Mixed carboxylic-sulfonic anhydride in reaction with imines: A straightforward route to water-soluble β-lactams via a Staudinger-type reaction

Article abstract of DOI:10.1039/c8ob00768c

The first example of employing a mixed carboxylic-sulfonic anhydride in reaction with imines is reported. Unlike its well-studied isostere homophthalic anhydride, benzo[c][1,2]oxathiin-3(4H)-one 1,1-dioxide gave no product of a formal [4 + 2] cycloaddition and only followed an alternative reaction pathway toward β-lactams, presumably, via a formal [2 + 2] cycloaddition (a Staudinger-type reaction). Optimized reaction conditions involve the use of triethylamine as a base promoter, which also allows isolating the product β-lactam benzene sulfonic acids as respective triethylammonium salts by conventional column chromatography. The reaction shows some preference to trans-isomer formation; pure diastereomers can be isolated in some cases.

Full text of DOI:10.1039/c8ob00768c

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Mixed Carboxylic-Sulfonic Anhydride in Reactions with Imines: A
Straightforward Route to Water-Soluble b-Lactams via a Staudinger-Type
Reaction
Olga Bakulina, Dmitry Dar’in and Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
Abstract
The first example of employing a mixed carboxylic-sulfonic anhydride in reactions with imines
is reported. Unlike with its well-studied isostere homophthalic anhydride, benzo[c][1,2]oxathiin-
3(4H)-one 1,1-dioxide gave no product of a formal [4+2] cycloaddition an only followed an
alternative reaction path toward b-lactams, presumably, via a formal [2+2] cycloaddition (a
Staudinger-type reaction). Optimized reaction conditions involve the use of triethylamine as a
base promoter, which also allows isolating the product b-lactam benzene sulfonic acids as
respective triethylammonium salt by conventional column chromatography. The reaction shows
some preference to trans-isomer formation; pure diastereomers can be isolated in some cases.
Introduction
b-Lactams (2-azetidinones) can be confidently regarded as privileged motifs1 in drug design.
Indeed, their successful application in constructing bioactive compounds continue to extend
beyond antibiotics (falling into four major classes - penicillins, cephalosporins, carbapenems and
monobactams)2 and serine b-lactamase inhibitors (exemplified by clavulanic acid, sulbactam and
tazobactam).3 Although the general acceptance of b-lactams as scaffolds for non-antibacterial
drug design was somewhat retarded by a misconception about their chemical reactivity,4 their
recent resurgence in the context of numerous important biological targets is evident. This is
eloquently illustrated by the approved cholesterol-lowering drug ezetimibe (1)5 acting as an
inhibitor of acyl-CoA cholesterol acylatransferase enzyme. The development, in the early 2000s
of this pioneering application of the b-lactam motif to the design of a chemically stable small
molecule drug was accompanied by the discovery of compounds with functional activity against
such targets as tryptase (2 or BMS-363131),6 matrix metalloprotease MMP-9 (3),7 fatty acid
amide hydrolase (4)8 and many others (Figure 1).9
1

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Figure 1. Prominent b-lactam antibiotics, b-lactamase inhibitors and examples of non-
antibacterial b-lactams (1-4).
Perhaps the most popular way of synthesizing b-lactams is the formal [2+2] cycloaddition of
imines (5) with ketene intermediates (6) generated in situ from a-C-H carboxylic acid
derivatives containing a good leaving group at the carbonyl carbon: e. g., acyl chlorides (7). In
the latter case, the process (known as the Staudinger reaction10) is essentially triggered by
elimination of HCl from 7 in the presence of a base promoter, acylation of 5 by a highly reactive
6 thus formed and a closure of the 2-azetidinone ring in zwitter-ionic intermediate 8 yielding b-
lactam 9 (Scheme 1) with two new stereogenic centers.11
Scheme 1. The Staudinger reaction as a popular way of accessing b-lactams 9.
Recently, Knapp and co-workers described an interesting variant of the Staudinger reaction
which was observed on addition of 5% methanolic sodium hydroxide solution to the reaction
2

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mixture containing homophthalic anhydride (HPA) and an imine 5.12 Although the latter
combination, in the absence of any base, is a proven pathway to d-lactams 10 via the so-called
Castagnoli-Cushman reaction13 (involving a 6-exo-dig intramolecular lactone ring opening by a
secondary amino group in the initial Mannich-type adduct 11),14 addition of a base triggered the
intramolecular carboxylate elimination in 11 leading to the formation of highly reactive ketene
intermediate 12 in which the formation of 2-azetidinone via a 4-exo-trig process was a preferred
course of the reaction. This led not only to an intriguing reactivity switch (much in the spirit of
diversity oriented synthesis,15 considering the skeletal divergence between d- an b-lactams
observed in this case) but also provided the first example of an ‘intramolecular’ ketene formation
– the process in which the leaving group on the ketene carbon precursor remained a part of the
product molecule. Due to the intramolecular character of two postulated steps in the latter
transformation (11‰12 and 12‰13), the formation of 13 occurred at low temperature, in
contrast to conventional Staudinger reactions typically requiring prolonged heating (Scheme 2).12
Scheme 2. The Staudinger and the Castagnoli-Cushman reaction between HPA and 5: an
example of diversity-oriented synthesis.
