Cl3N3O3Sþ; calc. 496.0995).
(RS)-2,2,5,5-Tetramethyl-N-(prop-2-en-1-yl)-3-(trichloroacetyl)-1,3-oxazolidine-4-carboxamide
(5a). According to GP 1: 2 (254 mg, 2.00 mmol), allyl isocyanide (134 mg, 2.00 mmol), and Cl3CCOOH
(327 mg, 2.00 mmol); 4 d. Purification by CC (AcOEt). Yield: 390 mg (55%). Colorless solid. M.p. 1578.
Rf (AcOEt) 0.82. IR (ATR): 3383, 2981, 2935, 1713, 1776. 1H-NMR (500.1 MHz, CDCl3): 1.09, 1.41, 1.44,
1.72 (4s, 4 Me); 3.99 – 4.01 (m, NHCH2); 4.10 (s, NCH); 5.13 – 5.15, 5.19 – 5.23 (2m, CH¼CH2); 5.69 – 5.78
(m, CH¼CH2); 6.10 – 6.11 (m, NH). 13C-NMR (125.8 MHz, CDCl3): 23.02, 25.88, 27.81, 30.51 (4 Me);
40.94 (CH2); 69.91 (NCH); 79.44 (OCMe2CH); 93.92 (CCl3); 99.34 (OCMe2N); 118.68 (CH¼CH2);
130.86 (CH¼CH2); 155.43 (NCO); 169.13 (NHCO). CI-MS: 357 (100, [M þ H]þ). HR-CI-MS: 357.0541
([M þ H]þ, C13H20Cl3N2Oþ3 ; calc. 357.0534).
(RS)-N-(4-Methoxybenzyl)-2,2,5,5-tetramethyl-3-(trichloroacetyl)-1,3-oxazolidine-4-carboxamide
(5b). According to GP 1: 2 (336 mg, 2.65 mmol), 1-(isocyanomethyl)-4-methoxybenzene (389 mg,
2.65 mmol), and Cl3CCOOH (433 mg, 2.65 mmol); 6 d. Purification by CC (tBuOMe/hexane 3 :7).
Yield: 528 mg (46%). Colorless solid. M.p. 167 – 1688. Rf (tBuOMe/hexane 3 :7) 0.11. IR (ATR): 3289,
1
3087, 2978, 2941, 1687, 1657, 1610, 1556, 1511. H-NMR (500.1 MHz, CDCl3): 1.38, 1.49, 1.74, 1.80 (4s,
2
3
2
3
2 Me2C); 3.79 (s, MeO); 4.24 (dd, J ¼ 14.3, J ¼ 5.0, 1 H, CH2); 4.47 (dd, J ¼ 14.3, J ¼ 6.2, 1 H, CH2);
4.78 (s, NCH); 5.91 – 5.92 (m, NH); 6.84 – 6.86 (m, 2 m-CH); 7.16 – 7.18 (m, 2 o-CH). 13C-NMR
(125.8 MHz, CDCl3): 25.79, 27.15, 27.60, 29.47 (2 Me2C); 43.60 (CH2); 55.44 (MeO); 70.67 (NCH); 82.53
(OCMe2CH); 93.64 (CCl3); 99.47 (OCMe2N); 114.40 (2 m-CH); 129.27 (C(Ph)CH2); 129.63 (2 o-CH);
157.76 (NCO); 159.42 (C(Ph)OMe); 168.35 (NHCO). CI-MS: 437 (17, [M þ H]þ). HR-CI-MS: 454.1071
([M þ H þ NH3]þ, C18H27Cl3N3Oþ4 ; calc. 454.1067).
(RS)-N-Cyclohexyl-2,2,5,5-tetramethyl-3-(trichloroacetyl)-1,3-oxazolidine-4-carboxamide (5c). Ac-
cording to GP 1: 2 (254 mg, 2.00 mmol), cyclohexyl isocyanide (218 mg, 2.00 mmol), and Cl3CCOOH
(327 mg, 2.00 mmol); 3 d. Purification by crystallization from AcOEt and hexane. Yield: 414 mg (52%).
Colorless solid. M.p. 1988. IR (ATR): 3358, 3007, 2973, 2932, 2858, 1689, 1656, 1533. 1H-NMR
(499.9 MHz, CDCl3): 1.06 – 1.18 (m, 3 H, 2 CH2); 1.29 – 1.35 (m, CH2); 1.36, 1.48 (2s, 2 Me); 1.59 – 1.61 (m,
1 H, CH2); 1.67 – 1.69 (m, CH2); 1.74, 1.85 (2s, 2 Me); 1.87 – 1.88 (m, CH2); 3.72 – 3.80 (m, NHCH); 4.73
(s, NCH); 5.66 (d, 3J ¼ 7.9, NH). 13C-NMR (125.7 MHz, CDCl3): 24.84, 25.48 (2 CH2); 25.71, 27.12, 27.71,
29.50 (4 Me); 32.89, 33.11 (2 CH2); 48.67 (NHCH); 70.66 (NCH); 82.50 (OCMe2CH); 93.69 (CCl3);
99.29 (OCMe2N); 157.83 (NCO); 167.57 (NHCO). CI-MS: 399 (100, [M þ H]þ). HR-EI-MS: 398.0936
(Mþ, C16H25Cl3N2Oþ3 ; calc. 398.0931).

