Synthesis and crystal structure of 3,3,6,6-tetramethylmorpholine-2,5-dione, and its 5-monothioxo and 2,5-dithioxo derivatives

Article abstract of DOI:10.1002/hlca.201000318

The synthesis of 3,3-dimethylmorpholine-2,5-diones 4a was achieved conveniently via the 'direct amide cyclization' of the linear precursors of type 3, which were prepared by coupling of 2,2-dimethyl-2H-azirin-3-amines 2 with 2-hydroxyalkanoic acids 1. Thionation of 4a with Lawesson's reagent yielded the corresponding 5-thioxomorpholin-2-ones 10 and morpholine-2,5-dithiones 11, respectively, depending on the reaction conditions. The structures of 3aa, 4aa, 10a, and 11a were established by X-ray crystallography. All attempts to prepare S-containing morpholine-2,5-dione analogs or thiomorpholine-2,5-diones by cyclization of corresponding S-containing precursors were unsuccessful and led to various other products. The structures of some of them have also been established by X-ray crystallography.

Full text of DOI:10.1002/hlca.201000318

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Synthesis and Crystal Structure of 3,3,6,6-Tetramethylmorpholine-2,5-dione,
and Its 5-Monothioxo and 2,5-Dithioxo Derivatives
by Nasser Mawad1), Fatemeh Ghorbani-Salman Pour2), Anthony Linden, and Heinz Heimgartner*
Organisch-Chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-6354282; fax: þ 41-44-6356812; e-mail: heimgart@oci.uzh.ch)
The synthesis of 3,3-dimethylmorpholine-2,5-diones 4a was achieved conveniently via the ꢂdirect
amide cyclizationꢃ of the linear precursors of type 3, which were prepared by coupling of 2,2-dimethyl-
2H-azirin-3-amines 2 with 2-hydroxyalkanoic acids 1. Thionation of 4a with Lawessonꢃs reagent yielded
the corresponding 5-thioxomorpholin-2-ones 10 and morpholine-2,5-dithiones 11, respectively, depend-
ing on the reaction conditions. The structures of 3aa, 4aa, 10a, and 11a were established by X-ray
crystallography. All attempts to prepare S-containing morpholine-2,5-dione analogs or thiomorpholine-
2,5-diones by cyclization of corresponding S-containing precursors were unsuccessful and led to various
other products. The structures of some of them have also been established by X-ray crystallography.
Introduction. – In the last 30 years, we have demonstrated that the ꢂdirect amide
cyclizationꢃ [1] is a useful method for the synthesis of cyclodepsipeptides, which contain
a,a-disubstituted a-amino acids, e.g., a-aminoisobutyric acid (Aib) [2]. The combina-
tion with the ꢂazirine/oxazolone methodꢃ [3] for the preparation of the linear precursors
offers a convenient and efficient access to this class of compounds. For example, the
reaction sequence starting with an a-hydroxy acid 1 and azirine 2a yielding compound 3
(n ¼ 1), followed by repeated hydrolysis and azirine coupling, and finally cyclization
leads to cyclodepsipeptides of type 4 with 6-, 9-, 12-, and 15-membered rings [1b]
(Scheme 1). Analogously, 16- and 19-membered cyclodepsipeptides are accessible from
b-hydroxy acids [4]. Furthermore, cyclodepsipeptides with an alternating sequence of
a-hydroxy and a,a-disubstituted a-amino acids can be prepared by coupling segments
of type 3, followed by ꢂdirect amide cyclizationꢃ [1c][5].
The synthesis and stability of morpholine-2,5-diones (4a), which are the smallest
cyclodepsipeptides, was studied already 60 years ago [6]. But only in the last couple of
years have these compounds attracted increasing interest as natural products [7],
biologically active compounds [8], and particularly as monomers of biodegradable
polymers [9]. There are three types of cyclization leading to 4a, i.e., lactonization,
lactamization, and cyclization of N-(2-bromoacetyl)glycine sodium salts (for reviews,
see [10]). In the case of a,a-disubstituted glycines, a very simple and efficient protocol
is the ꢂdirect amide cyclizationꢃ of 3 (n ¼ 1) [1b]. Surprisingly, all attempts to prepare
the analogous seven-membered 1,4-oxazepane-2,5-diones 5 by the same method failed,
and only the 14-membered cyclodimers were obtained [11].
1
)
)
Stay at the University of Zꢁrich, 09.2000 – 09.2001.
Diploma thesis, University of Zꢁrich, 2000.
2
ꢄ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
2327
Scheme 1
In connection with our interest in heterocyclic thiones, e.g., 1,3-thiazole-5(4H)-
thiones 6 [12], 5,5-dimethyl-3-methylidenpyrrolidine-2-thione (7) [13], 5-benzylidene-
3-phenylrhodanine (8) [14], and 1H-imidazole-2-thiones 9 [15], we became interested
in thioxo analogs of morpholine-2,5-diones. Therefore, we studied various reactions
toward the only scarcely known mono- and dithioxomorpholines of type 10 and 11.
Besides attempted cyclizations of thioxo derivatives of 3a (n ¼ 1), the stepwise
thionation of 4a with Lawessonꢃs reagent [16] to yield 5-thioxomorpholin-2-ones 10
and morpholine-2,5-dithiones 11 was investigated.
Results and Discussion. – Synthesis and Thionation of Morpholine-2,5-diones. The
reaction of a-hydroxy acids 1a – 1c with 2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine
(2b) in MeCN at 08 ! room temperature led to the diamides 3aa – 3ac in 95 – 96% yield
(Scheme 2), in accordance with the general reactivity of 2H-azirin-3-amines [3a]. In
comparison with the reactions of the corresponding 2,2,N,N-tetramethyl-2H-azirin-3-
amines [17], the reaction times were longer, but the yields were higher. The structures
of the products have been established by their spectroscopic data and, in the case of
3aa, by X-ray crystallography (Fig. 1).
The conformation of 3aa is as expected for peptides containing Aib [19]: the torsion
angles f (C(2)ꢀC(3)ꢀN(4)ꢀC(5)) and y (N(1)ꢀC(2)ꢀC(3)ꢀN(4)) of the Aib unit
are ꢀ 46.1(3) and ꢀ 49.0(3)8, respectively, i.e., close to the values for helical peptide
structures (e.g., ca. ꢀ 47 and ꢀ 578 for the a-helix). Both amide groups are almost
planar (C(3)ꢀC(2)ꢀN(1)ꢀC(7): 178.6(2)8; C(3)ꢀN(4)ꢀC(5)ꢀC(6): ꢀ 175.8(2)8),

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2
Fig. 1. ORTEP Plot [18] of the molecular structure of 3aa (50% probability ellipsoids, arbitrary
numbering of the atoms)
but the orientation of the Ph ring at N(1) is nearly orthogonal to the plane of the amide
group (C(2)ꢀN(1)ꢀC(7)ꢀC(8): ꢀ 99.9(2)8). The N(4)ꢀH group forms an intra-
molecular H-bond with the O(6)-atom of the OH group, thereby forming a five-
membered loop with a graph set motif [20] of S(5). As a result, the torsion angle
N(4)ꢀC(5)ꢀC(6)ꢀO(6) is 9.5(3)8. The OH group forms an intermolecular H-bond
with the amide O(5)-atom of a neighboring molecule, thereby linking the molecules
into one-dimensional chains which run parallel to the [100] direction and have a graph
set motif of C(5).
The cyclization of 3aa – 3ac to give the morpholine-2,5-diones 4aa – 4ac was
performed according to the protocol described in [1b]: a stirred suspension3) of the
diamides in dry toluene was heated to 90 – 1008, and a stream of dry HCl gas was
3
)
At the reaction temperature of ca. 1008, the diamides of type 3a (n ¼ 1) were dissolved.

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2329
bubbled through the solution for 10 – 30 min. After removing the precipitated N-
methylaniline hydrochloride and purification of the product by crystallization or
chromatography, 4aa – 4ac [1b] were obtained in 61, 27, and 22% yield, respectively
(Scheme 2)4). The elucidation of the structures was based on the spectroscopic5) and
analytical data, and, in the cases of 4aa (Fig. 2,a) and 4ab [21], the structures were
confirmed by X-ray crystallography.
Fig. 2. ORTEP Plots [18] of the molecular structures of a) 4aa, b) 10a (polymorph 1), and c) 11a (50%
probability ellipsoids, arbitrary numbering of the atoms)
Conceivable intermediates for the acid-catalyzed cyclization of 3 to 4 are shown in
Scheme 2 (see also [1b]). In analogy to previously described ꢂdirect amide cyclizationsꢃ,
we propose that the first step is the formation of a 1,3-oxazol-5(4H)-one A [2].
4
)
)
The cyclization of the corresponding N,N-dimethyl derivatives 3 (n ¼ 1) yielded the morpholin-2,5-
diones 4aa – 4ac in 87, 30, and 75% yield, respectively [1b].
The previously reported 13C chemical shift of C(2) of 4ac proved to be incorrect. The signals of the
two C¼O groups appear at 169.1 and 165.3 ppm (Table 1).
5

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Helvetica Chimica Acta – Vol. 93 (2010)
Whereas, in analogous intermediates with a longer tether between the oxazolone ring
and the nucleophilic group, the attack at C(5) may occur directly, this seems not
possible in the present case. Therefore, the ring opening to give the acylium ion B,
which cyclizes via formation of the lactone group, is a likely process.
The thionation of morpholine-2,5-diones 4aa – 4ac with 0.5 equiv. Lawessonꢃs
reagent (L.R.; 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) in
toluene at 90 – 1008 for 20 – 30 min gave the thiolactams 10a – 10c, respectively, in 68 –
98% yield as the sole products (Scheme 3). The observed selectivity confirms the
generally known reactivity of C¼O compounds on thionations with L.R. [16], i.e.,
thionations of amides (lactams) are faster than those of esters (lactones). The
structures have been deduced from the spectroscopic data. The most characteristic
differences to those of 4aa – 4ac, in addition to elemental analyses, are the missing
C¼O absorption at ca. 1680 cmꢀ1 in the IR spectrum and the absorption of C(5)¼S at
193 – 200 ppm in the 13C-NMR spectrum (Table 1). Furthermore, X-ray crystal-
structure determinations were performed in the cases of 10a (Fig. 2,b) and 10b [21].
Scheme 3
Table 1. Characteristic Spectroscopic Data of Compounds 4a, 10, and 11
Compound
IR (KBr) [cmꢀ1]a)
13C-NMR (CDCl3) [ppm]
EI-MS Mþ· [m/z (%)]
C(2)¼O
1743 (1750)
1746 (1748)
1747 (1740)
1738
1749
1742
–
C(5)¼O
1677 (1680)
1686 (1680)
1682 (1690)
–
–
–
–
–
C(2)
C(5)
4aa
4ab
4ac
10a
10b
10c
12a
12b
170.2
169.5
169.1
169.4
168.3
169.7
216.8
215.2
169.8
166.2
165.3
200.5
193.7
192.7
199.9
193.3
172 (100)b)
233 (18) [1b]
219 (19) [1b]
188 (100)b)
249 (100)
235 (100)
203 (7)
–
265 (4)
b
a) Values in brackets from [1b]. ) CI-MS (NH3): [M þ 1]þ.
The thionation of the lactone group of 10a and 10b has been achieved under more
drastic conditions [22]: suspensions of 10a and 10b, and 2.5 equiv. of L.R. in toluene
were heated to reflux for 2 – 6 d leading to morpholine-2,5-dithiones 11a and 11b in 49
and 28% yield, respectively, as yellow crystalline materials. Again, the structures have