Results and discussion
Inspired by this important result, we were curious to see whether any substantial preference
toward the Staudinger vs. the Castagnoli-Cushman course of the reaction would be displayed
under similar conditions by an isostere of HPA, namely, benzo[c][1,2]oxathiin-3(4H)-one 1,1-
dioxide (14), which is essentially a mixed cyclic carboxylic-sulfonic anhydride. Its preparation
from sodium 2-formylbenzenesulfonate (15) via sultone 1616 had been described (in the context
of subsequent thermolysis reactions)17 and worked rather well in our hands. Sultone 16 was ring-
opened by cyanide anion to give nitrile 17. The latter was hydrolyzed to mixed carboxylic-
3

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sulfonic diacid 18 and cyclodehydrated by SOCl2 to provide the target mixed anhydride 14
(Scheme 3).
Scheme 3. Preparation of mixed carboxylic-sulfonic anhydride 14.
The initial uncatalyzed model reaction of 14 with imine 19a conducted in acetonitrile over 16 h
led to a nearly complete consumption of the starting materials and a formation of a mixture of
multiple products among which one product clearly predominated and was isolated in a pure
form and low yield by repeated column chromatography. Drawing an analogy with the
analogous reaction involving HPA (Scheme 2), we anticipated that the product thus obtained
could have either the b-lactam structure (20a) or be indeed a sultam isostere of the traditional
1
Castagnoli-Cushman d-lactam adducts (20a‰). Although the H and 13C NMR spectra did not
allow assigning the structure to either 20a or 20a‰ unambiguously, it was done based on a clear
heteronuclear correlation between the carbonyl carbon and the ethyl group’s CH2 observed in the
product’s HMBC spectrum (Scheme 4).
Scheme 4. Initial reaction of 14 with an imine (19a).
In our view, this clearly attested to the Staudinger-type reaction pathway being the only favored
course of the reaction of 14 with imines, which can be rationalized by a substantially higher
4

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tendency of the sulfonate anion to act as a leaving group (compared to carboxylate anion in 11)
and to give rise to ketene-type intermediates (similar to 12). Therefore, we set off to improve the
yield of b-lactam product 20a in order to develop a practically sound approach to this new type
of benzenesulfonic acid-containing adducts.
Since the formation of 20a most likely required deprotonation of the a-position in 14 or its initial
Mannich adduct with 19a (analogous to 11), we tried to employ sodium acetate (1.1 equiv.) as a
relatively weak base promoter which, as we had hoped, could also transform 20a to the
respective sodium salt and thus facilitate its isolation. Experiments with AcONa were conducted
in parallel in different solvents (DMF, toluene, chlorobenzene, 1,2-dichloroethane, ethyl acetate,
THF and methyl tert-butyl ether. The crude reaction mixtures were concentrated and analyzed by
1H NMR. Although no noticeable improvement compared to the uncatalyzed reaction was
observed, the screening of solvents revealed that the use of THF markedly suppressed by-
product formation and led to the cleanest crude reaction mixture of all with respect to target
compound 20a. Further capitalizing on this finding, we performed subsequent reactions in THF
and employed triethylamine as a stronger base. To our delight, it not only improved the yield of
20a but also permitted convenient isolation of the respective triethylammonium salts of the
product sulfonic acid by column chromatography on silica gel. Several manipulations with the
reaction’s temperature regimen showed that the best isolated yield (66%) of 20a was obtained
after column chromatography when the reaction started at 0 ºC, gradually allowed to warm up to
ambient temperature and continued at that temperature overnight. The only persistent minor
(<5%) by-product observed by 1H NMR (though not isolated characterized) was monoamide 21a
whose formation is fully justified (vide infra) based on the mechanistic understanding of the
reaction. The protocol optimized for the synthesis of 20a was subsequently applied to the
synthesis of other 2-azetidinones (20b-r) studied in this work (Scheme 5).
Scheme 5. Optimized protocol for the synthesis of 2-azetidinones 20a-r.
b-Lactam products 20a-r obtained as triethylammonium salts according to the protocol reported
1
herein are shown in Table 1. H NMR analysis of the crude reaction mixtures prior to product
5

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isolation demonstrated that in the majority of cases (except for 20q-r derived from imines of
aliphatic aldehydes) trans-isomer predominated over cis. The vicinal coupling constant (3J)
between H-3 and H-4 of the 2-azetidinone ring is an established and reliable criterion for relative
stereochemistry assignment in 3,4-disubstituted 2-azetidinones.18-24 It was successfully applied in
our case and further confirmed by a single-crystal X-ray analysis of a representative compound
(trans-20h, see ESI for details). Chromatographic isolation of the products generally either
improved the diastereomeric ratios compared to the initial ones observed in the crude reaction
mixtures or, in some cases, even allowed isolating and characterizing pure trans- and/or cis-
isomers. The isolated yields were generally good, except for two cases 20n and 20o which
provided unexpectedly low yields due to the formation of a complex product mixture (Table 1).
