Reactions of acid chlorides/ketenes with 2-substituted 4,5-dihydro-4,4- dimethyl-1,3-thiazoles: Formation of penam derivatives

Article abstract of DOI:10.1002/hlca.201300165

Addition reactions of acid chlorides with various 2-substituted 4,5-dihydro-4,4-dimethyl-5-(methylsulfanyl)-1,3-thiazoles under basic conditions were studied. Two kinds of products were obtained from these additions, β-lactams and non-β-lactam adducts. When the reaction was carried out with 4,5-dihydro-1,3-thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2+2] cycloaddition and led to the correspoding β-lactam. On the other hand, acid chlorides and 4,5-dihydro-1,3-thiazoles bearing an α-H-atom at the C(2)-substituent underwent C(α)- and/or N-addition reactions and furnished non-β-lactam adducts, i.e., C(α)- and/or N-acylated 1,3-thiazolidines. The attempted transformations of sulfonyl esters of exo-6-hydroxy penams to endo-6-azido penams failed, although they were successful with mono-β-lactams under the same conditions. Copyright

Full text of DOI:10.1002/hlca.201300165

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Reactions of Acid Chlorides/Ketenes with 2-Substituted 4,5-Dihydro-4,4-
dimethyl-1,3-thiazoles: Formation of Penam Derivatives
by Junxing Shi1)2), 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)
Addition reactions of acid chlorides with various 2-substituted 4,5-dihydro-4,4-dimethyl-5-(meth-
ylsulfanyl)-1,3-thiazoles under basic conditions were studied. Two kinds of products were obtained from
these additions, b-lactams and non-b-lactam adducts. When the reaction was carried out with 4,5-
dihydro-1,3-thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2 þ 2]
cycloaddition and led to the correspoding b-lactam. On the other hand, acid chlorides and 4,5-
dihydro-1,3-thiazoles bearing an a-H-atom at the C(2)-substituent underwent C(a)- and/or N-addition
reactions and furnished non-b-lactam adducts, i.e., C(a)- and/or N-acylated 1,3-thiazolidines. The
attempted transformations of sulfonyl esters of exo-6-hydroxy penams to endo-6-azido penams failed,
although they were successful with mono-b-lactams under the same conditions.
1. Introduction. – A convenient synthesis of 4,4-disubstituted 1,3-thiazole-5(4H)-
thiones 1, the less well-known disulfur analogs of 1,3-oxazol-5(4H)-ones (azlactones),
was developed in the 1980s [2]. The method also allowed the preparation of
enantiomerically pure examples [3]. In a series of experiments, it has been shown
that the C¼S group of 1 is the most reactive part of the molecule [4]. Therefore,
derivatives 1 have been used as models for 1,3-dipolar cycloadditions [5], hetero-
DielsꢀAlder reactions [6], and [2 þ 2] cycloadditions [7] with C¼S compounds, as well
as for the study of BF3-catalyzed reactions with oxiranes [8] and thiophilic vs.
carbophilic additions of organometallic compounds [9].
After transformation of the C¼S group of 1a (R1 ¼ Ph, R2 ¼ R3 ¼ Me) to the MeS
derivative 2a (R2 ¼ R3 ¼ Me), treatment of the latter with 1 mol-equiv. of dichloro-
acetyl chloride (Cl2CHCOCl; 3a) followed by addition of Et3N led to a 2 :1 mixture of
the b-lactam derivative 4a (a ꢂpenamꢃ) and the 2-methyliden-1,3-oxazin-6-one 53) in a
total yield of 44% [10] (Scheme 1). Under analogous reaction condtitions, cis-2b (R2 ¼
Me, R3 ¼ iPr) gave a single product 4b with all-cis-configuration (all substituents MeS,
iPr, and Ph in exo positions) in 94% yield. The reaction of 2a with N3CH2COCl yielded
the penam of type 4 with exo-orientation of the N3 group at C(6) [10].
1
)
Part of the Ph.D. thesis of J. S., Universitꢀt Zꢁrich, 1993; presented in part at the 55th Annual
Meeting of the Polish Chemical Society, Białystok, 2012, Abstracts, S06_K06, p. 227 [1].
Present address: RFS Pharma, 1860 Montreal Road, Tucker, Georgia 30084, USA.
The structure of 5 was established by X-ray crystallography (H. Heimgartner, J. H. Bieri, R. Prewo,
A. Linden, C. Jenny, Private Communication CCDC, Cambridge, England, 1993; CSD refcode:
HACPUW).
2
3
)
)
ꢄ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 96 (2013)
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Scheme 1
b-Lactam antibiotics belong to the most efficient agents in fighting bacterial
infections4). Mostly, the b-lactam antibiotics are the products of fermentation and
semi-synthesis, and, despite many efforts, only a couple of monocyclic b-lactams are
produced by total synthesis. Nevertheless, there is a continuing interest in new synthetic
methods towards this highly desired class of compounds (see, e.g., [12]). Among the
various methods for the preparation of b-lactams, the acid chloride/imine (ketene/
imine) addition is one of the most frequently used. Since its discovery by Staudinger in
1907 [13], the scope and limitations of this method have been studied extensively, and
much progress has been made on the synthesis of monocyclic b-lactams [14]. However,
for the synthesis of bicyclic b-lactams, e.g., penams, this method suffers in two ways: the
poor yield of the reaction, and the low or inappropriate stereoselectivity. Although the
problem of the undesired configuration at C(6) has been solved by the transformation
of 6-epipenicillin to penicillin [15], the epimerization is a multistep process and affords
the product only in low yield. Therefore, a number of studies concerning the formation
of the penam skeleton via the reaction of 4,5-dihydro-1,3-thiazoles with various acetyl
chlorides/base, i.e., the imine/ketene addition, have been published [16]. Furthermore,
the continuing interest in penam derivatives is reflected by the elaboration of new
methods for their preparation (e.g., [17]), the synthesis of analogs such as
selenapenams [18], and the modifcation of known compounds, e.g., 6-aminopenicillic
acid (6-APA) [19].
The aim of the present study was the extension of the reaction 2 ! 4 to 4,5-dihydro-
1,3-thiazoles of type 2 with a PhCH2 or a Me group at C(2), as well as on acetyl
chlorides bearing an AcO or phthalimido group. Furthermore, a method for trans-
formation of 6-exo-substituted penams to the corresponding 6-endo-azido derivatives
should be elaborated.
2. Results and Discussion. – 2.1. Reactions of 4,5-Dihydro-1,3-thiazoles 2 with
Acetyl Chlorides and Et3N. The substituted 4,5-dihydro-4,4-dimethyl-5-(methylsul-
fanyl)-1,3-thiazoles 2 were synthesized by treatment of the corresponding 4,4-dimethyl-
1,3-thiazole-5(4H)-thione 1 with MeLi in THF at ꢀ 788 [9a]. When 2a was treated with
(acetoxy)acetyl chloride (AcOCH2COCl; 3b) in CH2Cl2 at room temperature in the
presence of Et3N, two products, endo-6a and exo-6a, were formed in a ratio of ca. 2 :1,
isolated in 62% yield after chromatographic workup. The two stereoisomers were
separated by preparative TLC. On the basis of the spectroscopic data, the structures of
4
)
For recent reviews, see [11].

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isomeric penams 6 were assigned (Scheme 2). As it has been shown that, in [2 þ 2]
cycloadducts of 4,5-dihydro-1,3-thiazoles with ketenes, the ring S-atom is unmistakably
oriented trans to the group with a heteroatom at C(6) [20], endo-6a and exo-6a were
assigned both as 5,6-trans products. Then, the remaining possibility for the presence of
isomers must be the result of different configurations of the MeS substituent at C(2), as
the reaction started from racemic 2a. Hence, endo-6a and exo-6a were assigned as the
diastereoisomers with 2-endo- and 2-exo-5,6-trans-bicyclic penams, respectively.
Finally, the structure of endo-6a was confirmed by X-ray crystallography (Fig. 1).
Similarly, the reaction of 2a and phthalimidoacetyl chloride 3c also gave a mixture of
two diastereoisomers, endo-6b/exo-6b 3 :1 in a low yield of 15% (Scheme 2).
Scheme 2
Since the space group of endo-6a is centrosymmetric, the compound in the crystal is
racemic. Whereas the AcO group at the b-lactam ring is exo-oriented, i.e., cis to the Ph
group, the MeS group at the thiazolidine ring occupies the endo-position.
On the other hand, acid chlorides 3a – 3c reacted with the 2-PhCH2-substituted 4,5-
dihydro-1,3-thiazole 2b under the same conditions (CH2Cl2, room temperature) to give
different products. The reaction of 2b with excess 3a furnished two products in almost
equal amounts. According to the NMR spectra, the second product consists of a 1:1
mixture of diastereoisomers. The mass and NMR spectra revealed that they were
derived from 1:1 and 1:2 adducts of 2b and 3a by elimination of 1 and 2 equivalents,
respectively, of HCl. The IR spectra excluded the presence of b-lactam structures, as
both products lack the absorption at ca. 1750 cmꢀ1, i.e., the characteristic b-lactam C¼O
stretching band. In both compounds, an amide/lactam group was indicated by IR
absorptions at 1700 and 1720/1710 cmꢀ1, and 13C-NMR signals at 163.9 and 159.5 ppm,
respectively. On the basis of the specroscopic data, structures 7a and 8 were proposed
for these products (Scheme 3). Treatment of 7a with excess 3a and Et3N in boiling
hexane led to 8 in 31% yield.
The same starting materials 2a and 3a reacted in refluxing hexane in the presence of
Et3N, and the same product 7a was formed together with a new compound 9. Again,
lack of absorptions for a corresponding C¼O group indicated that no b-lactam was
formed; the C¼O signals appeared at 1600 cmꢀ1 and 179.5 ppm. Furthermore, a NH
1
signal was detected at 10.92 ppm in the H-NMR spectrum. The structure of 9 was
established by X-ray crystallography (Fig. 2).
Similar reactions of 2b with 3b and 3c, respectively, in refluxing hexane gave a
single 1:1 adduct 7b or 7c in each case (Scheme 4). Furthermore, 4,5-dihydro-2-methyl-
1,3-thiazole 2c reacted with 3a under similar conditions to give the ꢂ1:2 adductꢃ 10 in
low yield. The structures of all these products were determined on the basis of their