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been determined on the basis of the spectroscopic data (Table 1) and confirmed by X-
ray crystal-structure determinations (11a (Fig. 2,c), 11b [21]).
The six-membered rings of 4aa and 10a (polymorph 1) have a conformation
midway between that of a highly flattened boat and a twist-boat, where C(6) shows the
most significant deviation from the ring plane. The N(4)ꢀH group forms an
intermolecular H-bond with the amide O(5)-atom and the S(5)-atom, respectively,
of a neighboring molecule. This interaction forms closed loops, thereby linking pairs of
molecules into centrosymmetric dimers, which have a graph set motif [20] of R22(8) (for
a similar structure, see [21]). In another crystallization of 10a, a second polymorph was
obtained, in which two symmetry-independent molecules are in the asymmetric unit.
The six-membered ring in each molecule has a flattened boat conformation. The NꢀH
group in molecule A forms an intermolecular H-bond with the S-atom of a neighboring
molecule A. This interaction forms closed loops, thereby linking pairs of molecules of
type A into centrosymmetric dimers, which have a graph set motif of R22(8). The
molecules of type B form the same type of centrosymmetric dimers.
In the dithione 11a, the molecule sits across a crystallographic center of inversion.
Thus, the O-atom and NH group are necessarily disordered in the model with equal site
occupation factors of 0.5. The proximity of the N- and O-atoms in the model makes it
difficult to accurately refine their positions. Therefore, some of the bond lengths
involving these atoms are only approximate, and a reliable analysis of the ring
conformation is not achievable. The N(4)ꢀH group forms an intermolecular H-bond
with the S(2)-atom of a neighboring molecule. This interaction links the molecules into
infinite one-dimensional chains, which run parallel to the [101] direction and have a
graph set motif of C(5). The centrosymmetric disorder in the molecules results in
disorder also of these chains, which run in one direction in one orientation of the
disorder and in the opposite direction in the alternate disordered orientation.
Attempted Cyclizations of S-Containing Diamides. In the past, we have shown that
the reaction of 2H-azirin-3-amines of type 2 with thio acids 12 leads to monothiodi-
amides 13 with a terminal thioamide group [23] (Scheme 4). Under acidic conditions,
the latter cyclize to 1,3-oxathiazole-5(4H)-thiones 14, which undergo a spontaneous
isomerization to yield 1,3-thiazol-5(4H)-ones 15. Treatment of 15 with Me2NH gave the
Scheme 4

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monothiodiamides of type 16 (R1 ¼ R2 ¼ Me). Under modified conditions, a one-pot
isomerization 13 ! 16 was elaborated. This reaction sequence was used for the selective
synthesis of Aib-containing endothiopeptides [23d][24].
In [23d], we described the acid-catalyzed reactions of compounds 17 (R ¼ tBu, THP
(¼tetrahydro-2H-pyran-2-yl)). Whereas the treatment of a solution of 17a (R ¼ tBu) in
dry toluene at 808 with HCl gas for 2 min gave the isomeric product 18a in 53% yield, an
analogous reaction (30 min, 908) led to a mixture of 1,3-thiazol-5(4H)-one 19a (60%)
and 2-thioxomorpholin-5-one 20 (6%; Scheme 5). The latter was obtained in 30% yield
via deprotection of the THP derivative 17b (R ¼ THP) and subsequent acid-catalyzed
cyclization (toluene, 908, HCl gas).
Scheme 5
With these results in mind, we attempted to synthesize S-analogues of morpholine-
2,5-diones via acid-catalyzed cyclization of suitable S-containing precursors. In a first
experiment, the crude THP-protected mandelic thioacid 21 was reacted with azirine 2b
to give the desired monothiodiamide 22 in 52% yield (Scheme 6). As an unexpected
minor product (20%), 23 was obtained, the structure of which was established by X-ray
crystallography (Fig. 3). Since the space group is centrosymmetric, the crystals are
racemic. The amide NH group forms an intramolecular H-bond with O(7) of the
carbonate group, thereby forming a five-membered ring with a graph set motif of
S(5)6).
Deprotection of 22 to give 24 was achieved in quantitative yield by treatment with
pyridinium para-toluenesulfonate (PPTS) in EtOH (Scheme 6). With the aim of
preparing the 2-thioxomorpholin-5-one 20 (Scheme 5), HCl gas was bubbled through a
solution of 24 in dry toluene at 100 – 1108 for 20 min, leading to a complex mixture of
products. Chromatographic workup gave, in addition to 33% of the starting material 24,
three isomeric products in ca. 26, 12, and 6% yield, with the mass of the expected 20
(ESI-MS: m/z 236 ([M þ 1]þ)). Unfortunately, the spectroscopic data of the two main
isomers do not fit those of 20, and the structures of the products are not known so far.
6
)
The formation of 23 may be explained via the exchange of the THP protecting group for the
(isobutyloxy)carbonyl group in the conversion of mandelic acid (1c) to 21 or an incomplete THP
protection of 1c and its twofold reaction with ClCO2 Bu and N-methylmorpholine (NMM, see
i
below).

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Scheme 6
Fig. 3. ORTEP Plot [18] of the molecular structure of 23 (50% probability ellipsoids, arbitrary
numbering of the atoms)
In a similar reaction as shown in Scheme 6, the conversion of 2-hydroxyisobutyric
acid (1a) to the O-protected monothiodiamide 25 was achieved in 92% yield
(Scheme 7). In this case, the protection of the OH group and the activation of the
carboxylic function of 1a were accomplished simultaneously by treatment with

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Scheme 7
i
ClCO2 Bu and NMM. Deprotection of the OH group with 0.8m NaOH in dioxane
yielded 26 (85%), the precursor for the cyclization, whose structure was established by
X-ray crystallography (Fig. 4).
Fig. 4. ORTEP Plot [18] of the molecular structure of one of the three independent molecules of 26 (50%
probability ellipsoids, arbitrary numbering of the atoms)
There are three symmetry-independent molecules of 26 in the asymmetric unit, but
their conformations differ only very slightly, the main difference being slightly different
orientations of the Ph ring. In each molecule, the amide NH group forms an
intramolecular H-bond with the O-atom of the OH group, thereby creating a five-
membered loop with a graph set motif of S(5). The OH group forms an intermolecular

Helvetica Chimica Acta – Vol. 93 (2010)
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H-bond with the amide O-atom of a neighboring symmetry-independent molecule and
thereby links the three independent molecules into infinite one-dimensional chains.
These chains run parallel to the [110] direction and are composed of repeating ··· A ···
B ··· C ··· units, which produce a tertiary graph set motif of C33(15).
The cyclization of 26 under the usual conditions of the ꢂdirect amide cyclizationꢃ,
i.e., by bubbling dry HCl gas through a suspension of 26 in toluene at 1008, led also to a
complex mixture of products, and chromatographic workup gave, unexpectedly, the 1,3-
thiazol-5(4H)-one 27 in 20% yield (Scheme 7). In addition, traces of 10a (Scheme 3)
were detected, but none of the desired 3,3,6,6-tetramethyl-2-thioxomorpholin-5-one of
type 20. The formation of 27 may be rationalized by the cyclization of 26 to give the
corresponding 1,3-oxazole-5(4H)-thione and subsequent rearrangement to 27 as shown
in Scheme 4.
To prepare thiomorpholine-2,5-dione 28 via acid-catalyzed cyclization of 29, 2-
bromoisobutyric acid (30) was reacted with 2b to afford 31 in 97% yield (Scheme 8).
The replacement of Br with the SH group was attempted by treatment of 31 with
Na3PO3S according to the method described in [25]. Unfortunately, no 29 was obtained,
and the only product, isolated in 28% yield as colorless plates, was 32. Most likely, it was
formed from 31 by elimination of HBr.
Scheme 8
The structure of 32 was established by X-ray crystallography (Fig. 5,a). The space
group is non-centrosymmetric, but achiral. The NH group forms an intermolecular H-
bond with the amide O(5)-atom of a neighboring molecule, thereby linking the

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Helvetica Chimica Acta – Vol. 93 (2010)
molecules into infinite one-dimensional chains, which run parallel to the [001] direction
and have a graph set motif of C(4).
Fig. 5. ORTEP Plots [18] of the molecular structures of a) 32 and b) 34 (50% probability ellipsoids,
arbitrary numbering of the atoms)
Finally, the sulfanyl diamide 29 was obtained in 95% yield from the reaction of 2-
sulfanylisobutyric acid (33) [25] with 2b in MeCN at room temperature (Scheme 8).
Unfortunately, the conversion of the Br compound 30 to the sulfanyl derivative 33 was
achieved in only 22% yield and was the yield-limiting step (see [25]). The cyclization of
29 was attempted under the conditions of the ꢂdirect amide cyclizationꢃ, i.e., a stream of
dry HCl gas was bubbled through a suspension of 29 in toluene at 1008 for 15 min.
After usual workup, the crude solid product, which was assumed to be 28, was purified
by chromatography to give the sulfanyl acid 34 in 60% yield (Scheme 8).
The unexpected structure of the product was again established by X-ray
crystallography (Fig. 5,b). The carboxylic OH group forms an intermolecular H-bond
with the amide O(3)-atom of a neighboring molecule. This interaction links pairs of
molecules across a center of inversion into dimers, which have a graph set motif of
R22(7). The SH group forms an intermolecular H-bond with the C¼O O(6)-atom of the
COOH group of the same neighboring molecule and so forms a second set of links
between the H-bonded dimers. This latter interaction has a graph set motif of R22(8).
The amide NH group is not involved in any H-bonding interactions.
The formation of 34, which is the product of the hydrolysis of the terminal amide
group of 29, may be explained via the acid-catalyzed intramolecular condensation to
give the 1,3-oxazol-5(4H)-one 35 (Scheme 8) and subsequent hydrolytic ring opening.
This reaction sequence, i.e., the selective cleavage of the terminal amide group in Aib
peptides, is generally observed by treatment of peptides of type 29 with acids in
aqueous media [17][26]. It is the basis of the ꢂazirine/oxazolone methodꢃ in peptide
synthesis. On the other hand, it has been shown that, under anhydrous conditions, the
formed 1,3-oxazol-5(4H)-ones are stable and can be isolated [23a]. Therefore, it may