Table 1. b-Lactams synthesized via condensation of 14 with imines 19a-r.
3J (Hz)
trans/cis
1.8/5.6
2.0/5.9
1.7/5.6
2.1/5.7
<1.0/5.5
2.2/5.8
2.0/5.7
2.0/5.5
2.0/5.9
2.2/5.7
2.1/5.7
2.0/5.8
2.1/5.7
2.3/5.6
2.2/ND
Isolated yield,
Entry
R1
R2
dra
b
%
1
2
20a
20b
20c
20d
20e
20f
p-Tol
p-Tol
Et
PMB
5:1
trans
5.8:1
2:1
66 (7.7:1)
78 (trans)
63 (9:1)
58c
3
4-MeOC6H4
4-FC6H4
Me
4
cyclohexyl
n-Bu
5
3,4-(MeO)2C6H3
2-MeOC6H4
4-ClC6H4
4.6:1
7.5:1
4.5:1
2.3:1
1.8:1
8:1
64 (5:1)
65 (8.5:1)
50 (10:1)
51d ,e
6
Bn
07
8
20g
20h
20i
n-Pr
4-O2NC6H4
4-MeO2CC6H4
4-MeOC6H4
3-O2NC6H4
3-BnOC6H4
2-thienyl
n-Pr
9
i-Pr
60f
10
11
12
13
14
15
20j
CH2CO2Me
Me
66 (trans)
50% (4:1)g
64 (trans)
59 (trans)
21 (trans)
29 (trans)
20k
20l
2:1
(2-furyl)CH2
cyclopropyl
PMB
4.3:1
8:1
20m
20n
20o
5-nitrofur-2-yl
3-thienyl
9:1
(pyrid-3-yl)CH2
trans
6

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16
17
18
20p
20q
20r
pyrid-3-yl
n-Pr
cyclohexyl
n-Bu
2.2:1
1.9/5.6
2.1/5.4
2.2:5.6
61 (2.8:1)h
64i
Et
1:1.8
1:1.6
i-Pr
48 (1:1.1)
1
b
aDiastereomeric ratio (trans/cis) in reaction mixture (determined by crude H NMR). The dr of
isolated products is given in parentheses. cA 6:1 trans/cis mixture (48%) and the pure cis-isomer
(10%) were isolated by column chromatography. The pure trans-isomer (39%) and a 1:8
trans/cis mixture (12%) were isolated by column chromatography. Structure of trans-20h was
confirmed by single-crystal X-ray analysis. The pure trans-isomer (26%) and a 1:1.1 trans/cis
mixture (34%) were isolated by column chromatography. The pure trans-isomer (30%) was
isolated by column chromatography and characterized. The pure cis- (10%) and trans- (28%)
isomers were isolated after repeated column chromatography. The pure cis-isomer (30%) and a
d
e
f
g
h
i
8:1 trans/cis mixture (11%) were isolated by column chromatography.
Quite surprising was also our inability to obtain any b-lactam product from reactions of 14 with
imines derived from aromatic amines. This however, can be given the following explanation
from the mechanistic standpoint. Obviously, the reduced reactivity of the N-aryl imines in
reaction with 14 implies that interaction of the imine nitrogen atom with an electrophilic entity is
critically important for the formation of b-lactam product. Considering the much higher
reactivity of the carbonyl group of 14 compared to the analogous functionality in HPA, it is not
illogical to suppose that the interaction of 14 with the imine via direct imine acylation25 could be
the first, triggering event en route to the b-lactam product 20. N-acylation of the imine will likely
facilitate the a-deprotonation of the phenacetyl component in putative N-acyl iminium
intermediate 22 with triethylamine or, in case of the less productive uncatalyzed reaction (vide
supra), by the weakly basic unreacted imine. a-Deprotonation, in turn, inevitably leads to the
closure of the 2-azetinone ring and provides 20, which may even occur in a concerted fashion
with a-deprotonation. Of course, the postulated highly electrophilic 22 could also rapidly react
with any adventitious water and this would give the observed minor carboxamide by-product 21
(Scheme 6). It should be noted that performing reaction in presence of 4Ö molecular sieves
failed to suppress the formation of 21.
Scheme 6. Proposed mechanism for the formation of 20 in the reaction of 14 an 19.