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Fig. 1. ORTEP Plot [21] of the molecular structure of endo-6a (with 30% probability ellipsoids; arbitrary
numbering of atoms)
Scheme 3

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Fig. 2. ORTEP Plots [21] of the molecular structures of a) 9 and b) 7b (with 50% probability ellipsoids;
arbitrary numbering of atoms)
Scheme 4
spectroscopic and analytical data and, in the case of 7b, the structure was established by
X-ray crystallography (Fig. 2).
The space groups of 9 and 7b are centrosymmetric, therefore, the compounds in the
crystals are racemic. The thiazolidine NH group of 9 forms an intramolecular H-bond
with the O-atom of the side-chain C¼O group; graph set motif [22] S(6). In the case of
7b, the exocyclic C¼C bond is (Z)-configured.
It should be mentioned that all attempts to synthesize spiropenams by the acid
chloride/imine cycloaddition failed. Under various conditions, C(4)-spirocyclic 4,5-
dihydro-1,3-thiazoles [9c] reacted neither with 3a nor with 3b in the presence of Et3N.
In most cases, the starting materials were recovered in high yields. Similarly, the bulky

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2-(tert-butyl)-4,5-dihydro-4,4-dimethyl-5-(methylsulfanyl)-1,3-thiazole [9c] also failed
to react with 2a and 2b under similar conditions.
2.2. Synthesis of Monocyclic a-Hydroxy b-Lactams and Attempted Transformations
to a-Azido b-Lactams. With the aim of elaborating reaction conditions for the
transformation of penams of type 6 to the corresponding 6-endo-azido derivatives,
monocyclic b-lactams were prepared as model compounds. Thus, benzalaniline (N-
benzylideneaniline; 11), in CH2Cl2 and in the presence of Et3N, was reacted with acid
chlorides 3b and 3c, respectively, at room temperature to give the corresponding
monocyclic b-lactams 12a and 12b in good-to-excellent yield (Scheme 5)5). In the case
of 3c, only the trans-isomer 12b was obtained, whereas, in the case of 3b, a 1:1 mixture
of cis- and trans-12a was isolated. The cis/trans-configurations were assigned on the
1
basis of the J(HꢀC(3),HꢀC(4)) values in the H-NMR spectra [24] (see also [23]).
Scheme 5
In several publications, the transformation of cis- and trans-substituted 3-
hydroxyazetidinones to the corresponding 3-azido derivatives with inverted config-
uration has been described (e.g., [25]). Our intention was to use the mixture of cis/
trans-12a as a model for this purpose. First, 12a was hydrolyzed by treatment with
NaHCO3 in MeOH/H2O at 08 to give cis/trans-3-hydroxy-b-lactams 13
[23a][23c][25b][26] (Scheme 6). The diastereoisomers trans-13 and cis-13 were
separated successfully by flash chromatography. Their subsequent sulfonylation with
4-chlorophenylsulfonyl chloride (cf. [23a][25]) gave the sulfonates trans-14 and cis-14,
respectively, in excellent yields. Treatment of the sulfonates with NaN3 in DMF at 50 –
608 afforded via stereoselective SN2 reaction the 3-azido-b-lactams cis-15 and trans-15,
respectively, with complete conversion of the configurations (Scheme 6).
The successful replacement of the OH group in monocyclic b-lactams by the N3
group (see above and [25]) encouraged us to apply this method to the bicyclic b-lactams
6a. In analogy to the monocyclic b-lactams 12, the diastereoisomer mixture 6a, as well
as the separated 2-endo- and 2-exo-diastereoisomers endo-6a and exo-6a, were
hydrolyzed under mild conditions to give the corresponding 6-hydroxypenams 16
(Scheme 7). The diastereoisomers endo-16 and exo-16 formed from the mixture endo-
6a/exo-6a could be separated easily by preparative TLC6).
The structure of exo-16 was established by X-ray crystallography (Fig. 3). Since the
space group is centrosymmetric, the compound in the crystal is racemic. The
5
)
For analogous recent studies, see [12b][23]. Selective syntheses of cis-12a under similar conditions
[23a] or at ꢀ 788 [23b] were reported, those of cis- and trans-12b were described in [23d][23e].
The hydrolyses of the pure diastereoisomers endo-6a and exo-6a led to pure endo-16 and exo-16,
respectively, in a stereospecific manner.
6
)

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Scheme 6
Scheme 7
substituents MeS, Ph, and OH are all exo-oriented. The OH group forms an
intermolecular H-bond with the C¼O O-atom of a neighboring molecule and thereby
links the molecules into extended chains which run parallel to the [100] direction and
can be described by a graph set motif [22] of C(5).
Sulfonylation of 16 in CH2Cl2/Et3N at 08 with (4-chlorophenyl)- and (2,4-
dinitrophenyl)sulfonyl chlorides gave the corresponding sulfonates 17a and 17b,
respectively, in high yields. Under the same conditions, the reaction of 16 with
(trifluoromethyl)sulfonyl chloride was carried out, but the corresponding (sulfonyl-
oxy)penam 17c was obtained in only 27% yield as a crude and unstable product.
Surprisingly, 4,5-dihydro-4,4-dimethyl-5-(methylsulfanyl)-2-phenyl-1,3-thiazole (2a)
was formed via a decomposition reaction.
Substitution of the sulfonate 17a with NaN3 under same conditions, as in the case of
monocyclic b-lactams 14, failed; no substitution product, i.e., a 6-azidopenam, was
formed, and mainly starting material was recovered. Even reactions with the more
active substrates 17b and 17c did not result in any desired azido product. Instead, some
decomposition product 2a was formed. As the unstable triflated bicyclic penam 17c
decomposed already under the conditions of its preparation, triflation, and substitution
with NaN3 were conducted in a one-pot reaction under mild conditions (08). However,
this also failed to afford the desired azido compound, and again some cleavage product
2a was isolated. All further attempts to use the more nucleophilic and better soluble
azido reagents LiN3 and Bu4NN3 were also unsuccessful to give an azido penam.

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Fig. 3. ORTEP Plot [21] of the molecular structure of exo-16 (with 50% probability ellipsoids; arbitrary
numbering of atoms)
3. Conclusions. – The acid chloride/imine cycloaddition has been studied
extensively, and three mechanistic pathways have been proposed [27]: 1) direct
acylation of the imine with the acid chloride leads to the intermediate N-acyliminium
chloride A or the chloroalkyl amide B, which reacts with base to give the b-lactam; 2)
the initial formation of a ketene and subsequent [2 þ 2] cycloaddition with an imine,
perhaps via the zwitterionic intermediate C, yields the b-lactam; 3) deprotonation of
the initially formed A leads to C, which reacts to give the b-lactam (Scheme 8).
However, it is not possible to predict the stereochemical course of all of the reported
reactions with a single mechanisms, and it is likely that more than one mechanism is
involved7).
In the acid chloride/imine cycloaddition, especially with cyclic imines, the
heteroatom at the imine C-atom plays an important role in the determination of the
relative configuration of the resulting b-lactam. It has been reported that a 4,5-dihydro-
1,3-thiazole gives exclusively the 5,6-trans-configured penam from the reaction with N-
protected glycyl chloride [20]. This observation was confirmed in the present study, in
which only the 5,6-trans-b-lactams 6a and 6b were formed in the reaction of 4,5-
7
)
For some recent relevant articles and reviews, see [28][29].