Helvetica Chimica Acta – Vol. 93 (2010)
2337
be assumed that 34 is the product of the hydrolytic ring opening of the desired
thiomorpholine-2,5-dione 28, which, in analogy to the synthesis of morpholine-2,5-
diones 4 (Scheme 2), is formed from 29 via 35 (Scheme 8).
In conclusion, a convenient synthesis of 3,3-dimethylmorpholine-2,5-diones was
elaborated by a combination of the ꢂazirine/oxazolone methodꢃ and the ꢂdirect amide
cyclizationꢃ. The corresponding 5-monothioxo and 2,5-dithioxo derivatives are
accessible via stepwise thionation with Lawessonꢃs reagent. On the other hand,
attempted cyclizations of S-containing linear precursors were not successful and led to
mixtures of products. Whereas 1,3-oxazol-5(4H)-ones of type A (Scheme 2) under
acidic conditions are prone to undergo the ring enlargement to give 3,3-dimethylmor-
pholine-2,5-diones 4, the corresponding 1,3-thiazol-5(4H)-ones of type 27 (Scheme 7)
are stable under the conditions of the ꢂdirect amide cyclizationꢃ and do not show any
tendency for a ring-enlargement reaction.
We thank the analytical units of our institute for spectra and analyses. Financial support of the work
by F. Hoffmann-La Roche AG, Basel, is gratefully acknowledged.
Experimental Part
1. General. Solvents were purified by standard procedures. TLC: aluminium sheets, silica gel 60 F254
(SiO2; Merck). Prep. TLC: glass plates, SiO2 60 F254 (2 mm; Merck). Column chromatography (CC):
SiO2 C-560 (0.04 – 0.063 mm; Uetikon-Chemie). Medium-pressure liquid chromatography (MPLC):
LiChroprep Si 60, 15 – 25 mm (Merck); column: Kron-Lab 4/98-Pro, 480 ꢁ 30 mm or Labomatic, 380 ꢁ
20 mm. M.p.: Mettler-FP-5 or Bꢀchi B-450 apparatus; uncorrected. IR Spectra: Perkin-Elmer 781 or
Perkin-Elmer Spectrum one FT-IR spectrophotometer; in KBr unless otherwise stated; ˜n in cmꢀ1. 1H- and
13C-NMR spectra: Bruker-AC-300 or Bruker-ARX-300 instrument (300 and 75.5 MHz, resp.), in CDCl3;
multiplicity of C-atoms from DEPT spectra; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
Finnigan MAT-90, Finnigan SSQ-700 (EI and CI), or Finnigan TSQ-700 instrument (ESI); in m/z (rel.
%). Elemental analyses were performed by the Mikroanalytisches Laboratorium des Organisch-
chemischen Instituts der Universitꢀt Zꢁrich (Elementar Vario EL instrument).
General Procedure 1 (GP 1). Coupling of 2H-Azirin-3-amines with Carboxylic and Thiocarboxylic
Acids. To a stirred soln. of the acid in MeCN at 08, 2,2,N-trimethyl-N-phenyl-2H-azirin-3-amine (2b) was
added dropwise. The mixture was stirred at r.t. for 2 – 22 h, and then diluted with Et2O. The precipitate
was filtered off and purified by chromatography or recrystallization.
General Procedure 2 (GP 2). Direct Amide Cyclization. A stirred suspension of a dipeptide in dry
toluene was heated up to 90 – 1008 under N2. A strong stream of dry HCl gas was bubbled through the
soln. for 10 – 30 min at the chosen temp. The resulting soln. was purged with N2 for 30 min to remove
remaining HCl, the toluene was evaporated, and THF/Et2O 1:1 (10 ml) was added to the residue. After
30 min of stirring at r.t., the precipitated Me(Ph)NH · HCl was removed by filtration, followed by
evaporation of the solvent, to yield a solid crude product, which was purified by chromatography.
General Procedure 3 (GP 3). Monothionation with Lawessonꢃs Reagent (L.R.). A stirred suspension
of 1 equiv. of a morpholine-2,5-dione 4 and 0.5 equiv. of L.R. in dry toluene was heated to 90 – 1008, until
a clear soln. was obtained. Then, the soln. was heated to reflux for 30 min. By cooling the mixture to r.t.,
remaining L.R. precipitated and was removed by filtration. After evaporation of the toluene, the residue
was purified by CC.
General Procedure 4 (GP 4). Dithionation with Lawessonꢃs Reagent (L.R.). A stirred suspension of
1 equiv. of a 5-thioxomorpholin-2-one 10 and 2.5 equiv. of L.R. in dry toluene was heated to reflux for 2 –
6 d. By cooling the mixture to r.t., remaining L.R. precipitated and was removed by filtration. After
evaporation of the toluene, the residue was purified by CC.
2. Starting Materials. Compound 2b was prepared according to [27]. All other chemicals were
commercially available.

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3. Azirine Coupling with 2-Hydroxy Acids. 3.1. 2-(2-Hydroxy-2-methylpropanamido)-N-phenyl-N,2-
dimethylpropanamide (3aa). According to GP 1: 270.7 mg (4.8 mmol) of 2-hydroxyisobutyric acid (1a)
in MeCN (20 ml), 836.5 mg (4.8 mmol) of 2b, stirring for 2 h at r.t. The product was purified by CC
(SiO2; CH2Cl2/MeOH 20 :1) and recrystallized from MeCN. Yield: 1.2 g (95%). Colorless needles. M.p.
131 – 1348. IR: 3359s, 3059w, 3009w, 2992m, 2974m, 2930s, 1637vs, 1595s, 1525s, 1498s, 1463m, 1454m,
1399s, 1367s, 1357s, 1262m, 1226m, 1196s, 1180m, 1161w, 1126s, 1089s, 1070m, 1025w, 992m, 966m, 773m,
1
709s, 641m, 616m. H-NMR: 7.40 – 7.24 (m, 5 arom. H); 7.15 (br. s, NH); 3.28 (s, MeN); 1.47, 1.35 (2s,
2 Me2C). 13C-NMR: 175.2, 173.4 (2s, 2 C¼O); 144.7 (s, arom. C); 129.4, 128.2, 127.9 (3d, 5 arom. CH);
73.2, 57.9 (2s, 2 Me2C); 41.4 (q, MeN); 27.4, 26.1 (2q, 2 Me2C). ESI-MS: 579 (8, [2 M þ Na]þ), 301 (100,
[M þ Na]þ). Anal. calc. for C15H22NO3 (278.40): C 64.73, H 7.97, N 10.10; found: C 64.83, H 8.10, N 10.37.
Recrystallization from MeCN by slow evaporation of the solvent yielded colorless needles suitable
for the X-ray crystal-structure determination.
3.2. 2-(2-Hydroxy-3-phenylpropanamido)-N-phenyl-N,2-dimethylpropanamide (3ab). According to
GP 1: 408 mg (2.5 mmol) of dl-phenyllactic acid (1b) in MeCN (20 ml), 472 mg (2.7 mmol) of 2b,
stirring for 22 h at r.t. Purified by CC (SiO2; CH2Cl2/Et2O 6 :1). Yield: 773 mg (92%). Colorless needles.
M.p. 127 – 1288. IR: 3440s, 3324s, 2985w, 2932w, 1640vs, 1593m, 1527s, 1494vs, 1454m, 1394s, 1374m,
1
1285m, 1262w, 1206m, 1093s, 740w, 709s, 630w. H-NMR: 7.43 – 7.14 (m, 10 arom. H); 6.46 (br. s, NH);
3.98 – 3.89 (m, PhCH2CH); 3.25 (s, MeN); 3.05, 2.81 (AB-like, PhCH2CH); 2.13 (d, J ¼ 5, OH); 1.442,
1
1.439 (2s, Me2C). H-NMR (CD3OD): 7.42 – 7.15 (m, 10 arom. H); 4.00 – 3.80 (m, PhCH2CH); 3.21 (s,
MeN); 3.03 – 2.75 (AB of ABX, JAB ¼ 13.8, JAX ¼ 7.7, JBX ¼ 4.0, PhCH2CH); 1.39, 1.38 (2s, Me2C).
13C-NMR: 172.8, 171.2 (2s, 2 C¼O); 144.8, 136.7 (2s, 2 arom. C); 129.5, 129.3, 128.4, 127.7, 126.8 (5d, 10
arom. CH); 72.9 (d, PhCH2CH); 57.6 (s, Me2C); 40.3 (t, PhCH2); 41.3 (q, MeN); 26.9, 26.1 (2q, Me2C).
13C-NMR (CD3OD): 174.9 (s, 2 C¼O); 146.2, 138.9 (2s, 2 arom. C); 130.8, 130.4, 129.0, 128.8, 128.5, 127.3
(6d, 10 arom. CH); 73.6 (d, PhCH2CH); 58.2 (s, Me2C); 41.5 (t, PhCH2); 41.3 (q, MeN); 27.0, 26.7 (2q,
Me2C). ESI-MS: 703 (20, [2 M þ Na]þ), 363 (12, [M þ Na]þ), 341 (40, [M þ H]þ), 234 (100).
3.3. 2-(2-Hydroxy-2-phenylacetamido)-N-phenyl-N,2-dimethylpropanamide (3ac). According to
GP 1: 152 mg (1 mmol) of dl-mandelic acid (1c) in MeCN (6 ml), 192 mg (1.1 mmol) of 2b in MeCN
(8 ml), stirring for 3 h at r.t. Yield: 310 mg (95%). Colorless needles. M.p. 149 – 1508. IR: 3340vs, 3060w,
3030w, 3010w, 2981w, 2914w, 1645vs, 1594m, 1520vs, 1492vs, 1455m, 1392s, 1373m, 1362m, 1373w, 1362m,
1327m, 1268m, 1227m, 1204w, 1190w, 1090s, 1066m, 744w, 710s, 697m. 1H-NMR (CD3OD): 7.42 – 7.20 (m,
10 arom. H); 4.18 (s, PhCH); 3.15 (s, MeN); 1.47, 1.45 (2s, Me2C). 13C-NMR (CD3OD): 175.0, 174.0 (2s,
2 C¼O); 145.4, 141.5 (2s, 2 arom. C); 130.4, 129.3, 129.0, 128.8, 128.5, 127.9 (6d, 10 arom. CH); 75.1 (s,
PhCH); 58.3 (s, Me2C); 41.2 (q, MeN); 26.8, 26.6 (2q, Me2C).
4. Direct Amide Cyclization. 4.1. 3,3,6,6-Tetramethylmorpholine-2,5-dione (4aa) [1b]. According to
GP 2: 500 mg (1.8 mmol) of 3aa in dry toluene (100 ml), 908, HCl gas for 30 min. The product was
purified by CC (SiO2; CH2Cl2/Et2O 2 :1) and recrystallized from toluene. Yield: 187 mg (61%). Colorless
crystals. M.p. 139 – 1408. IR: 3354s, 3202w, 3073w, 2987m, 2932m, 1743vs, 1677s, 1643s, 1528m, 1472s,
1
1444s, 1385w, 1369m, 1326s, 1228s, 1201m, 1154vs, 988m, 859m, 692w. H-NMR: 6.82 (br. s, NH); 1.75,
1.70 (2s, 2 Me2C). 13C-NMR: 170.2, 169.8 (2s, 2 C¼O); 82.9 (s, C(6)); 56.3 (s, C(3)); 29.4, 27.0 (2q,
2 Me2C). CI-MS (NH3): 172 (100, [M þ H]þ). Anal. calc. for C8H13NO3 (171.20): C 56.13, H 7.65, N 8.18;
found: C 55.91, H 7.57, N 8.23.
Recrystallization from toluene by slow evaporation of the solvent yielded colorless needles suitable
for the X-ray crystal-structure determination.
4.2. 6-Benzyl-3,3-dimethylmorpholine-2,5-dione (4ab) [1b][21]. According to GP 2: 2.19 g
(6.44 mmol) of 3ab in dry toluene (300 ml), 1008, HCl gas for 15 min. The product was purified by
CC (SiO2; CH2Cl2/Et2O 6 :1) and recrystallized from Et2O. Yield: 407 mg (27%). Colorless needles. M.p.
164 – 1658. IR: 3190s, 3066s, 2920s, 1746vs, 1686vs, 1498s, 1429vs, 1388s, 1360s, 1340s, 1283vs, 1204s, 1160vs,
1072vs, 1045s, 1004s, 932w, 908w, 820m, 767m, 740vs, 693vs. 1H-NMR: 7.34 – 7.24 (m, 5 arom. H); 5.13 (dd,
J ¼ 5.2, 4.5, PhCH2CH); 3.37 – 3.24 (AB of ABX, JAB ¼ 14.4, JAX ¼ 5.2, JBX ¼ 4.5, PhCH2CH); 1.49, 1.02
(2s, Me2C). 13C-NMR: 169.5, 166.2 (2s, 2 C¼O); 134.7 (s, arom. C); 130.4, 128.7, 127.4 (3d, 5 arom. CH);
79.2 (d, C(6)); 55.5 (s, C(3)); 41.5 (t, PhCH2); 29.0, 27.9 (2q, Me2C). CI-MS (NH3): 252 (14), 251 (100,
[M þ NH4]þ), 234 (15, [M þ H]þ).