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(RS)-2,2,5,5-Tetramethyl-N-(naphthalen-2-ylmethyl)-3-(trichloroacetyl)-1,3-oxazolidine-4-carbox-
amide (5d). According to GP 1: 2 (254 mg, 2.00 mmol), 2-(isocyanomethyl)naphthalene (334 mg,
2.00 mmol), and Cl3CCOOH (327 mg, 2.00 mmol); 2 d. Purification by washing with iPr2O and pentane.
Yield: 625 mg (68%). Colorless solid. M.p. 2098. IR (ATR): 3303, 3082, 2987, 2947, 1687, 1658, 1554.
1H-NMR (499.9 MHz, CDCl3): 1.41, 1.49, 1.75, 1.82 (4s, 4 Me); 4.44 (dd, 2J ¼ 14.5, 3J ¼ 5.0, 1 H, CH2); 4.71
(dd, 2J ¼ 14.5, 3J ¼ 6.4, 1 H, CH2); 4.84 (s, NCH); 6.11 – 6.14 (m, NH); 7.33 – 7.35 (m, 1 arom. H); 7.46 –
7.51 (m, 2 arom. H); 7.69 – 7.70 (m, 1 arom. H); 7.78 – 7.83 (m, 3 arom. H). 13C-NMR (125.7 MHz, CDCl3):
25.82, 27.15, 27.65, 29.48 (4 Me); 44.25 (CH2); 70.75 (NCH); 82.56 (OCMe2CH); 93.70 (CCl3); 99.54
(OCMe2N); 125.97, 126.37, 126.63, 127.08 (4 arom. CH); 127.87 (2 arom. CH); 128.99 (1 arom. CH);
133.01, 133.46, 134.67 (3 arom. C); 157.75 (NCO); 168.59 (NHCO). CI-MS: 457 (100, [M þ H]þ). HR-
EI-MS: 456.0780 (Mþ, C21H23Cl3N2O3þ ; calc. 456.0774).
(RS)-3,4-Dihydro-2,2-dimethyl-N-(prop-2-en-1-yl)-4-(trichloroacetyl)-2H-1,4-benzothiazine-3-car-
boxamide (6a). According to GP 1: 3 (354 mg, 2.00 mmol), allyl isocyanide (154 mg, 2.00 mmol), and
Cl3CCOOH (327 mg, 2.00 mmol); 12 d. Purification by CC (tBuOMe/hexane 3 :7). Yield: 99 mg (12%).
Yellow solid. M.p. 135 – 1378. Rf (tBuOMe/hexane 3 :7) 0.13. IR (ATR): 3302, 1681, 1661, 1578, 1538.
1H-NMR (500.1 MHz, CDCl3): 1.11, 1.71 (2s, 2 Me); 3.86 – 3.88 (m, NHCH2); 5.01 (s, NCH); 5.10 – 5.16
(m, CH¼CH2); 5.73 – 5.81 (m, CH¼CH2); 6.03 – 6.04 (m, NH); 7.26 – 7.29 (m, 2 arom. H); 7.37 – 7.40,
7.66 – 7.68 (2m, 2 arom. H). 13C-NMR (125.8 MHz, CDCl3): 26.76, 30.12 (2 Me); 41.98 (NHCH2); 50.35
(Me2C); 73.03 (NCH); 92.64 (CCl3); 116.92 (CH¼CH2); 127.29, 128.22, 128.52, 130.75 (4 arom. CH);
132.68 (C(8a)); 133.57 (CH¼CH2); 136.06 (C(4a)); 162.49 (NCO); 167.42 (NHCO). CI-MS: 407 (94,
[M þ H]þ). HR-CI-MS: 424.0421 ([M þ H þ NH3]þ, C16H23Cl3N3O2Sþ; calc. 424.0420).