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The proposed mechanism appears to be fully consistent with the experimental observations. At
the same time, if we consider the mechanism shown in Scheme 2 for an analogous reaction of
HPA, it would not fully justify the observed inertness of N-aryl imines in the triethylamine-
promoted reaction with 14. Indeed, the secondary amino group in 11 (or its hypothetical sulfa-
analog), even bearing an aryl substituent, is very likely to be acylated by ketene since even
intermolecular reactions of anilines with ketenes are known to proceed quite well.26 At the same
time, we cannot completely rule out the possibility that introduction of aryl substituents at the
imine nitrogen atom could be detrimental to b-lactam formation because it retards subsequent
acylation of the same nitrogen atom by a ketene moiety (using the HPA analogy shown in
Scheme 2). Although the proposed formation of 20 via the direct imine acylation/intramolecular
Mannich ring closure does not involve the formation of a ketene intermediate the net result of
this transformation (despite the proposed reversed order of events, which is also a subject of
ongoing debate27) is the Staudinger-type, formal [2+2] cycloaddition reaction of an imine 19
with 14 (a reactive equivalent of a ketene) which yields b-lactam 20.
Poor aqueous solubility is a major issue that hinders drug development28 and necessitates
invention of costly drug delivery strategies.29 Unfortunately, this problem has also affected the
field of b-lactam antibiotics: recent examples include cephalosporins ceftobiprole30 and
ceftaroline31 both of which are approved for clinical use and are administered as prodrugs due to
extremely low solubility of the principal active component. The triethylammonium sulfonate-
bearing b-lactams 20 synthesized in this work are essentially free from any solubility issues.
Besides being distinctly well-soluble in organic solvents (such as methanol, chloroform,
acetonitrile), compounds 20a-r all display excellent solubility in aqueous medium (estimated to
be >500 mM). This is, most likely, a consequence of them containing the triethylammmoniun
sulfonate moiety, a unique feature resulting from the use of 14 in the reaction with imines.
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Besides being the guarantor of high aqueous solubility of b-lactams 20, the benzenesulfonate
moiety can be transformed into the respective sulfonyl chloride and subsequently, to various
sulfonamides, which constitute an important class of pharmacophores.32 To illustrate this
possibility, we converted a representation product 20b (obtained as a pure trans-isomer) into
respective sulfonyl chloride 23 which, without further purification, was split into three equal
portions and reacted with ammonia, a primary and a secondary amine providing the respective
primary, secondary and tertiary sulfonamides 24a-c in good yields over two steps (Scheme 7).
Scheme 7. Transformation of compound 20b into sulfonyl chloride 23 and a series of
sulfonamides 24a-c.
Conclusions
In summary, we have investigated, for the first time, the use of a mixed carboxylic-sulfonic
anhydride in base-promoted reaction with imines. The reaction was shown to follow the only
productive course both in uncatalyzed and based-promoted format, namely, providing a product
of a Staudinger-type formal [2+2] cycloaddition between the anhydride and imine partners. The
use of triethylamine as a base not only gave a clean and high-yielding conversion into product b-
lactam bearing a triethylammonium benzenesulfonate moiety, it also enabled straightforward
purification of the latter by conventional column chromatography. The newly established variant
of a Staudinger-type reaction was found to work only for N-alkyl imines and to fail for N-aryl
counterparts, which was justified by a propose reaction mechanism. The presence of a unique
triethylammonium benzenesulfonate moiety in the b-lactam products thus obtained not only
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endows them with a marked aqueous solubility but also provides a reactive handle for
introducing various sulfonamides, which are important pharmacophoric groups from drug design
perspective. The medicinal chemistry potential of the new water-soluble b-lactams is currently
investigated in our laboratories and will be reported in due course.
Experimental
General information. NMR spectroscopic data were recorded with a 400 MHz spectrometer
(400.13 MHz for 1H and 100.61 MHz for 13C) in CDCl3 and in DMSO-d6 and were referenced to
residual solvent proton signals (/H = 7.26 and 2.50 ppm, respectively) and solvent carbon signals
(/C = 77.0 and 39.5 ppm, respectively). Melting points were determined with a Melting Point
Apparatus in open capillary tubes. Mass spectra were recorded with a HRMS-ESI-qTOF
spectrometer (electrospray ionization mode). Chlorobenzene was distilled over P2O5 and stored
over molecular sieves 4Å. Imines 19a-p,r were prepared from corresponding aldehydes and
amines by stirring with anhydrous MgSO4 at room temperature in DCM for 24-48 h and
subsequent concentration in vacuo. Imine 19q was prepared according to known procedure.33 All
imines 19 and anhydride 14 were stored at 5 °C in darkness.
Preparation of anhydride 14
3H-Benzo[c][1,2]oxathiole 1,1-dioxide (16). Sultone 16 was prepared from 15 in 2 steps
according to literature procedures.16 To a mixture of sodium 2-formylbenzenesulfonate
monohydrate 15 (34.0 g, 0.15 mol) and phosphorus pentachloride (34.0 g, 0.16 mol) phosphorus
oxychloride (30 mL, 0.32 mol) was slowly added. After initial vigorous reaction (HCl
evolution!) the mixture was stirred at 120 °C for 1 hour. The excess of POCl3 was removed
under reduced pressure and the solidified residue was triturated with crashed ice (300 g). After
stirring for 30 min in ice water the white crystals were filtered off, washed with water (2× 100
mL) and dried in air to give 32 g of 3-chloro-3H-benzo[c][1,2]oxathiole 1,1-dioxide which was
1
used in the next step without purification. H NMR (400 MHz, CDCl3) / 7.92 – 7.80 (m, 2H),
7.75 (td, J = 7.6, 1.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H).