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4.3. 6-Phenyl-3,3-dimethylmorpholine-2,5-dione (4ac) [1b]. According to GP 2: 326 mg (1 mmol) of
3ac in dry toluene (50 ml), 1008, HCl gas for 10 min. The product was recrystallized from Et2O/pentane
1:2. Yield: 48 mg (22%). Colorless needles. M.p. 197 – 1988. IR: 3187s, 3083s, 3001s, 2975s, 2929s, 1747vs,
1682vs, 1607vs, 1501s, 1458vs, 1441vs, 1415vs, 1388s, 1372s, 1355m, 1316vs, 1301vs, 1284vs, 1211m, 1163vs,
1079m, 1042vs, 1011s, 931m, 911m, 859s, 806vs, 752vs, 697vs. 1H-NMR: 7.43 – 7.30 (m, 5 arom. H); 5.84 (s,
PhCH); 1.54, 1.30 (2s, Me2C). 13C-NMR: 169.1, 165.3 (2s, 2 C¼O); 133.3 (s, arom. C); 128.2, 127.9, 125.2
(3d, 5 arom. CH); 78.9 (d, C(6)); 54.5 (s, C(3)); 27.6, 27.3 (2q, Me2C).
5. Thionation with Lawessonꢃs Reagent. 5.1. 3,3,6,6-Tetramethyl-5-thioxomorpholin-2-one (10a).
According to GP 3: 150 mg (0.876 mmol) of 4aa, 177 mg (0.438 mmol) of Lawessonꢃs reagent (L.R.),
dry toluene (10 ml), 908, 30 min. Purification by CC (SiO2; CH2Cl2/Et2O 2 :1). Yield: 164 mg (95%).
Colorless crystals. M.p. 174 – 1758. IR: 3166m, 3041m, 3005m, 2996m, 2977m, 1738vs, 1557s, 1462s, 1440m,
1421s, 1378w, 1365m, 1329s, 1204m, 1184m, 1143m, 1051s, 982s, 966m, 826m, 668m, 658w. 1H-NMR: 8.15
(br. s, NH); 1.84, 1.65 (2s, 2 Me2C). 13C-NMR: 200.5 (s, C(5)); 169.4 (s, C(2)); 82.8 (s, C(6)); 56.4 (s,
C(3)); 29.3, 27.0 (2q, 2 Me2C). CI-MS: 188 (100, [M þ H]þ). Anal. calc. for C8H13NO2S: (187.26): C 51.31,
H 6.99, N 7.48, S 17.12; found: C 51.38, H 6.47, N 7.31, S 17.24.
Recrystallization from toluene by slow evaporation of the solvent yielded colorless prisms suitable
for the X-ray crystal-structure determination. A second recrystallization, also from toluene, yielded
crystals of a second polymorph.
5.2. 6-Benzyl-3,3-dimethyl-5-thioxomorpholin-2-one (10b) [21]. According to GP 3: 276 mg
(1.19 mmol) of 4ab, 240 mg (0.59 mmol) of L.R., dry toluene (15 ml), 1008, 30 min. Purification by
CC (SiO2; CH2Cl2/pentane 3 :2), recrystallized from CH2Cl2/Et2O. Yield: 281 mg (96%). Colorless
needles. M.p. 174 – 1758. IR: 3286vs, 3067m, 3033m, 3002m, 2956w, 1749vs, 1552vs, 1497m, 1469s, 1454s,
1437m, 1414s, 1386vs, 1373m, 1279vs, 1170vs, 1103s, 1074s, 1028s, 1009vs, 972w, 953w, 893m, 785m, 761s.
1H-NMR: 7.35 – 7.24 (m, 5 arom. H); 5.55 (t-like, J ¼ 4.7, PhCH2CH); 3.65 – 3.48 (AB of ABX, JAB ¼ 14.2,
JAX ¼ 4.7, JBX ¼ 4.6, PhCH2CH); 1.58, 0.81 (2s, Me2C). 13C-NMR: 193.7 (s, C(5)); 168.3 (s, C(2)); 134.2 (s,
1 arom. C); 130.8, 128.8, 127.8 (3d, 5 arom. CH); 85.5 (d, C(6)); 57.3 (s, C(3)); 41.7 (t, PhCH2); 28.8, 27.0
(2q, Me2C). EI-MS: 250 (14), 249 (100, Mþ), 205 (15), 147 (11), 130 (23), 115 (26), 91 (51). Anal. calc.
for C13H15NO2S: (249.33): C 62.62, H 6.06, N 5.62, S 12.86; found: C 62.51, H 6.13, N 5.56, S 12.70.
5.3. 6-Phenyl-3,3-dimethyl-5-thioxomorpholin-2-one (10c). According to GP 3: 90 mg (0.4 mmol) of
4ac, 80 mg (0.2 mmol) of L.R., dry toluene (5 ml), 90 – 1008, 20 min. Purification by prep. TLC (SiO2;
CH2Cl2/pentane 3 :2), recrystallized from toluene. Yield: 66 mg (68%). Colorless needles. M.p. 198 –
1998. IR: 3149s, 3027s, 2918s, 1742vs, 1548vs, 1499m, 1462vs, 1411vs, 1366m, 1327vs, 1305s, 1267s,
1204s, 1178s, 1119s, 1078m, 1010vs, 912m, 828m, 780m, 743vs, 695vs, 656s. 1H-NMR ((D6)DMSO): 7.45 –
7.38 (m, 5 arom. H); 4.58 (s, PhCH); 1.58, 1.43 (2s, Me2C). 13C-NMR ((D6)DMSO): 192.7 (s, C(5)); 169.7
(s, C(2)); 137.1 (s, 1 arom. C); 128.7, 128.2, 127.8 (3d, 5 arom. CH); 84.7 (d, C(6)); 56.3 (s, C(3)); 26.5, 26.3
(2q, Me2C). EI-MS: 236 (14), 235 (100, Mþ), 134 (34), 107 (42), 105 (10), 101 (11), 100 (37), 86 (16), 84
(26), 77 (19).
5.4. 3,3,6,6-Tetramethylmorpholine-2,5-dithione (11a). According to GP 4: 100 mg (0.53 mmol) of
10a, 539 mg (1.34 mmol) of L.R., dry toluene (7 ml), reflux for 6 d. Purification by CC and prep. TLC
(SiO2; hexane/AcOEt 1:1), recrystallized from hexane/AcOEt 1:1. Yield: 49 mg (49%). Yellow crystals.
M.p. 156 – 1588. IR: 3248m, 3165s, 3046m, 2974m, 2928m, 1742w, 1560vs, 1528m, 1465s, 1418s, 1361m,
1318vs, 1279s, 1185m, 1142m, 1109vs, 1044s, 967m, 907m, 819m, 762m, 654m, 599m. 1H-NMR: 8.65 (br. s,
NH); 1.82, 1.72 (2s, 2 Me2C). 13C-NMR: 216.8 (s, C(2)); 199.9 (s, C(5)); 91.4 (s, C(6)); 64.9 (s, C(3)); 32.9,
30.0 (2q, 2 Me2C). EI-MS: 203 (7, Mþ), 175 (21), 143 (58), 110 (9), 100 (11), 86 (100), 85 (21), 75 (21).
Anal. calc. for C8H13NOS2: (203.33): C 47.26, H 6.44, N 6.89, S 31.54; found: C 47.14, H 6.46, N 6.61, S
31.30.
Recrystallization from toluene by slow evaporation of the solvent yielded colorless prisms suitable
for the X-ray crystal-structure determination.
5.5. 6-Benzyl-3,3-dimethylmorpholine-2,5-dithione (11b) [21]. According to GP 4: 95 mg
(0.38 mmol) of 10b, 384 mg (0.95 mmol) of L.R., dry toluene (10 ml), reflux for 2 d. Purification by
prep. TLC (SiO2; CH2Cl2/hexane 1:1). Yield: 28 mg (28%). Yellow solid. M.p. 123 – 1248. IR: 3151m,
3031s, 2945s, 1752w, 1656w, 1570s, 1496m, 1467m, 1454m, 1435m, 1385s, 1351m, 1246s, 1215s, 1177s, 1152s,
1131s, 1093m, 1070m, 1035m, 1014m, 973s, 947s, 908m, 703s. 1H-NMR: 8.61 (br. s, NH); 7.37 – 7.23 (m, 5