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Scheme 8
dihydro-1,3-thiazole 2a with (acetoxy)acetyl chloride (3b) and phthalimidoacetyl
chloride (3c), respectively (Scheme 2).
The substituent at C(a) of the acid chloride also has an influence on the
configuration of the formed b-lactam. It was found that a relatively bulky acid chloride
leads to the 3,4-trans-configured b-lactam, while a less sterically hindered acid chloride
had a minor influence on the configuration of the product. For instance, 3c and
benzalaniline (11) gave exclusively the b-lactam trans-12b, while 3b, under analogous
conditions, afforded a 1:1 mixture cis-12a/trans-12a (Scheme 5).
The efficiency of the cycloaddition reaction with cyclic imines depends to a great
extent on the substituent at the imine C-atom. For instance, the reaction of a 2-
unsubstituted 4,5-dihydro-1,3-thiazole with N3CH2COCl gave the correspoding penam
in a very poor yield [30], while the 2-Ph-substituted 2a afforded the bicyclic b-lactams
6a in a much higher yield (see also [10]). However, a sterically bulky substituent at C(2)
may obstruct the reaction, as the 2-tBu analog of 2a failed to react with 3a and with 3b,
respectively. For similar reasons, 4,4-spiro-4,5-dihydro-1,3-thiazoles of type 2a failed to
give any b-lactam under analogous reaction conditions.
When the substituent at C(2) of the 4,5-dihydro-1,3-thiazole 2 bears a H-atom in a-
position, the reaction with acid chlorides/Et3N proceeded via another pathway leading
to N- and/or C-acylated products. The formation of N-acylated products in reactions
with acid chlorides/Et3N has previously been reported [31]. They might be formed by
the nucleophilic attack of the imine N-atom onto the ketene or acid chloride (2b ! D,
Scheme 9), followed by a proton shift in the zwitterion D to give 7a. Apparently, this
process is favored over ring closure to form a b-lactam.
To the best of our knowledge, the C-acylation of a 4,5-dihydro-1,3-thiazole by an
acid chloride or a ketene has not been reported so far. A reasonable mechanism for the
reaction 2b ! 9 is depicted in Scheme 9: the enamine moiety in the tautomeric structure
2b’ may attack the ketene or acyl chloride to give E, followed by a prototropic
isomerization. Control experiments indicated that the C-acylation is even more favored
in the absence of Et3N (16% of 7a and 64% of 9). Therefore, an initial deprotonation

Helvetica Chimica Acta – Vol. 96 (2013)
1471
Scheme 9
of 2b by the base, to give a benzyl anion, which then could attack the ketene to give E,
is not necessary.
The formation of 2 :1 adducts in reactions of ketenes and 4,5-dihydro-1,3-thiazoles,
i.e., 2-methyliden-1,3-oxazin-6-ones or piperidine-2,4-diones, has already been reported
[10][32]. However, the structure of compound 8 is different from those of the above
reported bicycles, in which the substituents at C(2) were not involved in the formation
of the fused ring system. A control experiment showed that 8 was also formed via a
second acylation of the N-acylation product 7a: in refluxing hexane, in the presence of
3a and Et3N, 8 was obtained. A likely reaction mechanism is outlined in Scheme 10.
Deprotonation of 7a and subsequent addition to a second ketene molecule could form
intermediate F, which may undergo a cyclization via nucleophilic attack of the enamine
moiety onto the C¼O group. An alternative reaction sequence via C-acylation of 7a to
give G, deprotonation of the N-acyl moiety, and cyclization is also conceivable.
The exchange of the OH for the N3 group was successful in monocyclic b-lactams 13
(Scheme 6), but it failed in our bicyclic b-lactams 16 (Scheme 7). The reason could be
the stereochemical hindrance around the 6-sulfonate moiety in 17; both the fused
thiazolidine ring and the 5-Ph substituent contribute to this hindrance. The first
contribution was confirmed by the successful substitution in 13, and the latter was
supported by a report, in which a 5-unsubstituted 6-exo-hydroxy penam was converted
to the 6-endo-azido penam under similar conditions as ours [33].
The acid chloride/imine cycloaddition provides a versatile and convenient way to
produce monocyclic b-lactams in high yields. By choosing appropriate substituents on
both the acid chloride and the imine, a stereoselective formation of products could be
achieved. However, for bicyclic b-lactams, the yields are generally poor, especially for
the most desired 5-unsubstituted penams. To solve the problem, Nagao et al. [16e]
introduced a MeSe substituent at C(2) of 4,5-dihydro-1,3-thiazoles. With this

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 10
promoting group, the yield of the cycloadditions improved dramatically. The MeSe
group could be removed afterwards by selective reduction with Bu3SnH. Concerning
the configuration of the products, the method afforded exclusively the undesired
stereoisomers, namely the trans-b-lactams with the exo-oriented substituent at C(6).
Thus, to access biologically interesting products, an epimerization at C(6) is needed. As
the exo ! endo transformation was reported to be successful in bicyclic b-lactams [33],
the combination of Nagaoꢃs cycloaddition, deselenation, and the above transformation
would open the way to the synthesis of biologically attractive penams.
We thank the analytical sections of our institute for spectra and analyses, and the Swiss National
Science Foundation and F. Hoffmann-La Roche AG, Basel, for financial support.
Experimental Part
1. General. Solvents: CH2Cl2, Et2O, MeCN, hexane, and toluene were distilled over CaH2 and stored
over molecular sieves (4 ꢅ); THF was destilled over Na; DMF, MeOH, and EtOH (Merck) were dried
over molecular sieves (4 ꢅ). TLC: Merck TLC aluminum sheets, silica gel (SiO2) 60 F254. Column
chromatography (CC): SiO2 Merck 60 (0.04 – 0.063 mm). M.p.: Mettler-FP5 apparatus; uncorrected. IR
Spectra: Perkin-Elmer 297 or Perkin-Elmer 781 spectrophotometer; in CHCl3 unless otherwise stated; ˜n
in cmꢀ1. 1H-NMR Spectra: Bruker AC-300 (300 MHz), Bruker AM-400 (400 MHz), and Varian EM-390
(90 MHz) spectrometer, in CDCl3 at 300 K unless otherwise stated; d in ppm; TMS (0 ppm) or residual
CHCl3 (7.27 ppm) as internal standards; coupling constants J in Hz. 13C-NMR Spectra: Varian XL-200
(50.4 MHz) spectrometer; d in ppm; CDCl3 as internal standard (77.0 ppm); signal multiplicity from
DEPT spectra. MS: Varian MAT-711, Varian MAT-112, Finnigan MAT-90, Finnigan SSQ-700, or
Finningan TSQ-700 mass spectrometers; EI mode: direct injection, 70 eV; CI mode: with 2-
methylpropane or NH3; m/z (rel. %).
2. Acid Chloride/Imine Cycloaddition. General Procedure 1 (GP 1). Into a soln. of imine (4,5-
dihydro-1,3-thiazole 2 or benzalaniline (11); 5 mmol) and Et3N (1.01 g, 10 mmol) in CH2Cl2 (50 ml) at
r.t., a soln. of acid chloride 3 (10 mmol) in CH2Cl2 (2 ml) was added within 1 h. After stirring for 1 d,
505 mg (5 mmol) of Et3N was added in one portion, and additional 3 (5 mmol) was added dropwise
within 1 h. The mixture was maintained at r.t. for another 2 – 3 d, and then filtered through a SiO2 column.