To a stirred mixture of substance obtained in previous step (20.0 g), zinc dust (30.0 g) and
diethyl ether (230 mL) conc. aq. HCl was added dropwise at such a rate that the mixture slightly
boiled. After approximately 30 min (when TLC showed the full consumption of starting
material) the mixture was filtered through a pad of Celite, washed with ether (2×80 mL) and
evaporated. The obtained light yellow oil was triturated with cold water (250 mL), the crystals
formed were filtered, washed with water (150 mL) and n-hexane (100 mL) and dried in air to
afford 13.4 g pure title compound 16 (84% over 2 steps). 1H NMR (400 MHz, CDCl3) / 7.86 (d,
J = 7.8 Hz, 1H), 7.73 (td, J = 7.6, 1.1 Hz, 1H), 7.63 (td, J = 7.6, 1.0 Hz, 1H), 7.45 (dt, J = 7.7,
1.0 Hz, 1H), 5.55 (s, 2H). 13C NMR (101 MHz, CDCl3) / 135.2, 133.7, 131.7, 130.0, 123.3,
121.9, 71.1.
Sodium 2-(cyanomethyl)benzenesulfonate (17). Anhydride 14 was prepared from sultone 16
via intermediates 17 and 18 according to modified literature procedures.17 To a stirred solution of
sodium cyanide (3.7 g, 0.075 mol) in water (38 mL) a solution of sultone 16 (12.5 g, 0.073 mol)
in ethanol (400 mL) was added within 20 min. The mixture was refluxed for 4 hours. The
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solvents were removed in vacuo, the residue was refluxed with 60 mL of acetonitrile, cooled in
ice and the precipitated white crystals were filtered off and dried in air to give 11.6 g (72%) of
compound (17). 1H NMR (400 MHz, DMSO-d6) / 7.80 (dd, J = 7.6, 1.5 Hz, 1H), 7.48 – 7.37 (m,
2H), 7.32 (td, J = 7.4, 1.7 Hz, 1H), 4.37 (s, 2H). 13C NMR (101 MHz, DMSO-d6) / 134.5, 133.0,
130.5, 127.3, 127.0, 124.8, 119.4, 23.6.
2-(2-Sulfophenyl)acetic acid (18). To a solution of substance from previous step (2.8 g, 0.013
mol) in water (25 ml) conc. aq. HCl (25 mL) was added and the mixture was refluxed for 1 hour.
After cooling to ambient temperature the resulting mixture was filtered through a pad of Celite
and evaporated to dryness. The residue was dissolved in water (20 mL) and passed through a
column with Amberlyst(H) ion exchange resin. The collected fractions with product (detected by
pH) were evaporated at in vacuo and the resulting crude material was recrystallized from
1
acetonitrile to give 1.88 g (68%) of compound 18; mp 149–152 °C (MeCN). H NMR (400
MHz, DMSO-d6) / 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.33 (td, J = 7.2, 1.5 Hz, 1H), 7.31 – 7.14 (m,
2H), 4.03 (s, 2H). 13C NMR (101 MHz, DMSO-d6) / 172.5, 146.0, 132.5, 131.7, 129.6, 127.0,
126.7, 39.4.
Benzo[c][1,2]oxathiin-3(4H)-one 1,1-dioxide (14). Thionyl chloride (30 mL) was added to 2-
(2-sulfophenyl)acetic acid (864 mg, 4.0 mmol) and the mixture was stirred under reflux for 1
hour. After cooling to ambient temperature the clear yellow solution was decanted from small
amount of dark oil and evaporated to dryness under reduced pressure at 30–35 °C. The
crystalline residue was triturated with n-hexane (25 mL), filtered and dried in vacuo to give 650
1
mg (82%) of anhydride 14; mp 150–153 °C (decomp.). H NMR (400 MHz, CDCl3) / 8.03 (dd,
J = 7.8, 1.3 Hz, 1H), 7.73 (td, J = 7.6, 1.4 Hz, 1H), 7.69 – 7.56 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H),
4.28 (s, 2H). 13C NMR (101 MHz, CDCl3) / 160.9, 134.6, 133.6, 129.3, 129.0, 128.9, 125.0,
37.0.
General procedure for preparation of ꢀ-lactams 20. To an ice cooled solution of appropriate
imine 19 (0.5 mmol) in absolute THF (2 mL) anhydride 14 (99 mg, 0.5 mmol) was added. After
stirring for 5 min triethyl amine (56 mg, 0.55 mmol) was added and the mixture was stirred for
30 min in ice-bath and then at ambient temperature for overnight. The solvent was removed in
vacuo and the resulting crude material was subjected to column chromatography on silica gel.