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Helvetica Chimica Acta – Vol. 93 (2010)
arom. H); 5.52 (dd, J ¼ 5.6, 4.4, PhCH2CH); 3.72 – 3.54 (AB of ABX, JAB ¼ 14.4, JAX ¼ 5.6, JBX ¼ 4.4,
PhCH2); 1.65, 1.16 (2s, Me2C). 13C-NMR: 215.2 (s, C(2)); 193.3 (s, C(5)); 134.4 (s, 1 arom. C); 130.8,
128.7, 127.6 (3d, 5 arom. CH); 87.2 (d, C(6)); 64.3 (s, C(3)); 41.2 (t, PhCH2); 32.4, 31.6 (2q, Me2C). EI-MS:
265 (4, Mþ), 205 (21), 147 (20), 115 (39), 91 (51), 65 (14), 58 (100). CI-MS (NH3): 266 (100, [M þ H]þ),
234 (14), 232 (12), 208 (23), 206 (45). Anal. calc. for C13H15NOS2: (265.39): C 58.83, H 5.69, N 5.28, S
24.16; found: C 58.71, H 5.45, N 5.03, S 24.02.
6. Synthesis of Monothiodiamides and Attempted Acid-Catalyzed Cyclizations. 6.1. Synthesis of N-[1-
Methyl-1-(N-methyl-N-phenylthiocarbamoyl)ethyl]-2-phenyl-2-[(tetrahydro-2H-pyran-2-yl)oxy]acet-
amide (22). To a suspension of 1c (304 mg, 2 mmol) in dry MeCN (5 ml) at 08 were added 3,4-dihydro-
2H-pyrane (DHP; 195 mg, 2.3 mmol) and 0.04 ml of a 2m aq. HCl. The mixture was stirred for 3 h at r.t.,
the solvent was evaporated, and the residue was dried in vacuo to give crude THP-protected mandelic
1
acid as a mixture of two diastereoisomers. H-NMR: 7.51 – 7.30 (m, 5 arom. H); 5.23, 5.21 (2s, PhCH);
4.91, 4.58 (2t, CH of THP); 3.98 – 3.43 (2m, 1 CH2 of THP); 1.90 – 1.26 (m, 3 CH2 of THP). 13C-NMR:
176.8, 175.6 (2s, C¼O); 136.2, 135.6 (2s, 1 arom. C); 128.73, 128.68, 128.6, 127.6, 127.3, 126.6 (6d, 5 arom.
CH); 97.5, 97.1 (2d, CH of THP); 75.5, 72.5 (2d, PhCH); 63.0, 62.1 (2t, CH2 of THP); 30.3, 30.1, 25.2, 25.1,
19.3, 18.7 (6t, 3 CH2 of THP).
The crude protected mandelic acid was dissolved in abs. THF (5 ml), the soln. was cooled to ca.
i
ꢀ 108, and N-methylmorpholine (NMM; 405 mg, 4 mmol) and isobutyl chloroformate (ClCO2 Bu;
273 mg, 2 mmol) were added. After 5 min, freshly prepared H2S (from Na2S · H2O and 50% aq. H2SO4)
was bubbled through the mixture, which was stirred for 1 h at ꢀ 108. Then, Et2O was added, the mixture
was washed with 0.1m aq. H3PO4, the org. phase was dried (Na2SO4), the solvents were evaporated, and
the residue was dried under high vacuum. The crude THP-protected mandelic thioacid 21 was dissolved
in CH2Cl2, the soln. was cooled to 08, 2b (348 mg, 2 mmol) was slowly added, and the mixture was stirred
at r.t. for 15 h. Then, the mixture was extracted with 5% aq. NaHSO4 (3ꢁ), the aq. phases were washed
with CH2Cl2, and the combined org. phases were dried (Na2SO4). The solvent was evaporated and
chromatographic workup (CC, SiO2; CH2Cl2/Et2O 20 :1) gave two fractions, which were crystallized.
Data of 22. Yield: 443 mg (52%). M.p. 109 – 1108 (Et2O/pentane). Colorless crystals. IR: 3414w,
3248s, 2940s, 2871w, 1666vs, 1491vs, 1463vs, 1367vs, 1259m, 1238m, 1204s, 1184m, 1119vs, 1101vs, 1077s,
1037s, 967s, 909m, 777m, 708vs. 1H-NMR (2 diastereoisomers): 8.74, 8.67 (2 br. s, NH); 7.48 – 7.10 (m, 10
arom. H); 5.02, 4.98 (2s, PhCH); 4.85, 4.54 (2t, J ¼ 3, CH of THP); 4.00 – 3.80, 3.60 – 3.40 (2m, CH2 of
THP); 3.70 (s, MeN); 2.09 – 1.26 (m, 3 CH2 of THP); 1.62, 1.57, 1.54, 1.43 (4s, Me2C). 13C-NMR (2
diastereoisomers): 209.3 (s, C¼S); 169.4, 168.8 (2s, C¼O); 147.1, 138.5, 137.4 (3s, 2 arom. C); 129.5, 128.2,
127.84, 127.78, 127.0, 126.8 (6d, 10 arom. CH); 98.2, 95.3 (2d, CH of THP); 78.9, 77.5 (2d, PhCH); 62.82,
62.80 (2s, Me2C); 62.1, 62.0 (2t, 1 CH2 of THP); 51.4 (q, MeN); 30.5, 30.3 (2t, 1 CH2 of THP); 28.1, 28.0,
27.9, 27.8 (4q, Me2C); 25.4, 25.3 (2t, 1 CH2 of THP); 18.9, 18.8 (2t, 1 CH2 of THP). ESI-MS (CH2Cl2 þ
NaI): 449 (12, [M þ Na]þ), 427 (40, [M þ H]þ), 343 (53, [M ꢀ Ph(Me)N þ Na]þ), 175 (100).
(2-{[1-Methyl-1-(N-methyl-N-phenylthiocarbamoyl)ethyl]amino}-2-oxo-1-phenylethyl)(2-methyl-
propyl)carbonate (23). Yield: 167 mg (20%). Colorless crystals. 1H-NMR: 7.66 (br. s, NH); 7.44 – 7.20 (m,
10 arom. H); 5.68 (s, PhCH); 4.00 – 3.85 (m, CH2); 3.71 (s, MeN); 2.53 – 1.85 (m, Me2CH); 1.65, 1.60 (2s,
Me2C); 0.96, 0.95 (2d, J ¼ 6.7, Me2CH). 13C-NMR: 208.3 (s, C¼S); 165.9, 153.5 (2s, 2 C¼O); 147.5, 135.5
(2s, 2 arom. C); 129.6, 129.0, 128.7, 128.4, 127.5, 126.3 (6d, 10 arom. CH); 78.7 (d, PhCH); 74.7 (t, CH2);
63.0 (s, Me2C); 51.4 (q, MeN); 29.1 (q, Me2C); 27.8 (d, Me2CH); 19.0, 18.9 (2q, Me2CH). CI-MS: 444
(22), 443 (100, [M þ H]þ), 269 (16), 192 (27). Anal. calc. for C24H30N2O4S (442.58): C 65.13, H 6.83, N
6.33, S 7.24; found: C 65.00, H 6.71, N 6.25, S 7.42.
Suitable crystals for the X-ray crystal-structure determination were obtained from hexane by slow
evaporation of the solvent.
6.2. Synthesis of 2-Hydroxy-N-[1-methyl-1-(N-methyl-N-phenylthiocarbamoyl)ethyl]-2-phenylacet-
amide (24). A mixture of 22 (427 mg, 1 mmol) and pyridinium para-toluenesulfonate (PPTS, 30 mg) in
EtOH (20 ml) was heated under reflux for 15 h. Then, the solvent was evaporated, the residue was
purified by CC (SiO2; CH2Cl2/Et2O 20 :1), and recrystallization from AcOEt/hexane 1:1 yielded 348 mg
(quant.) of 24. M.p. 145 – 1468. Colorless solid. IR: 3324s, 3060m, 3004m, 2983m, 2982m, 1692s, 1673vs,
1652vs, 1592m, 1515vs, 1490vs, 1465vs, 1451vs, 1431s, 1370vs, 1359vs, 1256m, 1215s, 1182m, 1163m, 1101vs,
1068s, 1027m, 1017m, 1003m, 992m, 777s, 729m, 707s. 1H-NMR: 7.46 – 7.18 (m, 10 arom. H); 4.68 (s,