(RS)-3,4-Dihydro-N-(4-methoxybenzyl)-2,2-dimethyl-4-(trichloroacetyl)-2H-1,4-benzothiazine-3-
carboxamide (6b). According to GP 1: 3 (382 mg, 2.15 mmol), 1-(isocyanomethyl)-4-methoxybenzene
(317 mg, 2.15 mmol), and Cl3CCOOH (351 mg, 2.15 mmol); 5 d. Purification by CC (AcOEt/hexane
3 :7). Yield: 60 mg (6%). Colorless solid. M.p. 148 – 1508. Rf (AcOEt/hexane 3 :7) 0.44. IR (ATR): 3287,
1
3069, 3013, 2967, 2930, 2837, 1677, 1659, 1614, 1544, 1515. H-NMR (500.1 MHz, CDCl3): 1.14, 1.68 (2s,
Me2C); 3.79 (s, MeO); 4.31 (dd, 2J ¼ 14.6, 3J ¼ 5.4, 1 H, CH2); 4.39 (dd, 2J ¼ 14.6, 3J ¼ 5.7, 1 H, CH2); 5.00
(s, NCH); 6.01 – 6.02 (m, NH); 6.82 – 6.83 (m, 2 m-CH); 7.10 – 7.11 (m, 2 o-CH); 7.21 – 7.28 (m, CH(6),
CH(7)); 7.37 (dd, 3J ¼ 7.4, 4J ¼ 1.2, CH(8)); 7.56 – 7.58 (m, CH(5)). 13C-NMR (125.8 MHz, CDCl3): 26.78,
30.23 (Me2C); 43.33 (CH2); 50.14 (Me2C); 55.44 (MeO); 72.64 (NCH); 92.63 (CCl3); 114.28 (2 m-CH);
127.20, 128.15, 128.31 (CH(5), CH(6), CH(7)); 129.13 (2 o-CH); 129.68 (C(Ar)CH2); 130.65 (C(8));
132.44 (C(8a)); 135.83 (C(4a)); 159.24 (C(Ar)OMe); 162.61 (NCO); 167.26 (NHCO). CI-MS: 487 (95,
[M þ H]þ). HR-CI-MS: 487.0429 ([M þ H]þ, C21H22Cl3N2O3Sþ; calc. 487.0417).
(RS)-3,4-Dihydro-2,2-dimethyl-N-(2-phenylethyl)-4-(trichloroacetyl)-2H-1,4-benzothiazine-3-car-
boxamide (6c). According to GP 1: 3 (354 mg, 2.00 mmol), (2-isocyanoethyl)benzene (262 mg,
2.00 mmol), and Cl3CCOOH (327 mg, 2.00 mmol); 8 d. Purification by CC (tBuOMe/hexane 3 :7).
Yield: 63 mg (7%). Yellow solid. M.p. 112 – 1138. Rf (tBuOMe/hexane 3 :7) 0.19. IR (ATR): 3317, 3065,
2968, 2930, 1671, 1523. 1H-NMR (500.1 MHz, CDCl3): 1.00, 1.63 (2s, 2 Me); 2.77 – 2.80 (m, PhCH2);
3.46 – 3.52, 3.61 – 3.69 (2m, NHCH2); 4.94 (s, NCH); 5.79 – 5.80 (m, NH); 7.14 – 7.35 (m, 9 arom. H).
13C-NMR (125.8 MHz, CDCl3): 26.51, 29.95 (2 Me); 35.36 (PhCH2); 40.25 (NHCH2); 50.55 (Me2C);
73.21 (NCH); 92.59 (CCl3); 126.85, 127.31, 128.17, 128.24 (4 arom. CH); 128.85, 128.97 (4 arom. CH);
130.86 (1 arom. CH); 132.91 (C(8a)); 135.98 (C(4a)); 138.41 (1 arom. C); 162.27 (NCO); 167.55
(NHCO). CI-MS: 471 (96, [M þ H]þ). HR-CI-MS: 488.0742 ([M þ H þ NH3]þ, C21H25Cl3N3O2Sþ; calc.
488.0733).
General Procedure (GP 2) for the Synthesis of the Hydantoines 7 – 9. One equiv. of a EtONa soln.
(1m) was added to a suspension of 1 equiv. of the respective bisamide 4, 5, or 6 in anh. EtOH (10 ml per
mmol bisamide). After stirring at r.t. for 1 h, the solvent was removed at the rotary evaporator. The
purification of the crude product is described in the experiments.
(RS)-1,1,3,3-Tetramethyl-6-(prop-2-en-1-yl)-1H-imidazo[1,5-c][1,3]thiazole-5,7(6H,7aH)-dione
(7a). According to GP 2, with 4a (250 mg, 0.67 mmol). Purification by washing with cold EtOH and
drying in vacuum. Yield: 144 mg (85%). Orange solid. M.p. 408. IR (ATR): 2992, 2972, 2927, 1758, 1703.