2-(trans/cis-1-Ethyl-2-oxo-4-(p-tolyl)azetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20a). ?luent for chromatography EtOAc/MeOH/Et3N (80 :
15 : 5); mield 147 mg (66%), dr 7.7:1; colorless amorphous solid. 1H NMR (400 MHz, CDCl3) of
major trans-isomer / 10.00 (br.s, 1H), 8.05 (dd, J = 7.7, 1.0 Hz, 1H), 7.47 (dd, J = 7.7, 1.5 Hz,
1H), 7.45 – 7.40 (m, 1H), 7.32 – 7.27 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H),
5.47 (d, J = 1.3 Hz, 1H), 4.52 (d, J = 1.8 Hz, 1H), 3.63 (dq, J = 14.7, 7.4 Hz, 1H), 2.95 (qd, J =
7.3, 4.8 Hz, 6H), 2.94 – 2.87 (m, 1H), 2.33 (s, 3H), 1.18 (t, J = 7.4 Hz, 9H). 13C NMR (101
MHz, CDCl3) of major trans-isomer / 169.3, 144.2, 137.8, 134.7, 133.6, 130.6, 129.2, 127.8,
127.3, 127.2, 127.1, 64.1, 60.7, 46.0, 35.0, 21.2, 13.2, 8.5. HRMS m/z [M–H]– calcd for
C18H18NO4S 344.0962, found 344.0968.
2-(trans-1-(4-Methoxybenzyl)-2-oxo-4-(p-tolyl)azetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans-20b). The titled compound was filtered after precipitation from
1
reaction mixture; yield 210 mg (78%); colorless solid, mp 162–164 °C (EtOAc). H NMR (400
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MHz, DMSO-d6) / 8.89 (br.s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.33 (td, J = 7.5, 1.5 Hz, 1H),
7.23 (td, J = 7.5, 1.3 Hz, 1H), 7.19 – 7.11 (m, 7H), 6.92 (d, J = 8.7 Hz, 2H), 5.51 (d, J = 2.0 Hz,
1H), 4.69 (d, J = 15.1 Hz, 1H), 4.19 (d, J = 2.1 Hz, 1H), 3.75 (s, 3H), 3.71 (d, J = 15.1 Hz, 1H),
3.08 (q, J = 7.3 Hz, 6H), 2.32 (s, 3H), 1.16 (t, J = 7.3 Hz, 9H). 13C NMR (101 MHz, DMSO-d6)
/ 169.0, 159.0, 147.4, 137.5, 134.9, 134.0, 129.9, 129.6, 129.5, 128.8, 127.6, 127.32, 127.26,
126.9, 114.5, 64.5, 60.4, 55.5, 46.2, 43.6, 21.2, 9.1. HRMS m/z [M–H]– calcd for C24H22NO5S
436.1224, found 436.1215.
2-(trans/cis-2-(4-Methoxyphenyl)-1-methyl-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20c). Eluent for chromatography EtOAc/MeOH/Et3N (75 : 20
1
: 5); yield 112 mg (63%), dr 9:1; colorless amorphous solid. H NMR (400 MHz, CDCl3) of
major trans-isomer / 10.10 (br.s, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.47 (dd, J = 7.5, 0.9 Hz, 1H),
7.43 (t, J = 7.4 Hz, 1H), 7.34 – 7.27 (m, 3H), 6.89 (d, J = 8.5 Hz, 2H), 5.48 (s, 1H), 4.42 (d, J =
1.7 Hz, 1H), 3.80 (s, 3H), 3.05 – 2.95 (br.m, 6H), 2.83 (s, 3H), 1.21 (br.t, J = 6.2 Hz, 9H). 13C
NMR (101 MHz, CDCl3) of major trans-isomer / 169.7, 159.5, 144.2, 133.5, 130.5, 129.4,
128.5, 127.8, 127.6, 127.1, 114.0, 66.1, 61.7, 55.3, 46.1, 26.7, 8.7. HRMS m/z [M–H]– calcd for
C17H16NO5S 346.0755, found 346.0736.
2-(trans/cis-1-Cyclohexyl-2-(4-fluorophenyl)-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20d). Eluent for chromatography EtOAc/MeOH/Et3N (80 :
15 : 5); first was isolated trans/cis-20d mixture (dr 6:1), yield 96 mg (48%); colorless
1
amorphous solid. H NMR (400 MHz, CDCl3) of major trans-isomer / 10.11 (br.s, 1H), 8.06 –
8.01 (m, 1H), 7.46 – 7.38 (m, 4H), 7.33 – 7.27 (m, 1H), 7.03 (t, J = 8.7 Hz, 2H), 5.41 (d, J = 2.1
Hz, 1H), 4.49 (d, J = 2.1 Hz, 1H), 3.51 – 3.44 (m, 1H), 2.99 (qd, J = 7.3, 4.8 Hz, 6H), 2.10 –
2.02 (m, 1H), 1.83 – 1.53 (m, 6H), 1.21 (t, J = 7.3 Hz, 9H), 1.32 – 1.06 (m, 4H). 13C NMR (101
MHz, CDCl3) of major trans-isomer / 169.3, 162.5 (d, J = 245.9 Hz), 144.2, 135.1 (d, J = 3.1
Hz), 133.6, 130.6, 129.1 (d, J = 8.2 Hz), 127.7, 127.2, 127.1, 115.3 (d, J = 21.5 Hz), 63.4, 60.4,
52.9, 46.1, 31.5, 31.1, 25.22, 25.20, 25.0, 8.5. HRMS m/z [M–H]– calcd for C21H21FNO4S
402.1170, found 402.1156.