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The filtrate was washed subsequently with 2n HCl, 5% NaHCO3, and brine. After removal of the solvent
in vacuo, the residue was either chromatographed or recrystallized.
General Procedure 2 (GP 2). A soln. of imine (2 or 11; 1 mmol) and acid chloride 3 (1.2 mmol) in
hexane (15 ml) was heated at reflux for 3 h. Then, a soln. of Et3N (3 mmol) in hexane (1 ml) was added
within 1 h, and the mixture was maintained at reflux for another 3 h. After addition of Et2O (30 ml), the
mixture was filtered through a short SiO2 column, the filtrate was concentrated in vacuo, and the residue
was chromatographed or recrystallized.
2.1. Formation of Bicyclic b-Lactams. 2.1.1. 6-exo-Acetoxy-2,2-dimethyl-3-endo-(methylsulfanyl)-
and 6-exo-acetoxy-2,2-dimethyl-3-exo-(methylsulfanyl)-5-phenyl-4-thia-1-azabicyclo[3.2.0]-heptan-7-
one (endo-6a and exo-6a, resp.). According to GP 1, with 4,5-dihydro-4,4-dimethyl-5-(methylsulfanyl)-
2-phenyl-1,3-thiazole [9a] (2a; 762 mg, 3.215 mmol), Et3N (1.30 g, 12.86 mmol), and (acetoxy)acetyl
chloride (3b, 1.754 mg, 12.86 mmol). CC (hexane/Et2O 10 :1) yielded 672 mg (62%) of 6a/6a’. 2 :1 After
prep. TLC (hexane/Et2O 4 :1; 4 ꢁ developing), endo-6a and exo-6a were isolated in pure form.
Data of endo-6a. White crystals. M.p. 126 – 1288. IR: 2985w, 2920w, 1785s, 1755s, 1450w, 1390w,
1370m, 1275m, 1255w, 1235m, 1180m, 1160w, 1125m, 1060w, 1025w, 915w, 700m. 1H-NMR: 7.35 – 7.3 (m, 5
arom. H); 6.02 (s, HꢀC(6)); 4.55 (s, HꢀC(3)); 2.26 (s, MeS); 1.94 (s, endo-MeꢀC(3)); 1.64 (s, MeCO);
1.29 (s, exo-MeꢀC(3)). 13C-NMR: 167.9 (s, C(7)); 167.8 (s, MeCO); 136.9 (s, 1 arom. C); 128.1, 127.8,
126.2 (3d, 5 arom. CH); 84.4 (d, C(6)); 80.5 (s, C(5)); 72.7 (d, C(3)); 70.5 (s, C(2)); 27.5, 21.3 (2q, Me2C);
19.5 (q, MeCO); 16.6 (q, MeS). CI-MS: 340 (12), 339 (20), 338 (100, [M þ 1]þ), 290 (17), 238 (17). Anal.
calc. for C16H19NO3S2 (337.46): C 56.95, H 5.68, N 4.15, S 19.00; found: C 56.91, H 5.49, N 4.37, S 19.28.
Suitable crystals for the X-ray crystal-structure determination were grown from hexane/Et2O by slow
evaporation of the solvent at r.t.
Data of exo-6a. White crystals. M.p. 100.5 – 101.58. IR: 2990w, 2920w, 1770s, 1760s, 1450w, 1390w,
1370m, 1275m, 1250m, 1240m, 1185m, 1120m, 1050w, 1030m, 920w, 700m. 1H-NMR: 7.35 – 7.3 (m, 5 arom.
H); 5.90 (s, HꢀC(6)); 4.62 (s, HꢀC(3)); 2.28 (s, MeS); 1.87 (s, endo-MeꢀC(3)); 1.63 (s, MeCO); 1.10 (s,
exo-MeꢀC(3)). 13C-NMR: 168.5 (s, MeCO); 167.7 (s, C(7)); 137.0 (s, 1 arom. C); 128.2, 127.7, 126.3 (3d, 5
arom. CH); 85.3 (d, C(6)); 79.0 (s, C(5)); 70.7 (d, C(3)); 68.9 (s, C(2)); 22.2, 22.0 (2q, Me2C); 19.5 (q,
MeCO); 17.3 (q, MeS). CI-MS: 340 (11), 339 (19), 338 (100, [M þ 1]þ), 304 (19), 290 (16), 280 (16), 278
(10), 238 (35), 234 (26), 188 (7), 178 (7). Anal. calc. for C16H19NO3S2 (337.46): C 56.95, H 5.68, N 4.15, S
19.00; found: C 57.11, H 5.48, N 4.19, S 18.88.
2.1.2. 2,2-Dimethyl-3-endo/exo-(methylsulfanyl)-5-phenyl-6-exo-phthalimido-4-thia-1-azabicy-
clo[3.2.0]heptan-7-one (¼2-[2,2-Dimethyl-3-(methylsulfanyl)-7-oxo-5-phenyl-4-thia-1-azabicyclo-
[3.2.0]hept-6-yl]-1H-isoindole-1,3(2H)-dione; 6b). According to GP 2, with 2a (119 mg, 0.5 mmol),
phthalimidoacetyl chloride (3c, 134 mg, 0.6 mmol), and Et3N (152 mg, 1.5 mmol). Prep. TLC (hexane/
Et2O 10 :1): 31 mg (15%) of 6b as a mixture of two diastereoisomers. White crystals. M.p. 888. IR:
3030w, 3000w, 2980w, 2930w, 1790s, 1775s, 1725s, 1385s, 1270m, 1250m, 1110m, 965w, 710w, 700w.
1H-NMR (2 diastereoisomers, 1:3): 7.65 – 7.05 (m, 9 arom. H); 5.84, 5.67 (2s, HꢀC(6)); 4.67, 4.60 (2s,
HꢀC(3)); 2.30 (s, MeS); 2.06, 1.99, 1.45, 1.26 (4s, Me2C). 13C-NMR (2 diastereoisomers, 1:3): 168.0 (s,
C(7)); 167.3 (s, 2 C¼O); 137.3, 130.9 (2s, 3 arom. C); 134.1, 128.00, 127.97, 127.8, 125.5, 123.3 (6d, 9 arom.
C); 79.4 (s, C(5)); 73.1, 70.4 (2d, C(6)); 71.1, 69.6 (2s, C(2)); 69.2, 68.3 (2d, C(3)); 28.3, 22.5, 21.6, 22.3 (4q,
Me2C); 17.4, 16.8 (2q, MeS). CI-MS: 425 (11, [M þ 1]þ), 260 (16), 259 (100), 238 (21), 145 (5), 72 (5).
Anal. calc. for C22H20N2O3S2 (424.54): C 62.24, H 4.75, N 6.60, S 15.11; found: C 62.12, H 4.66, N 6.39, S
15.35.
2.2. Formation of Monocyclic b-Lactams. 2.2.1. 3-Acetoxy-1,4-diphenylazetidin-2-one (12a) [23a,b].
According to GP 1, with 3b (2.048 g, 15 mmol) and benzalaniline (¼ N-benzylideneaniline; 11, 0.905 g,
5 mmol). CC (hexane/Et2O 12 :1): 1.299 g (92%) of 12a (2 diastereoisomers). White crystals. M.p. 138 –
1398. IR: 1765s, 1760s, 1600w, 1500m, 1390m, 1380m, 1240m, 1145m, 1100w, 700m. 1H-NMR (2
diastereoisomers, 1:1): 7.45 – 7.25 (m, 9 arom. H); 7.15 – 7.05 (m, 1 arom. H); 5.97, 5.41 (2d, J ¼ 4.9, 1.7,
HꢀC(3)); 5.40, 4.96 (2d, J ¼ 4.9, 1.7, HꢀC(4)); 2.21, 1.69 (2s, Me). 13C-NMR (2 diastereoisomers, 1:1):
169.6, 161.7 (2s, 2 C¼O); 136.8 – 117.4 (12 arom. C); 82.4, 76.2 (2d, C(3)); 63.6, 61.3 (2d, C(4)); 20.4, 19.7
(2q, Me). CI-MS: 283 (19), 282 (100, [M þ 1]þ), 234 (9), 224 (8), 222 (10), 195 (11), 183 (10), 182 (60),
163 (12), 147 (19), 133 (7), 101 (15), 94 (47), 93 (9). Anal. calc. for C17 H15NO3 (281.32): C 72.58, H 5.37,
N 4.98; found: C 72.55, H 5.15, N 5.17.