1H-NMR (500.1 MHz, CDCl3): 1.39, 1.60, 1.72, 2.04 (4s, 4 Me); 4.03 – 4.05 (m, NCH2); 4.42 – 4.43 (m,
NCH); 5.18 – 5.20, 5.23 – 5.26 (m, CH¼CH2); 5.75 – 5.83 (m, CH¼CH2). 13C-NMR (125.8 MHz, CDCl3):

Helvetica Chimica Acta – Vol. 95 (2012)
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25.75, 25.89, 30.16, 33.35 (4 Me); 40.96 (NCH2); 53.27 (SCMe2CH); 69.46 (SCMe2N); 74.27 (NCH);
118.53 (CH¼CH2); 131.20 (CH¼CH2); 152.78 (NCON); 168.63 (NCOCH). CI-MS: 255 (100, [M þ
H]þ). HR-EI-MS: 254.1092 (Mþ, C21H23Cl3N2O3þ ; calc. 254.1089).
(RS)-6-(4-Methoxybenzyl)-1,1,3,3-tetramethyl-1H-imidazo[1,5-c][1,3]thiazole-5,7(6H,7aH)-dione
(7b). According to GP 2, with 4b (154 mg, 0.34 mmol). Purification by washing with cold EtOH and
drying in vacuum. Yield: 85 mg (74%). Yellow solid. M.p. 145 – 1478. IR (ATR): 2965, 2930, 2836, 1711,
1599, 1510. 1H-NMR (500.1 MHz, CDCl3): 1.37, 1.51, 1.74, 1.83 (4s, 2 Me2C); 3.73 (s, MeO); 4.21 (d, 2J ¼
14.5, 1 H, CH2); 4.27 (d, 2J ¼ 15.4, 1 H, CH2); 4.30 (s, NCH); 6.76 – 6.78 (m, 2 m-CH); 7.11 – 7.12 (m, 2 o-
CH). 13C-NMR (125.8 MHz, CDCl3): 26.71, 31.42, 32.58, 32.64 (2 Me2C); 44.29 (CH2); 48.48
(SCMe2CH); 55.35 (OMe); 70.44 (SCMe2N); 77.36 (NCH); 114.13 (2 m-CH); 129.05 (2 o-CH);
131.13 (C(Ar)CH2); 157.46 (NCON); 158.89 (C(Ar)OMe); 177.01 (NCOCH). CI-MS: 352 (71, [M þ
H þ NH3]þ). HR-CI-MS: 352.1691 ([M þ H þ NH3]þ, C17H26N3O3Sþ; calc. 352.1695).
(RS)-6-Cyclohexyl-1,1,3,3-tetramethyl-1H-imidazo[1,5-c][1,3]thiazole-5,7(6H,7aH)-dione (7c). Ac-
cording to GP 2, with 4c (200 mg, 0.48 mmol). Purification by washing with cold EtOH and drying in
vacuum. Yield: 89 mg (63%). Orange solid. M.p. 868. IR (ATR): 2928, 2858, 1767, 1750, 1704, 1672, 1599.
1H-NMR (500.1 MHz, CDCl3): 1.13 – 1.33; 1.63 – 1.65; 1.79 – 1.82; 2.07 – 2.16 (4m, 5 CH2); 1.36, 1.58, 1.70,
2.03 (4s, 4 Me); 3.78 – 3.84 (m, NCHCH2); 4.30 (s, NCHCO). 13C-NMR (125.8 MHz, CDCl3): 25.15
(CH2); 25.42, 25.81 (2 Me); 25.95, 29.38, 29.47 (3 CH2); 30.11, 33.49 (2 Me); 51.83 (NCHCH2); 53.49
(SCMe2CH); 69.63 (SCMe2N); 73.45 (NCHCO); 153.34 (NCON); 168.82 (NCOCH). ESI-MS: 321 (31,
[M þ Liþ þ H2O]þ). HR-CI-MS: 297.1639 ([M þ H]þ, C15H25N2O2Sþ; calc. 297.1637).
(RS)-1,1,3,3-Tetramethyl-6-(naphthalen-2-ylmethyl)-1H-imidazo[1,5-c][1,3]thiazole-5,7(6H,7aH)-
dione (7d). According to GP 2, with 4d (250 mg, 0.53 mmol). Purification by washing with cold EtOH
and drying in vacuum. Yield: 158 mg (84%). Orange solid. M.p. 588. IR (ATR): 3340, 2984, 1673, 1606,
1510. 1H-NMR (500.1 MHz, CDCl3): 1.30, 1.60, 1.71, 2.04 (4s, 4 Me); 4.43 (s, NCH); 4.76 – 4.77 (m, CH2);
7.45 – 7.49 (m, 2 arom. H); 7.50 – 7.52 (m, 1 arom. H); 7.79 – 7.83 (m, 3 arom. H); 7.85 – 7.86 (m, 1 arom. H).