2-(cis-1-Cyclohexyl-2-(4-fluorophenyl)-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (cis-20d). Next was isolated cis-20d, yield 21 mg (10%); colorless
solid, mp 142–144 °C. 1H NMR (400 MHz, CDCl3) / 10.33 (br.s, 1H), 7.75 (d, J = 7.3 Hz, 1H),
7.34 – 7.25 (m, 4H), 7.17 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.75 (t, J = 8.7 Hz, 2H),
5.87 (d, J = 5.7 Hz, 1H), 5.30 (d, J = 5.7 Hz, 1H), 3.58 – 3.45 (m, 1H), 3.16 – 3.02 (br.m, 6H),
2.17 – 2.08 (m, 1H), 1.94 – 1.86 (m, 1H), 1.85 – 1.67 (m, 3H), 1.63 – 1.57 (m, 1H), 1.31 (t, J =
6.7 Hz, 9H), 1.36 – 1.08 (m, 4H). 13C NMR (101 MHz, CDCl3) / 169.2, 161.9 (d, J = 245.0 Hz),
143.8, 132.3 (d, J = 2.9 Hz), 130.9, 130.6, 129.9 (d, J = 8.1 Hz), 129.4, 126.87, 126.85, 114.1 (d,
J = 21.3 Hz), 59.7, 58.4, 53.3, 46.3, 31.5, 30.8, 25.31, 25.29, 25.1, 8.7. HRMS m/z [M–H]– calcd
for C21H21FNO4S 402.1170, found 402.1160.
2-(trans/cis-1-Butyl-2-(3,4-dimethoxyphenyl)-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20e). Eluent for chromatography EtOAc/MeOH/Et3N (75 : 20
1
: 5); yield 133 mg (64%), dr 5:1; pale yellow amorphous solid. H NMR (400 MHz, CDCl3) of
major trans-isomer / 10.07 (br.s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.31 (d, J =
6.3 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 5.48 (s, 1H), 4.46 (s, 1H), 3.88 (s,
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3H), 3.87 (s, 3H), 3.66 – 3.55 (m, 1H), 2.98 (br.s, 6H), 2.91 – 2.82 (m, 1H), 1.59 – 1.50 (m, 2H),
1.44 – 1.34 (m, 2H), 1.21 (br.s, 9H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) of
major trans-isomer / 169.6, 149.0, 148.8, 144.2, 133.6, 130.6, 130.3, 127.8, 127.4, 127.2, 119.6,
111.1, 110.5, 64.9, 60.8, 56.1, 55.9, 46.2, 40.0, 30.0, 20.3, 13.6, 8.6. HRMS m/z [M–H]– calcd
for C21H24NO6S 418.1330, found 418.1336.
2-(trans/cis-1-Benzyl-2-(2-methoxyphenyl)-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20f). Eluent for chromatography EtOAc/MeOH/Et3N (75 : 20
1
: 5); yield 137 mg (65%), dr 8.5:1; colorless amorphous solid. H NMR (400 MHz, CDCl3) of
major trans-isomer / 10.22 (br.s, 1H), 8.06 – 8.03 (m, 1H), 7.39 – 7.29 (m, 6H), 7.28 – 7.22 (m,
4H), 6.95 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 5.75 (d, J = 2.2 Hz, 8H), 4.88 (d, J = 15.0
Hz, 1H), 4.86 (d, J = 2.1 Hz, 1H), 3.87 (d, J = 15.0 Hz, 1H), 3.64 (s, 3H), 2.99 (qd, J = 7.3, 4.8
13
Hz, 6H), 1.21 (t, J = 7.3 Hz, 9H). C NMR (101 MHz, CDCl3) of major trans-isomer / 170.1,
158.3, 144.3, 136.4, 133.9, 130.4, 129.2, 128.5, 128.0, 127.7, 127.5, 127.4, 126.8, 125.4, 120.6,
111.0, 59.7, 58.8, 55.6, 46.1, 44.7, 8.5. HRMS m/z [M–H]– calcd for C23H20NO5S 422.1068,
found 422.1060.