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2.2.2. 3,4-trans-1,4-Diphenyl-3-phthalimidoazetidin-2-one (¼ 3,4-trans-2-(2-Oxo-1,4-diphenylazeti-
din-3-yl)-1H-isoindole-1,3(2H)-dione; 12b) [23d,e]. According to GP 1, with 3c (3.353 g, 15 mmol)
and 11 (0.905 g, 5 mmol). Recrystallization from Et2O/CH2Cl2/hexane: 1.068 g (58%) of 12b. White
crystals. M.p. 224 – 2258 ([23d]: 224 – 2308). IR: 1765m, 1725s, 1600w, 1500m, 1390m, 1150w, 1105w,
1090w, 970w, 715w, 700w. 1H-NMR (400 MHz): 7.9 – 7.85 (m, 2 arom. H); 7.8 – 7.75 (m, 2 arom. H); 7.4 –
7.25 (m, 9 arom. H); 7.1 – 7.05 (m, 1 arom. H); 5.40 (d, J ¼ 2.7, HꢀC(3)); 5.30 (d, J ¼ 2.7, HꢀC(4)).
13C-NMR: 166.7 (s, 2 C¼O); 162.0 (s, C(2)); 137.1 – 117.6 (18 arom. C); 62.7 (d, C(3)); 61.2 (d, C(4)). CI-
MS: 387 (16), 386 (100, [M þ NH4]þ), 369 (25, [M þ 1]þ), 366 (14). Anal. calc. for C23H16N2O3 (368.40):
C 74.99, H 4.38, N 7.60; found: C 74.78, H 4.66, N 7.63.
3. Reactions of Acid Chlorides with 4,5-Dihydro-1,3-thiazoles 2b and 2c. 3.1. (2Z)-3-(2,2-
Dichloroacetyl)-4,4-dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-1,3-thiazolidine (¼2,2-Di-
chloro-1-[(2Z)-4,4-dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-1,3-thiazolidin-3-yl]ethanone;
7a) and 6,6-Dichloro-7-(dichloromethyl)-2,3,6,7-tetrahydro-7-hydroxy-3,3-dimethyl-2-(methylsulfanyl)-
8-phenyl-5H-[1,3]thiazolo[3,2-a]pyridin-5-one (8). a) According to GP 1, with 2b (147 mg, 0.586 mmol),
Et3N (237 mg, 2.35 mmol), and 3a (348 mg, 2.35 mmol). CC (hexane/Et2O 10 :1): 114 mg (53%) of 7a
and 130 mg (47%) of 8 (mixture of 2 diastereoisomers).
Data of 7a. Brown crystals. M.p. 97 – 998. IR: 2960s, 2920s, 2860s, 1700s, 1600w, 1460w, 1375m, 1355m,
1
1340m, 1255w, 1170w. H-NMR: 7.35 – 7.3 (m, 5 arom. H); 6.64 (s, PhCH¼C); 6.11 (s, Cl2CH); 4.35 (s,
HꢀC(5)); 2.21 (s, MeS); 1.59, 1.47 (2s, Me2C). 13C-NMR: 163.9 (s, C¼O); 136.4 (s, C(2)); 134.7 (s, 1 arom.
C); 128.6, 127.9, 127.2 (3d, 5 arom. CH); 113.4 (d, PhCH¼C); 67.6 (s, C(4)); 65.2 (d, Cl2CH); 64.3 (d,
C(5)); 24.3, 20.5 (2q, Me2C); 16.0 (q, MeS). CI-MS: 366 (2), 364 (8), 362 (11, [M þ 1]þ), 252 (57), 236
(6), 206 (5), 205 (15), 204 (100), 191 (10), 135 (14). Anal. calc. for C15H17Cl2NOS2 (362.34): C 49.72, H
4.73, Cl 19.57, N 3.87, S 17.70; found: C 50.00, H 5.00, Cl 19.65, N 3.72, S 17.51.
Data of 8. Yellow oil. IR: 3540m, 3020w, 3000m, 2980m, 2920w, 1720s, 1710s, 1630s, 1510m, 1385s,
1370s, 1360s, 1310m, 1280m, 1250m, 1170m, 1125s, 1040m, 1020m, 910m, 850m, 810m, 700m, 650m.
1H-NMR (2 diastereoisomers, 1:1): 7.5 – 7.4 (m, 5 arom. H); 6.20, 6.18 (2s, Cl2CH); 4.24, 4.21 (2s,
HꢀC(2)); 3.22, 3.17 (2s, OH); 2.20, 2.14 (2s, MeS); 1.81, 1.74, 1.73, 1.55 (4s, Me2C). 13C-NMR (2
diastereoisomers, 1:1): 159.5 (s, C¼O); 139.9 (s, C(8a)); 135.5, 135.1 (2s, 1 arom. C); 131.4, 131.3, 128.7,
128.6, 128.56, 128.5 (6d, 5 arom. CH); 128.8, 128.7 (2s, C(8)); 106.3, 105.0 (2s, C(7)); 81.8, 81.6 (2s, C(6));
76.3, 76.2 (2d, Cl2CH); 72.1, 71.8 (2s, C(3)); 62.0, 61.8 (2d, C(2)); 25.2, 24.3, 21.8, 19.0 (4q, Me2C); 16.5,
14.9 (2q, MeS). CI-MS: 478 (13), 476 (53), 474 (100), 472 (76, [M þ 1]þ), 456 (6), 447 (8), 442 (7), 440
(16), 439 (6), 438 (34), 436 (35), 428 (12), 426 (24), 424 (21), 422 (14), 420 (13), 402 (13), 400 (27), 398
(20), 396 (15), 364 (8), 362 (6), 354 (6).
b) Into a soln. of 7a (66 mg, 0.18 mmol) and Et3N (55 mg, 0.54 mmol) in hexane (5 ml), 32 mg
(0.22 mmol) of 3a were added dropwise. The mixture was heated at reflux for 4 h. After removal of the
solvent in vacuo, the residue was chromatographed with hexane/Et2O 10 :1 to furnish 26 mg (31%) of 8.
3.2. (2E)-2-(3,3-Dichloro-2-oxo-1-phenylpropylidene)-4,4-dimethyl-5-(methylsulfanyl)-1,3-thiazoli-
dine (¼(3E)-1,1-Dichloro-3-[4,4-dimethyl-5-(methylsulfanyl)-1,3-thiazolidin-2-ylidene]-3-phenylpro-
pan-2-one; 9). a) According to GP 2, with 2-benzyl-4,5-dihydro-4,4-dimethyl-5-(methylsulfanyl)-1,3-
thiazole (2b; 301 mg, 1.2 mmol), 3a (195 mg, 1.32 mmol), and Et3N (303 mg, 3 mmol). CC (hexane/Et2O
10 :1): 159 mg (37%) of 7a and 195 mg (45%) of 9. White crystals. M.p. 138.5 – 1408. IR (KBr): 2950m,
1600s, 1510s, 1505s, 1380s, 1370s, 1330m, 1260m, 1165m, 1135m, 980w, 820m, 800m, 770m, 705m, 695m,
650m. 1H-NMR: 10.92 (s, NH); 7.6 – 7.25 (m, 5 arom. H); 5.91 (s, Cl2CH); 4.39 (s, HꢀC(5)); 2.17 (s, MeS);
1.57 (s, Me2C). 13C-NMR: 179.5 (s, C¼O); 170.8 (s, C(2)); 136.2 (s, 1 arom. C); 131.8, 129.0, 128.4 (3d, 5
arom. CH); 100.4 (s, PhC¼C); 69.1 (s, C(4)); 68.0 (d, Cl2CH); 63.2 (d, C(5)); 27.5, 23.3 (2q, Me2C); 15.5
(q, MeS). CI-MS: 366 (17), 365 (13), 364 (74), 363 (20), 362 (100, [M þ 1]þ), 330 (7), 328 (7). Anal. calc.
for C15H17Cl2NOS2 (362.34): C 49.72, H 4.73, Cl 19.57, N 3.87, S 17.70; found: C 49.50, H 4.48, Cl 19.77, N
3.99, S 17.40.
Suitable crystals for the X-ray crystal-structure determination were grown from hexane/Et2O by slow
evaporation of the solvent.
b) Into a soln. of 2b (189 mg, 0.75 mmol) in hexane (10 ml), 3a (167 mg, 1.13 mmol) was added. The
mixture was heated under reflux for 3 h. After addition of Et2O (30 ml), the mixture was filtered through