13C-NMR (125.8 MHz, CDCl3): 25.69, 25.87, 30.18, 33.37 (4 Me); 42.71 (CH2); 53.35 (SCMe2CH); 69.53
(SCMe2N); 74.29 (NCH); 126.29, 126.37, 126.57, 127.78, 128.00, 128.14, 128.65 (7 arom. CH); 133.04,
133.36, 133.55 (3 arom. C); 152.96 (NCON); 168.57 (NCOCH). CI-MS: 355 (100, [M þ H]þ). HR-EI-
MS: 354.1405 (Mþ, C20H22N2O2Sþ; calc. 354.1402).
(RS)-6’-(Naphthalen-2-ylmethyl)dispiro[cyclohexane-1,1’-imidazo[1,5-c][1,3]thiazole-3’,1’’-cyclo-
hexane]-5’,7’(6’H,7a’H)-dione (7e). According to GP 2, with 4e (277 mg, 0.50 mmol). Purification by
washing with cold EtOH and drying in vacuum. Yield: 205 mg (94%). Colorless solid. M.p. 1688. IR
(ATR): 2939, 2857, 1755, 1700. 1H-NMR (500.1 MHz, CDCl3): 1.11 – 2.12 (m, 19 H, CH2, c-Hex); 2.96 –
3.02 (m, 1 H, CH2, c-Hex); 4.38 (s, NCH); 4.76 – 4.77 (m, NCH2); 7.45 – 7.51 (m, 3 arom. H); 7.79 – 7.84
(m, 4 arom. H). 13C-NMR (125.8 MHz, CDCl3): 22.38, 24.12, 24.67, 25.37, 25.44, 25.52, 32.64, 36.56, 37.62,
42.06 (10 CH2, c-Hex); 42.58 (NCH2); 58.93 (SC(CH2)5CH); 73.97 (NCH); 75.62 (SC(CH2)5N); 126.25,
126.35, 126.58, 127.78, 127.92, 128.13, 128.61 (7 arom. CH); 133.03, 133.38, 133.65 (3 arom. C); 152.82
(NCON); 168.97 (NCOCH). CI-MS: 435 (100, [M þ H]þ). HR-CI-MS: 435.2100 ([M þ H]þ,
C26H31N2O2Sþ; calc. 435.2101).
(RS)-1,1-Dimethyl-6-(prop-2-en-1-yl)tetrahydro-1H-spiro[imidazo[1,5-c][1,3]thiazole-3,4’-pyr-
an]-5,7(6H,7aH)-dione (7f). According to GP 2, with 4f (163 mg, 0.39 mmol). Purification by washing
with CH2Cl2 and drying in vacuum. Yield: 79 mg (69%). Colorless solid. M.p. 107 – 1128. IR (ATR): 2964,
2859, 1711, 1597, 1512. 1H-NMR (499.9 MHz, CD3OD): 1.44, 1.60 (2s, 2 Me); 1.67 – 1.70 (m, 1 H,
CH2CCH2); 2.39 – 2.42, 3.11 – 3.17 (2m, CH2CCH2); 3.35 – 3.45 (m, 2 H, CH2CCH2, CH2OCH2); 3.62 –
3.70 (m, 1 H, CH2OCH2); 3.75 – 3.76 (m, NCH2); 3.91 – 3.99 (m, 2 H, CH2OCH2); 4.14 (s, NCH);
5.04 – 5.06, 5.18 – 5.21 (2m, CH¼CH2); 5.83 – 5.90 (m, CH¼CH2). 13C-NMR (125.7 MHz, CD3OD): 26.19,
34.91 (2 Me); 38.75 (CH2CCH2); 40.91 (CH2CCH2); 43.94 (NCH2); 50.06 (SCMe2CH); 68.60
(CH2OCH2); 68.98 (CH2OCH2); 78.35 (SC(CH2)2N); 79.28 (NCH); 115.54 (CH¼CH2); 136.56
(CH¼CH2); 157.95 (NCON); 176.45 (NCOCH). CI-MS: 297 (69, [M þ H]þ). HR-CI-MS: 314.1541
([M þ H þ NH3]þ, C14H24N3O3Sþ; calc. 314.1538).