Helvetica Chimica Acta – Vol. 93 (2010)
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PhCH); 3.96 (s, MeN); 1.60, 1.52 (2s, Me2C). 13C-NMR: 208.2 (s, C¼S); 170.3 (s, C¼O); 147.6, 139.3 (2s, 2
arom. C); 129.6, 128.7, 128.5, 128.4, 126.7, 126.3 (6d, 10 arom. CH); 74.2 (d, PhCH); 62.9 (s, Me2C); 51.3
(q, MeN); 29.3, 29.2 (2q, Me2C).
6.3. Attempted Cyclization of 24. Through a soln. of 24 (342 mg, 1 mmol) in abs. toluene (130 ml) at
100 – 1108, dry HCl gas was bubbled for 20 min. Then, the solvent was evaporated, the residue was
dissolved in THF/Et2O, and the mixture was stirred for 30 min. The precipitate (Me(Ph)NH · HCl) was
filtered off, and the solvent was evaporated. Chromatographic workup of the residue gave 33% of the
starting material 24 and three fractions of impure isomeric compounds with the mass of the expected 3,3-
dimethyl-6-phenyl-2-thioxomorpholin-5-one (20; ESI-MS (CH2Cl2 þ NaI): 236 ([M þ 1]þ)) in ca. 26, 12,
and 6% yield, resp.
6.4. Synthesis of [1-Methyl-1-({2-methyl-N-[1-methyl-1-(N-methyl-N-phenylthiocarbamoyl)ethyl]-
amino}carbonyl)ethyl](2-methylpropyl)carbonate (25). To a soln. of 2-hydroxy-2-methylpropanoic acid
i
(1a; 500 mg, 4.8 mmol) in dry THF (30 ml), NMM (2.43 g, 24 mmol) and ClCO2 Bu (1.6 g, 12 mmol)
were added at ꢀ 108. Immediately, a white solid precipitated. The mixture was stirred for ca. 5 min, then
a slow stream of H2S was bubbled through the soln. for 2.5 h. The mixture was diluted with Et2O and
extracted with 0.1m aq. H3PO4 (2ꢁ). The combined org. phase was dried (MgSO4), the solvent was
evaporated, and the residue was dried under high vacuum. The formed crude thioacid was dissolved in
abs. MeCN and cooled to 08, and 2b (835 mg, 4.8 mmol) was added slowly. The mixture was allowed to
reach r.t. and was stirred, until the starting material was completely consumed (TLC, 24 h). Then, the
solvent was evaporated, and the residue was dried under high vacuum. Purification by CC (SiO2; AcOEt/
hexane 1:2) gave 1.68 g (92%) of 25. 1H-NMR: 8.33 (br. s, NH); 7.38 – 7.16 (m, 5 arom. H); 3.82 (d, J ¼
6.8, CH2); 3.66 (s, MeN); 3.65 – 1.87 (m, Me2CH); 1.55, 1.46 (2s, 2 Me2C); 0.90 – 0.88 (m, Me2CH).
13C-NMR: 209.1 (s, C¼S); 170.2, 153.0 (2s, 2 C¼O); 147.2 (s, arom. C); 129.5, 128.4, 126.8 (3d, 5 arom.
CH); 82.7, 62.6 (2s, 2 Me2C); 51.4 (q, MeN); 27.7, 24.0 (2q, 2 Me2C); 27.1 (d, Me2CH); 18.9 (q, Me2CH).
ESI-MS: 417 (100, [M þ Na]þ). Anal. calc. for C20H30NO4S: (380.52): C 60.89, H 7.66, N 7.10, S 8.13;
found: C 60.73, H 7.50, N 7.28, S 7.99.
6.5. Synthesis of 2-Hydroxy-2-methyl-N-[1-methyl-1-(N-methyl-N-phenylthiocarbamoyl)ethyl]pro-
panamide (26). A soln. of 25 (982 mg, 2.58 mmol) in a mixture of dioxane (14.7 ml) and 0.8m NaOH
(14.7 ml) was stirred at r.t. for 30 min. After neutralizing by treatment with Dowex-50 (pyridinium form),
the soln. was diluted with H2O and extracted with CH2Cl2 (2ꢁ). The org. soln. was dried (Na2SO4), the
solvent was evaporated, and the residue was purified by CC (SiO2) and crystallized from hexane/AcOEt
2 :1: 646 mg (85%) of 26. M.p. 112 – 1148. Colorless crystals. IR: 3314s, 3006w, 2982s, 2930m, 1642vs,
1593m, 1492s, 1359m, 1262m, 1161m, 1135m, 1099s, 1012w, 1003m, 992w, 962m, 917m, 889w, 796w, 775s,
766m, 704vs, 671vs. 1H-NMR: 7.45 (s, NH); 7.45 – 7.25 (m, 5 arom. H); 3.74 (s, MeN); 1.59, 1.37 (2s,
2 Me2C). 13C-NMR: 209.0 (s, C¼S); 174.6 (s, C¼O); 144.4 (s, arom. C); 129.4, 128.3, 126.5 (3d, 5 arom.
CH); 73.14, 62.52 (2s, 2 Me2C); 52.0 (q, MeN); 29.0, 27.2 (2q, 2 Me2C). CI-MS: 297 (6), 296 (18), 295
(100, [M þ 1]þ), 228 (10), 192 (35), 121 (12). Anal. calc. for C15H22N2O2S (294.41): C 61.19, H 7.53, N 9.51,
S 10.89; found: C 61.01, H 7.42, N 9.33, S 10.81.
Suitable crystals for the X-ray crystal-structure determination were obtained from hexane/AcOEt by
slow evaporation of the solvent.
6.6. Cyclization of 26. According to GP 2, a soln. of 26 (284 mg, 0.97 mmol) in abs. toluene (50 ml) at
1008 under N2 was treated with dry HCl gas for 25 min. Usual workup and purification by prep. TLC
(SiO2; CH2Cl2/Et2O 2 :1) gave 50 mg (20%) of 2-(1-hydroxy-1-methylethyl)-4,4-dimethyl-1,3-thiazol-
5(4H)-one (27) as a yellow oil and traces of a product, which was proposed to be the expected 3,3,6,6-
tetramethyl-2-thioxomorpholin-5-one. Treatment of 27 with toluene led to a colorless solid. IR: 3387s
(br), 2980m, 2934m, 2874w, 1721vs, 1659vs, 1514s, 1460m, 1365m, 1227m, 1193m, 967m, 919w, 848w,
827m, 810m, 768w, 651m, 621m. 1H-NMR: 3.56 (br. s, OH); 1.51, 1.41 (2s, 2 Me2C). 13C-NMR: 211.3 (s,
C¼O); 172.4 (s, C¼N); 83.1 (s, C(4)); 67.3 (s, Me2C); 28.4, 24.3 (2q, 2 Me2C). Anal. calc. for C8H13NO2S:
(187.26): C 15.31, H 7.00, N 7.48, S 17.12; found: C 15.07, H 7.22, N 7.29, S 17.34.
7. Attempted Synthesis of 3,3,6,6-Tetramethylthiomorpholine-2,5-dione (28). 7.1. 2-Bromo-2-methyl-
N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]propanamide (31). According to GP 1: 802 mg
(4.8 mmol) of 2-bromo-2-methylpropanoic acid (30) in MeCN (35 ml), 836 mg (4.8 mmol) of 2b,
2.5 h at r.t. Purification by CC (SiO2; CH2Cl2/MeOH 10 :1) and drying under high vacuum. Yield: 1.6 g