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a short SiO2 column, and the filtrate was concentrated in vacuo. CC (hexane/Et2O 10 :1) afforded 43 mg
(16%) of 7a and 174 mg (64%) of 9.
3.3. (2Z)-3-[(2-Acetoxy)acetyl]-4,4-dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-1,3-thiazoli-
dine (¼2-(Acetyloxy)-1-[(2Z)-4,4-dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-1,3-thiazolidin-3-
yl]ethanone; 7b). According to GP 2, with 2b (228 mg, 0.908 mmol), 3b (248 mg, 1.817 mmol), and Et3N
(367 mg, 3.63 mmol). CC (hexane/Et2O 10 :1): 112 mg (35%) of 7b. White crystals. M.p. 87 – 88.58. IR:
3005w, 2920w, 1745s, 1680s, 1610w, 1490w, 1445w, 1420w, 1385s, 1370m, 1315m, 1240m, 1170m, 1070m,
910m, 695m. 1H-NMR: 7.4 – 7.35 (m, 5 arom. H); 6.32 (s, PhCH¼C); 4.93 (s, CH2); 4.37 (s, HꢀC(5)); 2.26
(s, MeCO); 2.17 (s, MeS); 1.68, 1.53 (2s, Me2C). 13C-NMR: 170.3 (s, MeCO); 166.5 (s, C¼O); 135.7 (s,
C(2)); 135.2 (s, 1 arom. C); 128.4, 127.8, 126.8 (3d, 5 arom. CH); 114.5 (d, PhCH¼C); 67.4 (s, C(4)); 64.5
(d, C(5)); 63.3 (t, CH2); 24.9 (q, MeCO); 21.0, 20.4 (2q, Me2C); 16.0 (q, MeS). CI-MS: 354 (12), 353 (21),
352 (100, [M þ 1]þ), 351 (11), 304 (7). Anal. calc. for C17H21NO3S2 (351.49): C 58.09, H 6.02, N 3.99, S
18.24; found: C 58.22, H 5.91, N 4.02, S 18.03.
Suitable crystals for the X-ray crystal-structure determination were grown from hexane/Et2O by slow
evaporation of the solvent.
3.4. (2Z)-4,4-Dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-3-(phthalimidoacetyl)-1,3-thiazo-
lidine (¼2-{2-[(2Z)-4,4-Dimethyl-5-(methylsulfanyl)-2-(phenylmethylidene)-1,3-thiazolidin-3-yl]-2-ox-
oethyl}-1H-isoindole-1,3(2H)-dione; 7c). According to GP 2, with 2b (69 mg, 0.275 mmol), 3c (74 mg,
0.33 mmol), and Et3N (83 mg, 0.82 mmol). CC (hexane/Et2O 8 :1): 30 mg (25%) of 7c. Pale-yellow
powder. M.p. 55 – 568. IR (KBr): 2920w, 1770w, 1720s, 1680m, 1610w, 1420m, 1390m, 1370m, 1290w,
1270w, 1230w, 1110w, 955w, 750w, 715w, 695w. 1H-NMR: 7.9 – 7.85 (m, 2 arom. H); 7.75 – 7.7 (m, 2 arom.
H); 7.4 – 7.25 (m, 5 arom. H); 6.57 (s, CH¼C); 4.84, 4.76 (AB, J ¼ 16.4, CH2); 4.41 (s, HꢀC(5)); 2.29 (s,
MeS); 1.68, 1.52 (2s, Me2C). 13C-NMR: 167.6, 165.7 (2s, 3 C¼O); 135.7 (s, C(2)); 135.2, 131.9 (2s, 3 arom.
C); 133.9, 128.4, 127.9, 126.8, 123.3 (5d, 9 arom. CH); 115.5 (d, CH¼C); 67.7 (s, C(4)); 64.4 (d, C(5)); 41.7
(t, CH2); 24.9, 21.0 (2q, Me2C); 15.9 (q, MeS). CI-MS: 441 (12), 440 (28), 439 (100, [M þ 1þ]), 391 (5).
Anal. calc. for C23H22N2O3S2 (438.57): C 62.99, H 5.06, N 6.39, S 14.62; found: C 63.18, H 5.32, N 6.34, S
14.41.
3.5. (2Z)-3-(Dichloroacetyl)-2-(3,3-dichloro-2-oxopropylidene)-4,4-dimethyl-5-(methylsulfanyl)-1,3-
thiazolidine (¼(3Z)-1,1-Dichloro-3-[3-(2,2-dichloroacetyl)-4,4-dimethyl-5-(methylsulfanyl)-1,3-thiazoli-
din-2-ylidene]propan-2-one; 10). According to GP 2, with 4,5-dihydro-2,4,4-trimethyl-5-(methylsul-
fanyl)-1,3-thiazole (2c; 175 mg, 1 mmol), 3a (178 mg, 1.2 mmol), and Et3N (251 mg, 2.5 mmol). CC
(hexane/Et2O 10 :1): 53 mg (19%) of 10. Yellow oil. IR: 3200w, 3000m, 2980m, 2920m, 1725s, 1660m,
1595m, 1530s, 1515s, 1505s, 1390m, 1370m, 1320s, 1270m, 1160s, 1120m, 810m. 1H-NMR: 6.52 (s, CH¼C);
6.27, 5.90 (2s, 2 Cl2CH); 4.29 (s, HꢀC(5)); 2.29 (s, MeS); 1.65, 1.59 (2s, Me2C). 13C-NMR: 184.7, 165.7 (2s,
2 C¼O); 163.2 (s, C(2)); 96.1 (d, CH¼C); 71.6 (s, C(4)); 69.5, 64.5 (2d, 2 Cl2CH); 62.1 (d, C(5)); 24.0, 20.4
(2q, Me2C); 15.8 (q, MeS). CI-MS: 402 (8), 400 (28), 399 (9), 398 (49), 397 (9), 396 (35, [M þ 1]þ), 312
(5), 290 (13), 289 (9), 288 (69), 287 (14), 286 (100), 202 (6).
4. Hydrolysis of 3-Acetoxyazetidin-2-one 12a and 6-Acetoxy Penam 6a. 4.1. trans- and cis-3-hydroxy-
1,4-diphenylazetidin-2-one (trans-13 and cis-13, resp.). Into a soln. of 12a (410 mg, 1.46 mmol) in MeOH
(50 ml) at 08, a soln. of sat. aq. NaHCO3 (2 ml) was added. The mixture was maintained at 08 for 30 min.
Then, AcOEt (200 ml) and H2O (80 ml) were added. The org. phase was separated, and the aq. phase was
extracted with AcOEt (3 ꢁ 120 ml). The combined org. phase was washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo. CC (hexane/Et2O 8 :1) of the residue afforded 153 mg (44%) of
trans-13 and 151 mg (43%) of cis-13.
Data of trans-13 [25b]. White crystals. M.p. 181 – 1838 ([25b]: 180 – 1818). IR: 3350w, 1750s, 1600w,
1505m, 1385m, 1140w. 1H-NMR: 7.4 – 7.2 (m, 9 arom. H); 7.1 – 7.05 (m, 1 arom. H); 4.92 (d, J ¼ 1.8,
HꢀC(4)); 4.76 (dd, J ¼ 1.8, 6.2, HꢀC(2)); 3.49 (d, J ¼ 6.2, OH). 13C-NMR ((D5)pyridine): 168.0 (s, C¼O);
138.3, 137.9 (2s, 2 arom. C); 129.6, 128.8, 126.6, 124.3, 117.9 (5d, 10 arom. CH); 85.5 (d, C(3)); 66.6 (d,
C(4)). CI-MS: 258 (16), 257 (100, [M þ NH4]þ), 241 (16), 240 (100, [M þ 1]þ). Anal. calc. for C15H13NO2
(239.28): C 75.30, H 5.48, N 5.85; found: C 75.42, H 5.27, N 6.00.
Data of cis-13 [25b]. White crystals. M.p. 199 – 2018 ([25b]: 206 – 2078). IR: 3600w, 3000w, 1750s,
1
1600w, 1500m, 1455w, 1385m, 1265m, 1150w, 1115m, 700m. H-NMR: 7.45 – 7.25 (m, 9 arom. H); 7.15 –
7.05 (m, 1 arom. H); 5.33 (d, J ¼ 5.4, HꢀC(4)); 5.21 (dd, J ¼ 5.4, 9.2, HꢀC(3)); 2.21 (d, J ¼ 9.2, OH).