(RS)-6-(4-Methoxybenzyl)-1,1-dimethyltetrahydro-1H-spiro[imidazo[1,5-c][1,3]thiazole-3,4’-pyr-
an]-5,7(6H,7aH)-dione (7g). According to GP 2, with 4g (201 mg, 0.40 mmol). Purification by washing
with cold EtOH and crystallization from AcOEt. Yield: 106 mg (70%). Colorless oil. M.p. 171 – 1758. IR

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Helvetica Chimica Acta – Vol. 95 (2012)
1
(ATR): 2960, 2855, 1710, 1601, 1511. H-NMR (499.9 MHz, CD3OD): 1.44, 1.60 (2s, Me2C); 1.68 – 1.71
(m, 1 H, CH2CCH2); 2.42 – 2.44, 3.13 – 3.19 (2m, CH2CCH2); 3.36 – 3.54 (m, 2 H, CH2CCH2, OCH2);
3.62 – 3.67 (m, 1 H, OCH2); 3.76 (s, OMe); 3.91 – 3.99 (m, 2 H, CH2OCH2); 4.14 (s, NCH); 4.27 – 4.28 (m,
NCH2); 6.85 – 6.86 (m, 2 m-CH); 7.22 – 7.23 (m, 2 o-CH). 13C-NMR (125.7 MHz, CD3OD): 26.20, 34.92
(CMe2); 38.79 (CH2CCH2); 40.95 (CH2CCH2); 44.84 (NCH2); 50.08 (SCMe2CH); 55.68 (MeO); 68.62,
68.99 (CH2OCH2); 78.40 (SC(CH2)2N); 79.33 (NCH); 114.93 (2 m-CH); 129.54 (2 o-CH); 132.84
(C(Ar)CH2); 158.06 (NCON); 160.24 (C(Ar)OMe); 176.41 (NCOCH). CI-MS: 395 (6, [M þ H þ
NH3]þ). HR-CI-MS: 394.1796 ([M þ H þ NH3]þ, C19H28N3O4Sþ; calc. 394.1801).
(RS)-1,1-Dimethyl-6-(2-phenylethyl)tetrahydro-1H-spiro[imidazo[1,5-c][1,3]thiazole-3,4’-pyr-
an]-5,7(6H,7aH)-dione (7h). According to GP 2, with 4h (141 mg, 0.29 mmol). Purification by washing
with cold EtOH and drying in vacuum. Yield: 60 mg (57%). Colorless solid. M.p. 1298. IR (ATR): 2962,
1
2945, 2913, 2842, 1763, 1702. H-NMR (500.1 MHz, CDCl3): 1.20, 1.58 (2s, 2 Me); 1.73 – 1.76 (m, 1 H,
CH2CCH2); 1.92 – 1.95 (m, 1 H, CH2CCH2); 2.31 – 2.37 (m, 1 H, CH2CCH2); 2.89 – 2.99 (m, PhCH2);
3.33 – 3.42 (m, 2 H, CH2CCH2, CH2OCH2); 3.50 – 3.55 (m, 1 H, CH2OCH2); 3.65 – 3.71, 3.73 – 3.79 (2m,
NCH2); 3.97 – 3.99 (m, 1 H, CH2OCH2); 4.10 – 4.12 (m, 1 H, CH2OCH2); 4.35 (s, NCH); 7.19 – 7.24 (m, 3
arom. H); 7.26 – 7.30 (m, 2 arom. H). 13C-NMR (125.8 MHz, CDCl3): 25.73, 26.02 (2 Me); 33.98 (PhCH2);
37.55 (CH2CCH2); 39.82 (NCH2); 42.32 (CH2CCH2); 52.35 (SCMe2CH); 65.83 (CH2OCH2); 67.18
(CH2OCH2); 72.91 (SC(CH2)2N); 73.45 (NCH); 126.86 (1 arom. CH); 128.67, 129.03 (4 arom. CH);
137.67 (1 arom. C); 152.93 (NCON); 168.57 (NCOCH). CI-MS: 362 (100, [M þ H]þ). HR-CI-MS:
361.1584 ([M þ H]þ, C19H25N2O3Sþ; calc. 361.1586).
(RS)-1,1,3,3-Tetramethyl-6-(prop-2-en-1-yl)-1H-imidazo[1,5-c][1,3]oxazole-5,7(6H,7aH)-dione
(8a). According to GP 2, with 5a (358 mg, 1.00 mmol). Purification by washing with cold EtOH and
drying in vacuum. Yield: 170 mg (71%). Colorless solid. M.p. 1978. IR (ATR): 2991, 2942, 1639, 1591.
1H-NMR (500.1 MHz, CD3OD): 1.34, 1.44, 1.62, 1.71 (4s, 4 Me); 3.75 – 3.76 (m, CH2); 3.95 (s, NCH);
5.03 – 5.05, 5.16 – 5.20 (2m, CH¼CH2); 5.81 – 5.88 (m, CH¼CH2). 13C-NMR (125.8 MHz, CD3OD): 25.81,
28.11, 28.88, 31.12 (4 Me); 43.43 (CH2); 72.02 (NCH); 81.13 (OCMe2CH); 96.49 (OCMe2N); 115.40
(CH¼CH2); 136.35 (CH¼CH2); 156.78 (NCON); 176.44 (NCOCH). CI-MS: 239 (100, [M þ H]þ). HR-
CI-MS: 239.1392 ([M þ H]þ, C12H19N2O3þ ; calc. 239.1390).