2342
Helvetica Chimica Acta – Vol. 93 (2010)
(97%). M.p. 135.4 – 136.28. Colorless crystals. IR: 3294s, 3039w, 3002m, 2981m, 2928m, 1663vs, 1643vs,
1594m, 1532s, 1493s, 1471m, 1394m, 1372s, 1360m, 1288m, 1221m, 1203m, 1111m, 930m, 916m, 775m,
715s, 645m. 1H-NMR: 7.80 (br. s, NH); 7.65 – 7.45 (m, 5 arom. H); 3.51 (s, MeN); 2.10, 1.68 (2s, 2 Me2C).
13C-NMR: 179.6, 175.0 (2s, 2 C¼O); 144.9 (s, arom. C); 129.4, 128.5, 128.1 (3d, 5 arom. CH); 62.5, 59.5
(2s, 2 Me2C); 41.5 (q, MeN); 32.0, 25.0 (2q, 2 Me2C). CI-MS: 341 (100, [M þ H]þ). Anal. calc. for
C15H21BrN2O2 (341.24): C 52.80, H 6.20, N 8.21, Br 23.42; found: C 52.73, H 6.24, N 8.22, Br 23.30.
7.2. Attempted Synthesis of 2-Methyl-N-[1-methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]-2-sulfa-
nylpropanamide (29). According to [25], to a soln. of 31 (1.0 g, 2.9 mmol) in DMF (6.3 ml) was added a
soln. of Na3PO3S · 12 H2O (2.3 g, 5.8 mmol) in H2O (31.5 ml). The mixture was stirred for 5 h, then the
pH was lowered to 4.0 by addition of 3.5% HCl, and stirring was continued overnight. The mixture was
extracted with CH2Cl2 (3ꢁ), washed with brine, and dried (MgSO4). The filtered org. soln. was
evaporated, and the residue was dried under high vacuum to yield 210 mg (27.5%) of 2-Methyl-N-[1-
methyl-1-(N-methyl-N-phenylcarbamoyl)ethyl]prop-2-enamide (32) as a colorless solid.
Recrystallization from MeOH/hexane gave colorless crystals suitable for an X-ray crystal-structure
determination.
7.3. Synthesis of 29. According to GP 1: 167.2 mg (1.4 mmol) of 2-methyl-2-sulfanylpropanoic acid
(33), which was prepared from 30 according to the protocol described in [25], in MeCN (20 ml), 242 mg
(1.4 mmol) of 2b, 16 h at r.t. Purification by CC (SiO2; CH2Cl2/Et2O 2 :1) and drying under high vacuum.
Yield: 389 mg (95%). M.p. 140 – 1418. Colorless solid. IR: 3421s, 2927s, 1655vs, 1624vs, 1615s, 1516s,
1466vs, 1391s, 1372m, 1281m, 1245m, 1225m, 1152m, 942m, 815m, 775m, 758s, 691s, 604s. 1H-NMR: 7.43
(s, NH); 7.41 – 7.23 (m, 5 arom. H); 3.27 (s, MeN); 1.49, 1.48 (2s, 2 Me2C); 1.44 (br. s, SH). 13C-NMR:
173.5, 173.1 (2s, 2 C¼O); 144.7 (s, arom. C); 129.4, 128.5, 127.9 (3d, 5 arom. CH); 58.2, 47.5 (2s, 2 Me2C);
41.5 (q, MeN); 29.8, 25.7 (2q, 2 Me2C). CI-MS: 295 (100, [M þ H]þ), 188 (25, [C8H14NOS]þ), 108 (26,
[C7H8N]þ). Anal. calc. for C15H22NO2S (294.41): C 61.19, H 7.53, N 9.52, S 10.89; found: C 61.30, H 7.27, N
9.54, S 10.71.
7.4. Attempted Cyclization of 29. According to GP 2, a stirred suspension of 29 (90 mg, 0.32 mmol)
in dry toluene (15 ml) was heated to 1008 under N2. An intense stream of dry HCl gas was bubbled
through the soln. for 15 min. Then, the soln. was purged with N2 for 30 min to remove remaining HCl,
toluene was evaporated, and THF/Et2O 1:1 (20 ml) was added to the residue. After 30 min of stirring at
r.t., the suspension was filtered, and the solvent was evaporated leading to a solid crude product, which
was purified by prep. TLC (SiO2; CH2Cl2/Et2O 2 :1). Yield: 40 mg (60%) of 2-methyl-2-[(2-methyl-2-
sulfanylpropanoyl)amino]propanoic acid (34). Colorless solid. IR: 3330s, 3039w, 2987m, 2968m, 2924s,
2854m, 1744w, 1655vs, 1624vs, 1592s, 1530vs, 1495s, 1469m, 1381s, 1369s, 1356m, 1276m, 1221m, 1040m,
1
1022m, 974m, 890m, 776s, 706s, 699s. H-NMR: 7.78 (br. s, NH); 2.74, 2.65 (2s, 2 Me2C); 1.24 (s, SH).
13C-NMR: 175.4, 173.0 (2s, 2 C¼O); 58.6, 57.3 (2s, 2 Me2C); 36.2, 31.1 (2q, 2 Me2C). Anal. calc. for
C8H15NO3S (205.28): C 46.81, H 7.37, N 6.82, S 15.62; found: C 46.73, H 7.25, N 6.90, S 15.75.
8. X-Ray Crystal-Structure Determination of 3aa, 4aa, 10a, 11a, 23, 26, 32, and 34 (Table 2 and
Figs. 1 – 5)7). All measurements, with the exception of those of 23, were performed on a Nonius
KappaCCD diffractometer [28] using graphite-monochromated MoKa radiation (l 0.71073 ꢅ) and an
Oxford Cryosystems Cryostream 700 cooler. Data reduction was performed with HKL Denzo and
Scalepack [29]. In the case of 23, the measurements were made on a Rigaku AFC5R diffractometer using
graphite-monochromated MoKa radiation (l 0.71073 ꢅ) and a 12-kW rotating anode generator. The data
collection and refinement parameters are given in Table 2, and views of the molecules are shown in
Figs. 1 – 5. The intensities were corrected for Lorentz and polarization effects, and absorption corrections
based on the multi-scan method [30] were applied in the cases of 10a, 11a, 26, and 34. The structures of
3aa, 10a, 11a, 23, 26, 32, and 34 were solved by direct methods using SIR92 [31] and those of 4aa and the
second polymorph of 10a by using SHELXS97 [32], which revealed the positions of all non-H-atoms. In
the case of the second polymorph of 10a and 26, there are two and three symmetry-independent
molecules, resp., in the asymmetric unit. The atomic coordinates for these structures were tested carefully
7
)
CCDC-789182 – 789190 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 93 (2010)
2343
Table 2. Crystallographic Data for Compounds 3aa, 4aa, 10a, 11a, 23, 26, 32, and 34
3aa
4aa
10a (polymorph 1) 10a (polymorph 2) 11a
Crystallized from
Empirical formula
Mr
MeCN
C15H22N2O3
278.35
toluene
C8H13NO3
171.19
toluene
C8H13NO2S
187.26
toluene
C8H13NO2S
187.26
toluene
C8H13NOS2
203.32
Crystal color, habit
Crystal dimensions
[mm]
colorless, prism colorless, prism colorless, prism
0.25 ꢁ 0.30 ꢁ 0.35 0.12 ꢁ 0.12 ꢁ 0.20 0.10 ꢁ 0.15 ꢁ 0.30 0.20 ꢁ 0.20 ꢁ 0.25 0.08 ꢁ 0.20 ꢁ 0.28
colorless, prism
yellow, prism
Temp. [K]
Crystal system
Space group
Z
160(1)
monoclinic
P21/c
160(1)
monoclinic
P21/n
4
160(1)
monoclinic
P21/n
160(1)
160(1)
monoclinic
P21/c
triclinic
ꢀ
P1
4
4
4
2
Reflections for cell
determination
2q Range for cell
determination [8]
Unit cell parameters:
a [ꢅ]
4594
2117
56335
31739
25594
4 – 60
2 – 55
2 – 60
4 – 60
2 – 55
5.8729(1)
19.2439(4)
13.6467(3)
90
93.8172(8)
90
1538.89(5)
1.201
0.0838
f and w
60
7.9778(4)
5.9714(4)
18.626(1)
90
94.380(3)
90
884.7(1)
1.285
0.0981
w
5.6490(1)
22.0010(4)
8.2026(1)
90
108.7734(8)
90
965.21(3)
1.289
0.297
8.7363(1)
11.3121(2)
11.3342(1)
66.6701(6)
70.2665(6)
71.5837(5)
946.37(2)(1)
1.314
5.6152(2)
14.8426(5)
6.3708(2)
90
111.185(1)
90
495.09(3)
1.364
0.491
b [ꢅ]
c [ꢅ]
a [8]
b [8]
g [8]
V [ꢅ3]
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
0.303
f and w
60
f and w
60
f and w
55
2q(max) [8]
55
Transmission factors
[min; max]
–
–
0.843; 0.955
0.822; 0.943
0.828; 0.967
Total reflections
measured
Symmetry-indepen- 4478
dent reflections
Reflections used
[I > 2s(I)]
32625
11734
2019
1319
22304
2808
2316
39683
5530
4520
9550
1122
997
3148
Parameters refined
Final R(F)
wR(F)
Weighting parameter 0.01
[a]a)
190
0.0761
0.0765
113
114
225
63
0.0571
0.0602
0.015
0.0583
0.0739
0.005
0.0410
0.0507
0.008
0.0405
0.0521
0.007
Goodness-of-fit
3.247
2.058
–
4.197
6(2) ꢁ 10ꢀ6
2.874
–
2.920
–
Secondary extinction 4.9(9) ꢁ 10ꢀ6
coefficient
Final D(max)/s
0.0002
0.002
0.0002
0.002
0.0002
D1 (max; min)
0.39; ꢀ 0.44
0.29; ꢀ 0.27
0.35; ꢀ 0.30
0.50; ꢀ 0.33
0.28; ꢀ 0.27
[e ꢅꢀ3
]
a) wꢀ1 ¼ s2 (Fo) þ (aFo)2.
for a relationship from a higher-symmetry space group using the program PLATON [33], but none could
be found. In the case of 11a, the molecule sits across a crystallographic center of inversion, so that the O-
atom and NH group are necessarily disordered with equal site occupation factors of 0.5. The non-H-

2344
Helvetica Chimica Acta – Vol. 93 (2010)
Table 2 (cont.)
23
26
32
34
Crystallized from
Empirical formula
Mr
hexane
C24H30N2O4S
442.57
hexane/AcOEt
C15H22N2O2S
294.41
MeOH/hexane
C15H20N2O2
260.33
toluene
C8H15NO3S
205.27
Crystal color, habit
Crystal dimensions
[mm]
colorless, prism
0.20 ꢁ 0.40 ꢁ 0.50
colorless, prism
0.22 ꢁ 0.27 ꢁ 0.32
colorless, plate
0.13 ꢁ 0.30 ꢁ 0.30
colorless, prism
0.20 ꢁ 0.20 ꢁ 0.25
Temperature [K]
Crystal system
Space group
Z
213(1)
monoclinic
C2/c
8
160(1)
monoclinic
P21/n
160(1)
monoclinic
Cc
4
160(1)
monoclinic
P21/n
12
4
Reflections for cell
determination
2q Range for cell
determination [8]
Unit cell parameters:
a [ꢅ]
25
104075
2126
17370
30 – 39
4 – 60
4 – 60
4 – 60
24.388(2)
7.002(4)
27.823(2)
90
10.0643(1)
11.9354(1)
40.4795(3)
90
8.8101(1)
17.8470(3)
9.9602(2)
90
10.3232(2)
9.5082(2)
11.1870(2)
90
b [ꢅ]
c [ꢅ]
a [8]
b [8]
97.336(6)
90
4712(2)
1.248
0.169
w
96.5109(3)
90
4831.09(7)
1.214
0.204
f and w
60
114.0449(7)
90
1430.19(4)
1.209
0.0808
w
112.5896(7)
90
1013.82(3)
1.345
0.296
f and w
60
g [8]
V [ꢅ3]
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
2q(max) [8]
55
60
Transmission factors
[min; max]
–
0.764; 0.961
–
0.904; 0.946
Total reflections
measured
Symmetry-indepen-
dent reflections
Reflections used
[I > 2s(I)]
5985
5404
3612
70128
13807
7052
19923
4058
3575
28726
2969
2081
Parameters refined
Final R(F)
280
553
175
127
0.0520
0.0482
0.005
0.0449
0.0494
0.005
0.0424
0.0420
0.005
0.0333
0.0427
0.005
wR(F)
Weighting parameter
[a]a)
Goodness-of-fit
Secondary extinction
coefficient
1.886
–
1.256
–
2.501
4.2(6) ꢁ 10ꢀ6
1.043
4(5) ꢁ 10ꢀ7
Final D(max)/s
D1 (max; min)
0.0008
0.51; ꢀ 0.28
0.0004
0.29; ꢀ 0.36
0.0006
0.18; ꢀ 0.18
0.0003
0.29; ꢀ 0.29
[e ꢅꢀ3
]
a) wꢀ1 ¼ s2 (Fo) þ (aFo)2.
atoms in each structure were refined anisotropically, except for the N-atom in 11a, which was refined
isotropically. The hydroxy, amide (except in 23, 26, and 32), and sulfide H-atoms were placed in the
positions indicated by a difference electron-density map, and their positions were allowed to refine with