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13C-NMR ((D5)pyridine): 168.3 (s, C¼O); 138.6, 135.7 (2s, 2 arom. C); 129.6, 128.9, 128.6, 128.4, 124.3,
117.8 (6d, 10 arom. CH); 78.6 (d, C(3)); 63.3 (d, C(4)). CI-MS: 258 (17), 257 (100, [M þ NH4]þ), 241 (5),
240 (30, [M þ 1]þ), 58 (5). Anal. calc. for C15H13NO2 (239.28): C 75.30, H 5.48, N 5.85; found: C 75.51, H
5.27, N 5.97.
4.2. 6-exo-Hydroxy-2,2-dimethyl-3-endo- and 3-exo-(methylsulfanyl)-5-phenyl-4-thia-1-azabicy-
clo[3.2.0]heptan-7-one (endo-16 and exo-16, resp.). In analogy to Exper. 4.1, the reaction of 6a
(460 mg, 1.36 mmol) with sat. NaHCO3 (3 ml) at 08 for 1 h afforded, after CC (hexane/Et2O 5 :1), 307 mg
(76%) of 16 as a mixture of two diastereoisomers. Prep. TLC (hexane/Et2O 4 :1) furnished endo- and
exo-16 in pure form.
Data of endo-16. White crystals. M.p. 103.5 – 104.58. IR: 3560m, 3380m, 3000m, 2980m, 2920m, 1760s,
1600w, 1480w, 1460w, 1445m, 1390m, 1370m, 1280s, 1210s, 1180s, 1150s, 1060m, 1030m, 1005m, 980m,
870m, 850m, 700s, 640m. 1H-NMR: 7.45 – 7.35 (m, 5 arom. H); 5.22 (d, J ¼ 9.6, HꢀC(6)); 4.54 (s, HꢀC(3));
2.32 (d, J ¼ 9.6, OH); 2.24 (s, MeS); 1.91, 1.32 (2s, Me2C). 13C-NMR: 173.3 (s, C¼O); 138.1 (s, 1 arom. C);
128.3, 128.1, 126.2 (3d, 5 arom. CH); 86.9 (d, C(6)); 81.7 (s, C(5)); 72.8 (d, C(3)); 69.9 (s, C(2)); 27.8, 21.3
(2q, Me2C); 16.7 (q, MeS). CI-MS: 296 (25, [M þ 1]þ), 240 (9), 239 (14), 238 (100). Anal. calc. for
C14H17NO2S2 (295.43): C 56.92, H 5.80, N 4.74, S 21.71; found: C 56.64, H 5.79, N 4.54, S 21.50.
Data of exo-16. White crystals. M.p. 141.5 – 142.78. IR: 3560w, 3330w, 2980m, 2920w, 1760s, 1450m,
1390m, 1370m, 1290m, 1260m, 1170m, 1145m, 700m. 1H-NMR: 7.45 – 7.35 (m, 5 arom. H); 5.07 (d, J ¼ 9.6,
HꢀC(6)); 4.54 (s, HꢀC(3)); 2.27 (s, MeS); 2.14 (d, J ¼ 9.6, OH); 1.85, 1.13 (2s, Me2C). 13C-NMR
((D6)acetone): 172.2 (s, C¼O); 139.8 (s, 1 arom. C); 128.3, 128.1, 126.9 (3d, 5 arom. CH); 89.6 (d, C(6));
80.9 (s, C(5)); 70.4 (d, C(3)); 68.8 (s, C(2)); 22.4, 22.3 (2q, Me2C); 17.0 (q, MeS). CI-MS: 313 (100, [M þ
NH4]þ), 296 (25, [M þ 1]þ), 284 (18), 283 (14), 269 (17), 267 (25), 238 (43).
Suitable crystals of exo-16 for the X-ray crystal-structure determination were grown from CH2Cl2/
Et2O/hexane by slow evaporation of the solvent.
5. Sulfonylation of 3-Hydroxyazetidin-2-ones 13 and 6-Hydroxy Penams 16. 5.1. trans-3-{[(4-
Chlorophenyl)sulfonyl]oxy}-1,4-diphenylazetidin-2-one (¼trans-2-Oxo-1,4-diphenylazetidin-3-yl 4-
Chlorobenzenesulfonate; trans-14). Into a soln. of trans-13 (190 mg, 0.795 mmol) in CH2Cl2 at 08,
Hꢀnigꢃs base (103 mg, 0.80 mmol) was added. After stirring for 10 min, a soln. of (4-chlorophenyl)sul-
fonyl chloride (252 mg, 1.19 mmol) in CH2Cl2 (2 ml) was added dropwise. The mixture was stirred
overnight allowing the temp. to rise to r.t. Then, CH2Cl2 (50 ml) was added. The org. phase was washed
with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization of the residue (CH2Cl2/
Et2O/hexane) furnished 296 mg (90%) of trans-14. White crystals. M.p. 187.0 – 187.58. IR: 1770s, 1600w,
1590w, 1500m, 1385s, 1190m, 1185m, 1145m, 1090m, 1070m, 870m, 845m, 830m, 700w. 1H-NMR: 7.85 – 7.8
(m, 2 arom. H); 7.55 – 7.5 (m, 2 arom. H); 7.45 – 7.35 (m, 3 arom. H); 7.3 – 7.2 (m, 6 arom. H); 7.15 – 7.05
(m, 1 arom. H); 5.15 (d, J ¼ 1.6, HꢀC(3)); 5.11 (d, J ¼ 1.6, HꢀC(4)). 13C-NMR ((D6)DMSO): 159.1 (s,
C¼O); 140.2, 135.8, 133.9, 133.2 (4s, 4 arom. C); 130.0, 129.8, 129.1, 128.9, 128.7, 126.9, 124.8, 117.6 (8d, 14
arom. CH); 84.7 (d, C(3)); 62.2 (d, C(4)). CI-MS: 433 (30), 432 (27), 431 (100, [M þ NH4]þ), 414 (12,
[M þ 1]þ). Anal. calc. for C21H16ClNO4S (413.88): C 60.94, H 3.90, Cl 8.57, N 3.38, S 7.75; found: C 61.10,
H 4.05, Cl 8.85, N 3.37, S 7.49.
5.2. cis-3-{[(4-Chlorophenyl)sulfonyl]oxy}-1,4-diphenylazetidin-2-one (¼cis-2-Oxo-1,4-diphenylaze-
tidin-3-yl 4-Chlorobenzenesulfonate; cis-14). In analogy to Exper. 5.1, from cis-13 (160 mg, 0.67 mmol),
Hꢀnigꢃs base (203 mg, 2.35 mmol), and (4-chlorophenyl)sulfonyl chloride (495 mg, 2.35 mmol).
Crystallization (CH2Cl2/Et2O/hexane): 259 mg (94%) of cis-14. White crystals. M.p. 209 – 2118. IR:
1765s, 1600w, 1500m, 1385m, 1190m, 1175m, 1085m, 870m, 830m, 700w. 1H-NMR: 7.5 – 7.25 (m, 13 arom.
H); 7.15 – 7.05 (m, 1 arom. H); 5.85 (d, J ¼ 5.0, HꢀC(3)); 5.34 (d, J ¼ 5.0, HꢀC(4)). 13C-NMR
((D6)DMSO): 160.0 (s, C¼O); 139.8, 136.2, 133.6, 131.9 (4s, 4 arom. C); 129.8, 129.2, 129.0, 128.7, 128.4,
127.8, 124.7, 117.1 (8d, 14 arom. C); 79.8 (d, C(3)); 60.2 (d, C(4)). EI-MS: 413 (9, Mþ), 296 (25), 295 (12),
294 (67), 239 (14), 238 (86), 221 (9), 183 (15), 182 (100), 181 (31), 180 (59), 175 (22), 159 (27), 152 (11),
131 (34). Anal. calc. for C21H16ClNO4S (413.88): C 60.94, H 3.90, Cl 8.57, N 3.38, S 7.75; found: C 60.81, H
3.79, Cl 8.29, N 3.38, S 7.97.
5.3. 6-exo-{[(4-Chlorophenyl)sulfonyl]oxy}-2,2-dimethyl-3-endo-(methylsulfanyl)-5-phenyl-4-thia-
1-azabicyclo[3.2.0]heptan-7-one (¼2,2-Dimethyl-3-endo-(methylsulfanyl)-7-oxo-5-phenyl-4-thia-1-aza-
bicyclo[3.2.0]hept-6-yl 4-Chlorobenzenesulfonate; endo-17a) and 6-exo-{[(4-Chlorophenyl)sulfony-