(RS)-6-(4-Methoxybenzyl)-1,1,3,3-tetramethyl-1H-imidazo[1,5-c][1,3]oxazole-5,7(6H,7aH)-dione
(8b). According to GP 2, with 5b (184 mg, 0.42 mmol). Purification by CC (AcOEt/EtOH 4 :1). Yield:
71 mg (52%). Colorless solid. M.p. 126 – 1318. Rf (AcOEt/EtOH 4 :1) 0.58. IR (ATR): 2985, 2939, 2835,
1711, 1667, 1642, 1510. 1H-NMR (499.9 MHz, CD3OD): 1.33, 1.46, 1.64, 1.70 (4s, 2 Me2C); 3.76 (s, MeO);
4.17 (d, 2J ¼ 15.4, 1 H, CH2); 4.37 – 4.39 (m, 2 H, CH2, NCH); 6.83 – 6.85 (m, 2 m-CH); 7.19 – 7.20 (m, 2 o-
CH). 13C-NMR (125.7 MHz, CD3OD): 25.71, 28.15, 28.93, 30.83 (2 Me2C); 44.34 (CH2); 55.69 (MeO);
69.41 (NCH); 81.08 (OCMe2CH); 96.90 (OCMe2N); 114.76 (2 m-CH); 129.29 (2 o-CH); 133.23
(C(Ar)CH2); 156.97 (NCON); 160.11 (C(Ar)OMe); 173.31 (NCOCH). CI-MS: 336 (5, [M þ H þ
NH3]þ). HR-CI-MS: 336.1930 ([M þ H þ NH3]þ, C17H26N3Oþ4 ; calc. 336.1923).
(RS)-6-Cyclohexyl-1,1,3,3-tetramethyl-1H-imidazo[1,5-c][1,3]oxazole-5,7(6H,7aH)-dione (8c). Ac-
cording to GP 2, with 5c (200 mg, 0.50 mmol). Purification by washing with cold EtOH and drying in
vacuum. Yield: 107 mg (76%). Colorless solid. M.p. 578. IR (ATR): 2978, 2932, 2857, 1765, 1705, 1603.
1H-NMR (499.9 MHz, CDCl3): 1.12 (s, Me); 1.15 – 1.33 (m, 2 CH2); 1.44, 1.47 (2s, 2 Me); 1.62 – 1.67 (m,
2 CH2); 1.75 (s, Me); 1.79 – 1.82, 2.05 – 2.16 (2m, CH2); 3.80 – 3.86 (m, NCH); 4.02 (s, NCH). 13C-NMR
(125.7 MHz, CDCl3): 22.87 (Me); 25.14 (CH2); 25.93 (2 CH2); 27.91 (Me); 29.16, 29.38 (2 CH2); 30.70
(Me); 51.92 (NCHCH2); 69.37 (NCH); 79.66 (OC(Me)2CH); 94.13 (OC(Me)2N); 156.11 (NCON);
169.72 (NCOCH). CI-MS: 281 (100, [M þ H]þ). HR-CI-MS: 281.1858 ([M þ H]þ, C15H25N2Oþ3 ; calc.
281.1860).
(RS)-1,1,3,3-Tetramethyl-6-(naphthalen-2-ylmethyl)-1H-imidazo[1,5-c][1,3]oxazole-5,7(6H,7aH)-
dione (8d). According to GP 2, with 5d (300 mg, 0.66 mmol). Purification by washing with cold EtOH
and drying in vacuum. Yield: 175 mg (78%). Colorless solid. M.p. 1148. IR (ATR): 2981, 2932, 1771, 1708.
1H-NMR (500.1 MHz, CDCl3): 1.04, 1.46, 1.49, 1.77 (4s, 4 Me); 4.15 (s, NCH); 4.78 – 4.79 (m, CH2); 7.45 –
7.49 (m, 2 arom. H); 7.51 – 7.53 (m, 1 arom. H); 7.79 – 7.83 (m, 3 arom. H); 7.86 – 7.87 (m, 1 arom. H).
13C-NMR (125.8 MHz, CDCl3): 23.02, 26.00, 27.89, 30.59 (4s, 4 Me); 42.81 (CH2); 70.03 (NCH); 79.64
(OC(Me)2CH); 94.07 (OC(Me)2N); 126.30, 126.36, 126.54, 127.76, 128.06, 128.12, 128.64 (7 arom. CH);

Helvetica Chimica Acta – Vol. 95 (2012)
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133.03 (1 arom. C); 133.34 (2 arom. C); 155.73 (NCON); 169.41 (NCOCH). CI-MS: 339 (100, [M þ
H]þ). HR-EI-MS: 338.1627 (Mþ, C20H22N2Oþ3 ; calc. 338.1630).