Helvetica Chimica Acta – Vol. 93 (2010)
2345
individual isotropic displacement parameters. All other H-atoms were fixed in geometrically calculated
positions, and each was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of
its parent C-atom. The refinement of each structure was carried out on F using full-matrix least-squares
procedures, which minimized the function Sw(j Fo jꢀj Fc j )2. A correction for secondary extinction was
applied in the cases of 3aa and 10a (polymorph 1), 32, and 34. Neutral atom scattering factors for non-H-
atoms were taken from [34a], and the scattering factors for H-atoms were taken from [35]. Anomalous
dispersion effects were included in Fc [36]; the values for f’ and f’’ were those of [34b]. The values of the
mass attenuation coefficients are those of [34c]. All calculations were performed using the teXsan [37]
crystallographic software package.
REFERENCES
[1] a) D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1984, 67, 526; b) D. Obrecht, H. Heimgartner,
Helv. Chim. Acta 1987, 70, 329; c) D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1990, 73, 221;
d) J. M. Villalgordo, H. Heimgartner, Helv. Chim. Acta 1997, 80, 748; e) I. Philipova, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2005, 88, 1711.
[2] H. Heimgartner, F. S. Arnhold, S. P. Fritschi, K. N. Koch, J. E. F. Magirius, A. Linden, J. Heterocycl.
Chem. 1999, 36, 1539; H. Heimgartner, in ꢂModern Problems of Organic Chemistryꢃ, Vol. 15, Eds.
R. R. Kostikov, M. A. Kuznetsov, M. S. Baird, Publishing House Lema, Saint Petersburg, 2010,
pp. 76 – 106.
[3] a) H. Heimgartner, Angew. Chem., Int. Ed. 1991, 30, 238; b) S. Stamm, H. Heimgartner, Eur. J. Org.
Chem. 2004, 3820; c) S. Stamm, A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89, 1; d) S.
Stamm, H. Heimgartner, Tetrahedron 2006, 62, 9671; e) W. Altherr, A. Linden, H. Heimgartner,
Chem. Biodiversity 2007, 4, 1144.
[4] K. N. Koch, A. Linden, H. Heimgartner, Helv. Chim. Acta 2000, 83, 233; K. N. Koch, A. Linden, H.
Heimgartner, Tetrahedron 2001, 57, 2311; K. N. Koch, H. Heimgartner, Helv. Chim. Acta 2000, 83, 1881.
[5] P. Kçttgen, A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89, 731; P. Kçttgen, A. Linden, H.
Heimgartner, Z. Naturforsch., B 2009, 64, 689.
[6] A. H. Cook, S. F. Cox, J. Chem. Soc. 1949, 2347.
[7] S. Suntornchashwej, N. Chaichit, M. Isobe, K. Suwanborirux, J. Nat. Prod. 2005, 68, 951.
[8] A. Arcelli, D. Balducci, A. Grandi, G. Porzi, M. Sandri, S. Sandri, Monatsh. Chem. 2004, 135, 951; A.
Arcelli, D. Balducci, S. de Fatima Estevao Neto, G. Porzi, M. Sandri, Tetrahedron: Asymmetry 2007,
18, 562; H. Su, Faming Zhuanli Shenqing Gongkai Shuomingshu 2007 (Chem. Abstr. 2007, 146,
501065).
[9] Y. Feng, D. Klee, H. Hçcker, J. Polymer Sci. Part A: Polymer Chem. 2005, 43, 3030; M. H. Chisholm,
J. Gallucci, C. Krempner, C. Wiggenhorn, Dalton Trans. 2006, 846; R. C. Pratt, B. G. G. Lohmeijer,
A. Mason, R. M. Waymouth, J. L. Hendrick, Polym. Prepr. 2006, 47, 101; Y. Zhao, Y. Hu, S. Cheng, J.
Chen, Polymer Bull. 2008, 61, 35; N. Franz, H.-A. Klok, Macromol. Chem. Phys. 2010, 211, 809.
[10] J. Vinsova, Chem. Listy 2001, 95, 22 (Chem. Abstr. 2001, 134, 226216); Y. Feng, J. Guo, Int. J. Mol. Sci.
2009, 10, 589.
[11] B. Iliev, A. Linden, H. Heimgartner, Helv. Chim. Acta 2003, 86, 3215; B. Iliev, A. Linden, R. Kunz, H.
Heimgartner, Tetrahedron 2006, 62, 1079.
[12] H. Heimgartner, Phosphorus, Sulfur, Silicon 1991, 58, 281; M. Kꢀgi, A. Linden, H. Heimgartner, G.
Mloston, Helv. Chim. Acta 1993, 76, 1715; G. Mloston, M. Petit, A. Linden, H. Heimgartner, Helv.
Chim. Acta 1994, 77, 435; J. Shi, H. Heimgartner, Helv. Chim. Acta 1996, 79, 371; M. Blagoev, A.
Linden, H. Heimgartner, Helv. Chim. Acta 1999, 82, 1458; A. Gebert, A. Linden, G. Mloston, H.
Heimgartner, Heterocycles 2002, 56, 393; A. Gebert, H. Heimgartner, Helv. Chim. Acta 2002, 85,
2073.
[13] L. Fisera, L. Jaroskova, I. Matejkova, H. Heimgartner, Heterocycles 1995, 40, 271.
[14] A. Linden, E. M. A. H. Awad, H. Heimgartner, Acta Crystallogr., Sect. C 1999, 55, 1877; C. Fu, M. V.
Thrane, A. Linden, H. Heimgartner, Tetrahedron 2004, 60, 5767; M. S. Seyfried, A. Linden, G.
Mloston, H. Heimgartner, Pol. J. Chem. 2006, 80, 1363; M. S. Seyfried, A. Linden, G. Mloston, H.
Heimgartner, Helv. Chim. Acta 2009, 92, 1800.

2346
Helvetica Chimica Acta – Vol. 93 (2010)
[15] G. Mloston, T. Gendek, H. Heimgartner, Helv. Chim. Acta 1998, 81, 1585; G. Mloston, T. Gendek, A.
Linden, H. Heimgartner, Helv. Chim. Acta 1999, 82, 290; G. Mloston, T. Gendek, A. Linden, H.
Heimgartner, Pol. J. Chem. 2008, 82, 1561.
[16] a) S. Scheibye, B. S. Pedersen, S.-O. Lawesson, Bull. Soc. Chim. Belg. 1978, 87, 229; b) M. P. Cava,
M. L. Levinson, Tetrahedron 1985, 41, 5061; c) M. Ori, T. Nishio, Heterocycles 2000, 52, 111 and 2001,
54, 201.
[17] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1987, 70, 102.
[18] C. K. Johnson, ꢂORTEP IIꢃ, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
[19] B. Di Blasio, V. Pavone, A. Lombardi, C. Pedone, E. Benedetti, Biopolymers 1993, 33, 1037; C.
Toniolo, M. Crisma, F. Formaggio, G. Valle, G. Cavicchioni, G. Precigoux, A. Aubry, J. Kamphuis,
Biopolymers 1993, 33, 1061; A. W. Burgess, Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2649; R.
Schweitzer-Stenner, W. Gonzales, G. T. Bourne, J. A. Feng, G. R. Marshall, J. Am. Chem. Soc. 2007,
129, 13095; C. Toniolo, F. Formaggio, in ꢂWiley Encyclopedia of Chemical Biologyꢃ, Ed. T. Begley,
J. Wiley & Sons, New York, 2009, Vol. 3, p. 606.
[20] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem., Int. Ed. 1995, 34, 1555.
[21] A. Linden, F. Ghorbani-Salman Pour, R. A. Breitenmoser, H. Heimgartner, Acta Crystallogr., Sect.
C 2001, 57, 634.
[22] D. S. Clyne, L. Weiler, Tetrahedron 1999, 55, 13659.
[23] a) D. Obrecht, H. Heimgartner, Chimia 1982, 36, 78; b) D. Obrecht, H. Heimgartner, Helv. Chim.
Acta 1982, 65, 1825; c) C. Jenny, H. Heimgartner, Helv. Chim. Acta 1986, 69, 374; d) A. Bꢀrtsch, B.
Bischof, H. Heimgartner, Pol. J. Chem. 2009, 83, 195.
[24] J. Lehmann, A. Linden, H. Heimgartner, Tetrahedron 1998, 54, 8721; J. Lehmann, A. Linden, H.
Heimgartner, Helv. Chim. Acta 1999, 82, 888; J. Lehmann, A. Linden, H. Heimgartner, Tetrahedron
1999, 55, 5359; J. Lehmann, H. Heimgartner, Helv. Chim. Acta 1999, 82, 1899; R. A. Breitenmoser,
H. Heimgartner, Helv. Chim. Acta 2001, 84, 786; R. A. Breitenmoser, A. Linden, H. Heimgartner,
Helv. Chim. Acta 2002, 85, 990; A. Budzowski, A. Linden, H. Heimgartner, Helv. Chim. Acta 2008,
91, 1471.
[25] C. Bieniarz, M. J. Cornwell, Tetrahedron Lett. 1993, 34, 939.
[26] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1981, 64, 482; P. Wipf, H. Heimgartner, Helv. Chim.
Acta 1986, 69, 1153; P. Wipf, H. Heimgartner, Helv. Chim. Acta 1987, 70, 354.
[27] J. M. Villalgordo, H. Heimgartner, Helv. Chim. Acta 1993, 76, 2830.
[28] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[29] Z. Otwinowski, W. Minor, in ꢂMethods in Enzymologyꢃ, Vol. 276, ꢂMacromolecular Crystallographyꢃ,
Part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[30] R. H. Blessing, Acta Crystallogr., Sect. A 1995, 51, 33.
[31] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli,
SIR92, J. Appl. Crystallogr. 1994, 27, 435.
[32] G. M. Sheldrick, ꢂSHELXS97ꢃ, Program for the Solution of Crystal Structures, University of
Gçttingen, Germany, 1997.
[33] A. L. Spek, ꢂPLATONꢃ, Program for the Analysis of Molecular Geometry, University of Utrecht,
The Netherlands, 2001.
[34] a) E. N. Maslen, A. G. Fox, M. A. OꢃKeefe, in ꢂInternational Tables for Crystallographyꢃ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh,
W. J. McAuley, in ꢂInternational Tables for Crystallographyꢃ, Ed. A. J. C. Wilson, Kluwer Academic
Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in
ꢂInternational Tables for Crystallographyꢃ, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[35] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[36] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[37] teXsan: Single Crystal Structure Analysis Software, Version 1.10, Molecular Structure Corporation,
The Woodlands, Texas, 1999.
Received August 20, 2010