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l]oxy}-2,2-dimethyl-3-exo-(methylsulfanyl)-5-phenyl-4-thia-1-azabicyclo[3.2.0]heptan-7-one (exo-17a).
Into a soln. of the diastereoisomer mixture of 16 (139 mg, 0.47 mmol) in CH2Cl2 (5 ml) at 08, Et3N
(95 mg, 0.94 mmol) was added. After 10 min, a soln. of (4-chlorophenyl)sulfonyl chloride (149 mg,
0.705 mmol) in CH2Cl2 (1 ml) was added dropwise. The mixture was maintained at r.t. overnight; then,
CH2Cl2 (30 ml) was added. The soln. was washed with brine, dried (Na2SO4), filtered, and concentrated
i.v. The residue, after purification by CC (hexane/Et2O 15 :1), afforded 197 mg (90%) of 17 as a 2 :1
mixture of diastereoisomers. Prep. TLC provided endo-17a and exo-17a in pure form.
Data of endo-17a. White crystals. M.p. 122 – 1238. IR: 1785s, 1590w, 1480w, 1385m, 1270m, 1190m,
1180m, 1090m, 990w, 890m, 825m, 700m, 650m. 1H-NMR: 7.5 – 7.3 (m, 9 arom. H); 5.84 (s, HꢀC(6)); 4.53
(s, HꢀC(3)); 2.26 (s, MeS); 1.89 (s, endo-MeꢀC(2)); 1.20 (s, exo-MeꢀC(2)). 13C-NMR: 166.4 (s, C¼O);
140.7, 136.6, 134.1 (3s, 3 arom. C); 129.4, 129.0, 128.5, 128.1, 126.4 (5d, 9 arom. CH); 87.4 (d, C(6)); 80.6 (s,
C(5)); 72.9 (d, C(3)); 70.8 (s, C(2)); 27.3, 21.3 (2q, Me2C); 16.7 (q, MeS). CI-MS: 487 (7), 472 (9), 470
(19, [M þ 1]þ), 240 (9), 239 (14), 238 (100), 145 (6). Anal. calc. for C20H20ClNO4S3 (470.03): C 51.11, H
4.29, N 2.98, S 20.46; found: C 51.40, H 4.10, N 3.07, S 20.93.
Data of exo-17a. White crystals. M.p. 131.5 – 132.78. IR: 2980m, 2930w, 1785s, 1590m, 1480m, 1450m,
1400m, 1390m, 1375m, 1275m, 1260m, 1190s, 1180m, 1090s, 1050m, 1000m, 895m, 825m, 700m, 650m,
625m. 1H-NMR: 7.5 – 7.25 (m, 9 arom. H); 5.71 (s, HꢀC(6)); 4.57 (s, HꢀC(3)); 2.27 (s, MeS); 1.81 (s, endo-
MeꢀC(2)); 1.01 (s, exo-MeꢀC(2)). 13C-NMR: 165.1 (s, C¼O); 140.7, 136.1, 134.0 (3s, 3 arom. C); 129.4,
129.0, 128.5, 127.9, 126.5 (5d, 9 arom. CH); 88.2 (d, C(6)); 79.1 (s, C(5)); 70.9 (d, C(3)); 69.1 (s, C(2));
25.3, 22.1 (2q, Me2C); 17.3 (q, MeS). CI-MS: 491 (6), 490 (10), 489 (48), 488 (23), 487 (100, [M þ NH4]þ),
472 (5), 470 (11, [M þ 1]þ).
5.4. 2,2-Dimethyl-3-endo/exo-(methylsulfanyl)-6-exo-{[(2,4-dinitrophenyl)sulfonyl]oxy}-5-phenyl-4-
thia-1-azabicyclo[3.2.0]heptan-7-one (¼2,2-Dimethyl-3-(methylsulfanyl)-7-oxo-5-phenyl-4-thia-1-azabi-
cyclo[3.2.0]hept-6-yl 2,4-Dinitrobenzenesulfonate; 17b). In analogy to Exper. 5.3, from 16 (2 :1 mixture
of 3-endo- and 3-exo-isomers; 267 mg, 0.9 mmol) and (2,4-dinitrophenyl)sulfonyl chloride (360 mg,
1.35 mmol), 410 mg (87%) of 17b were obtained as a 2 :1 mixture of diastereoisomers. Pale yellow foam.
M.p. 55 – 578. IR: 3090w, 3030w, 3010w, 2920w, 1785s, 1610w, 1560s, 1545s, 1450w, 1410m, 1390m, 1375m,
1
1350s, 1270w, 1190s, 1090m, 1050w, 1000w, 980m, 890m, 830m, 700m, 645m, 620m. H-NMR (3-endo/3-
exo-isomers, 2 :1): 8.6 – 8.55 (m, 1 arom. H); 8.5 – 8.4 (m, 1 arom. H); 8.15 – 8.0 (m, 1 arom. H); 7.45 – 7.15
(m, 5 arom. H); 5.98, 5.90 (2s, HꢀC(6)); 4.62, 4.55 (2s, HꢀC(3)); 2.28, 2.27 (2s, MeS); 1.89, 1.82, 1.23, 1.03
(4s, Me2C). 13C-NMR: 165.5, 164.2 (2s, C¼O); 150.3, 147.8, 147.7, 136.2, 135.8, 134.6, 134.4 (7s, 4 arom. C);
132.7, 132.6, 128.7, 128.5, 128.2, 127.9, 127.8, 126.8, 126.4, 126.2, 120.1 (11d, 8 arom. CH); 89.8, 88.9 (2d,
C(6)); 80.4, 78.9 (2s, C(5)); 72.8, 70.9 (2s, C(2)); 71.0, 69.2, (2d, C(3)); 27.2, 22.0, 21.6, 21.2 (4q, Me2C);
17.3, 16.6 (2q, MeS). CI-MS: 545 (17), 544 (23), 543 (100, [M þ NH4]þ), 527 (5), 526 (10, [M þ 1]þ ), 511
(3). Anal. calc. for C20H19N3O8S3 (525.58): C 45.71, H 3.64, N 7.99, S 18.30; found: C 45.86, H 3.74, N 8.18,
S 18.09.
6. Substitution Reaction of 14 with Azides. 6.1. cis-3-Azido-1,4-diphenylazetidin-2-one (cis-15) [24b].
A mixture of trans-14 (100 mg, 0.24 mmol) and NaN3 (156 mg, 2.4 mmol) in DMF (5 ml) was heated to
558 for 1 d. Then, AcOEt (30 ml) and brine (10 ml) were added. The aq. phase was extracted with AcOEt
(3 ꢁ 10 ml). The combined org. phase was dried (Na2SO4), filtered, and concentrated in vacuo. The
residue, after purification by CC (hexane/Et2O 20 :1), furnished 53 mg (82%) of cis-15. White crystals.
M.p. 130 – 1318 ([24b]: 132 – 1348). IR: 2120s, 1760s, 1600w, 1500m, 1385m, 1135m, 700w. 1H-NMR: 7.35 –
7.3 ( m, 3 arom. H); 7.3 – 7.2 (m, 6 arom. H); 7.05 – 7.0 (m, 1 arom. H); 5.26 (d, J ¼ 5.4, HꢀC(3)); 4.97 (d,
J ¼ 5.4, HꢀC(4)). 13C-NMR: 161.4 (s, C¼O); 136.0, 132.4 (2s, 2 arom. C); 129.1, 129.0, 128.8, 127.4, 124.7,
117.4 (6d, 10 arom. CH); 67.3 (d, C(3)); 60.6 (d, C(4)). CI-MS: 283 (14), 282 (100, [M þ NH4]þ), 265 (3,
[M þ 1]þ), 254 (31), 237 (12). Anal. calc. for C15H12N4O (264.29): C 68.17, H 4.58, N 21.20; found: C
68.26, H 4.38, N 20.93.
6.2. trans-3-Azido-1,4-diphenylazetidin-2-one (trans-15). a) In analogy to Exper. 6.1, from cis-14
(166 mg, 0.4 mmol) and NaN3 (260 mg, 4 mmol), 92 mg (87%) of trans-15 were obtained. Colorless oil
([24b]: m.p. 81 – 838). IR: 3060w, 3030w, 3005w, 2920w, 2115s, 1760s, 1600s, 1500s, 1490s, 1455m, 1380s,
1355m, 1330m, 1320m, 1300m, 1280m, 1260m, 1145s, 1105w, 1090w, 1080w, 1030w, 990w, 900w, 850m, 700s,
690s, 630w, 605m. 1H-NMR: 7.45 – 7.25 (m, 9 arom. H); 7.15 – 7.05 (m, 1 arom. H); 4.88 (d, J ¼ 2.1,
HꢀC(3)); 4.52 (d, J ¼ 2.1, HꢀC(4)). 13C-NMR: 161.3 (s, C¼O); 136.6, 135.2 (2s, 2 arom. C); 129.3, 129.2,

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129.1, 125.9, 124.6, 117.4 (6d, 10 arom. CH); 72.3 (d, C(3)); 62.8 (d, C(4)). CI-MS: 299 (100, [M þ 1 þ 2
NH3]þ), 282 (73, [M þ NH4]þ), 271 (39), 265 (2, [M þ 1]þ), 254 (27), 237 (8). Anal. calc. for C15H12N4O
(264.29): C 68.17, H 4.58, N 21.20; found: C 68.18, H 4.67, N 20.95.
b) In analogy to Exper. 6.1, from cis-14 (83 mg, 0.2 mmol) and LiN3 (98 mg, 2 mmol), 52 mg (98%)
of trans-15 were obtained.
7. Attempted Substitution Reactions of 17. In analogy to Exper. 6, the mixture of diastereoisomers 17a
(ca. 0.3 mmol) and NaN3 (ca. 3 mmol) in DMF (5 ml) was heated to 50 – 608. After usual workup, only
starting material was recovered. Under similar conditions, reactions with 17b and 17c were also not
successful, and, in addition to starting material, significant amounts of 2a were isolated.
8. X-Ray Crystal-Structure Determinations of endo-6a, 7b, 9, and exo-16 (see Table and Figs. 1 – 3)8).
The measurements for compounds endo-6a, 7b, and 9 were conducted on a Nicolet R3 diffractometer,
those for compound exo-16 on a Rigaku AFC5R diffractometer and a 12-kW rotating anode generator,
using graphite-monochromated MoKa radiation (l ¼ 0.71073 ꢅ). The intensities were corrected for
Lorentz and polarization effects, but not for absorption. In all cases, equivalent reflections were merged.
Data collection and refinement parameters are given in the Table. The structures were solved by direct
methods using SHELXS86 [34], which revealed the positions of all non-H-atoms. The non-H-atoms were
refined anisotropically. In the cases of 9 and exo-16, the H-atom of the NH and OH group, resp., were
placed in the positions indicated by a difference electron-density map, and their positions were allowed to
refine together with an isotropic displacement parameter. All other H-atoms in all structures were placed
in geometrically calculated positions and refined by using a riding model where each H-atom was
assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its parent atom (1.5 Ueq
for the Me groups). The refinement of each structure was carried out on F2 using full-matrix least-
squares procedures, which minimized the function Sw(F2o – Fc2 )2. A correction for secondary extinction
was not applied. One reflection, whose intensity was considered to be an extreme outlier, was omitted
from the final refinement of the structure of endo-6a.
Neutral-atom scattering factors for non-H-atoms were taken from [35a], and the scattering factors
for H-atoms were taken from [36]. Anomalous dispersion effects were included in Fc [37]; the values for
f’ and f’’ were those of [35b]. The values of the mass-attenuation coefficients are those of [35c]. All
calculations were performed using the SHELXL97 [38] program.
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Received April 19, 2013