(RS)-4,4-Dimethyl-2-(prop-2-en-1-yl)-3a,4-dihydro-1H-imidazo[5,1-c][1,4]benzothiazine-1,3(2H)-
dione (9a). According to GP 2, with 6a (62 mg, 0.15 mmol). Purification by CC (CH2Cl2). Yield: 30 mg
(67%). Colorless solid. M.p. 84 – 898. Rf (CH2Cl2) 0.30. IR (ATR): 2990, 2966, 2927, 2880, 1775, 1704.
1H-NMR (500.1 MHz, CDCl3): 1.34, 1.74 (2s, 2 Me); 4.14 – 4.24 (m, NCH2); 4.28 (s, NCH); 5.23 – 5.25,
5.29 – 5.33 (2m, CH¼CH2); 5.80 – 5.88 (m, CH¼CH2); 7.01 – 7.04 (m, CH(7)); 7.08 – 7.10 (m, CH(6));
7.13 – 7.16 (m, CH(8)); 8.22 – 8.24 (m, CH(9)). 13C-NMR (125.8 MHz, CDCl3): 23.93, 24.87 (2 Me); 41.17
(CH2); 42.29 (Me2C); 64.91 (NCH); 119.10 (CH¼CH2); 121.03 (C(9)); 122.18 (C(5a)); 124.74, 125.49,
126.54 (C(6), C(7), C(8)); 130.62 (C(9a)); 130.67 (CH¼CH2); 153.42 (NCON); 167.66 (NCOCH). EI-
MS: 228 (100, Mþ). HR-EI-MS: 288.0939 (M þ, C15H16N2O3Sþ; calc. 288.0933).
(RS)-2-(4-Methoxybenzyl)-4,4-dimethyl-3a,4-dihydro-1H-imidazo[5,1-c][1,4]benzothiazine-1,3(2H)-
dione (9b). According to GP 2, with 6b (70 mg, 0.14 mmol). Purification by CC (tBuOMe/hexane 3 :7).
Yield: 40 mg (78%). Colorless solid. M.p. 1208. Rf (tBuOMe/hexane 3 :7) 0.52. IR (ATR): 3000, 2967,
2932, 2835, 1771, 1704, 1614, 1586, 1515. 1H-NMR (499.9 MHz, CDCl3): 1.19, 1.71 (2s, 2 Me2C); 3.78 (s,
MeO); 4.23 (s, NCH); 4.65 – 4.71 (m, CH2); 6.83 – 6.85 (m, 2 m-CH); 7.00 – 7.03 (m, CH(7)); 7.07 – 7.08
(m, CH(6)); 7.12 – 7.15 (m, CH(8)); 7.37 – 7.38 (m, 2 o-CH); 8.21 – 8.23 (m, CH(9)). 13C-NMR
(125.7 MHz, CDCl3): 23.83, 24.87 (2 Me2C); 42.23 (CH2); 42.41 (Me2C); 55.39 (MeO); 64.88 (NCH);
114.20 (2 m-CH); 121.13 (C(9)); 122.28 (C(5a)); 124.73, 125.45, 126.55 (C(6), C(7), C(8)); 127.95
(C(9a)); 130.42 (2 o-CH); 130.68 (C(Ar)CH2); 153.70 (NCON); 159.61 (C(Ar)OMe); 167.85
(NCOCH). CI-MS: 370 (100, [M þ H]þ). HR-CI-MS: 369.1270 ([M þ H]þ, C20H21N2O3Sþ; calc.
369.1273).
(RS)-4,4-Dimethyl-2-(2-phenylethyl)-3a,4-dihydro-1H-imidazo[5,1-c][1,4]benzothiazine-1,3(2H)-
dione (9c). According to GP 2, with 6c (44 mg, 0.09 mmol). Rf (CH2Cl2) 0.65. Yield: 20 mg (63%).
Colorless oil. IR (ATR): 2958, 2928, 2857, 1771, 1715. 1H-NMR (499.9 MHz, CDCl3): 1.17, 1.69 (2s, 2 Me);
3.01 – 3.02 (m, PhCH2); 3.79 – 3.85, 3.89 – 3.95 (2m, NCH2); 4.21 (s, NCH); 7.02 – 7.05, 7.08 – 7.09 (2m, 2
arom. H); 7.13 – 7.31 (m, 6 arom. H); 8.21 – 8.23 (m, CH(9)). 13C-NMR (125.7 MHz, CDCl3): 23.76, 24.90
(2 Me); 33.82 (PhCH2); 40.13 (NCH2); 42.28 (Me2C); 64.91 (NCH); 121.04 (C(9)); 122.33 (C(5a));
124.73, 125.50, 126.58, 126.98 (4 arom. CH); 128.79, 129.05 (4 arom. CH); 130.74 (C(9a)); 137.59
(PhCH2); 153.72 (NCON); 167.92 (NCOCH). EI-MS: 352 (100, Mþ). HR-EI-MS: 352.1242 (Mþ,
C20H20N2O2Sþ; calc. 352.1246).
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Received August 10, 2012