2-(trans/cis-2-(4-Chlorophenyl)-4-oxo-1-propylazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20g). Eluent for chromatography EtOAc/MeOH/Et3N (80 :
1
15 : 5); yield 97 mg (50%), dr 10:1; colorless amorphous solid. H NMR (400 MHz, CDCl3) of
major trans-isomer / 10.10 (br.s, 1H), 8.05 (dd, J = 7.8, 1.3 Hz, 1H), 7.50 (dd, J = 7.7, 1.4 Hz,
1H), 7.44 (td, J = 7.5, 1.4 Hz, 1H), 7.38 – 7.29 (m, 5H), 5.45 (d, J = 1.6 Hz, 1H), 4.46 (d, J = 2.0
Hz, 1H), 3.55 (dt, J = 14.0, 7.7 Hz, 1H), 2.98 (qd, J = 7.3, 4.8 Hz, 6H), 2.80 (ddd, J = 14.1, 7.5,
5.8 Hz, 1H), 1.62 – 1.49 (m, 2H), 1.21 (t, J = 7.3 Hz, 9H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3) of major trans-isomer / 169.3, 144.0, 136.5, 133.7, 133.3, 130.7, 128.9,
128.6, 127.8, 127.4, 127.3, 64.2, 61.3, 46.1, 42.0, 21.2, 11.6, 8.5. HRMS m/z [M–H]– calcd for
C18H17ClNO4S 378.0572, found 378.0581.
2-(trans-2-(4-Nitrophenyl)-4-oxo-1-propylazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans-20h). Eluent for chromatography EtOAc/MeOH/Et3N (80 : 15 :
1
5); first was isolated trans-20h, yield 77 mg (39%); colorless solid, mp 176–178 °C (EtOAc). H
NMR (400 MHz, CDCl3) / 10.04 (br.s, 1H), 8.22 (d, J = 8.7 Hz, 2H), 8.02 (dd, J = 7.8, 1.3 Hz,
1H), 7.58 (d, J = 8.7 Hz, 2H), 7.52 (dd, J = 7.7, 1.2 Hz, 1H), 7.46 (td, J = 7.5, 1.3 Hz, 1H), 7.34
(td, J = 7.6, 1.3 Hz, 1H), 5.47 (d, J = 1.8 Hz, 1H), 4.56 (d, J = 2.0 Hz, 1H), 3.60 (dt, J = 14.1, 7.7
Hz, 1H), 3.00 (qd, J = 7.3, 4.8 Hz, 6H), 2.88 – 2.77 (m, 1H), 1.64 – 1.47 (m, 2H), 1.21 (t, J = 7.3
Hz, 9H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) / 168.9, 147.7, 145.7, 144.0,
133.0, 130.8, 128.4, 127.6, 127.6, 123.7, 64.0, 61.7, 46.1, 42.3, 21.2, 11.6, 8.5. HRMS m/z [M–
H]– calcd for C18H17N2O6S 389.0802, found 389.0785.
Next was isolated trans/cis-20h mixture (dr 1:8), yield 23 mg (12%); colorless amorphous solid.
1H NMR (400 MHz, CDCl3) of major cis-isomer / 10.26 (br.s, 1H), 7.95 (d, J = 8.8 Hz, 2H),
7.75 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.23 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 (td, J =
7.6, 0.9 Hz, 1H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 6.07 (d, J = 5.4 Hz, 1H), 5.39 (d, J = 5.5 Hz, 1H),
3.71 (dt, J = 13.8, 7.7 Hz, 1H), 3.10 (qd, J = 7.3, 4.9 Hz, 6H), 2.97 (ddd, J = 13.6, 7.6, 5.8 Hz,
1H), 1.68 – 1.55 (m, 2H), 1.32 (t, J = 7.3 Hz, 9H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
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CDCl3) of major cis-isomer / 168.8, 147.1, 143.8, 143.7, 130.2, 130.1, 129.6, 129.0, 127.3,
126.9, 122.7, 60.5, 59.5, 46.2, 42.8, 21.0, 11.6, 8.6. HRMS m/z [M–H]– calcd for C18H17N2O6S
389.0802, found 389.0794.
2-(trans-1-Isopropyl-2-(4-(methoxycarbonyl)phenyl)-4-oxoazetidin-3-yl)-benzenesulfonic
acid triethylammonium salt (trans-20i). Eluent for chromatography EtOAc/MeOH/Et3N (80 :
15 : 5); first was isolated trans-20i, yield 67 mg (26%); colorless solid, mp 157–159 °C (EtOAc);
1H NMR (400 MHz, CDCl3) / 7.99 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3
Hz, 2H), 7.47 – 7.39 (m, 2H), 7.34 – 7.24 (m, 1H), 5.43 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 1.9 Hz,
1H), 3.90 (s, 3H), 3.89 – 3.77 (m, 1H), 2.93 (q, J = 7.3 Hz, 6H), 1.35 (d, J = 6.8 Hz, 3H), 1.15 (t,
J = 7.3 Hz, 9H), 1.04 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) / 169.1, 166.9, 144.8,
144.2, 133.3, 130.6, 129.8, 129.7, 127.7, 127.5, 127.2, 127.2, 63.4, 60.3, 52.1, 46.0, 45.3, 21.4,
20.8, 8.5. HRMS m/z [M–H]– calcd for C20H20NO6S 402.1016, found 402.1025.
1
Next was isolated trans/cis-20i mixture (dr 1:1.1), yield 87 mg (34%); amorphous solid. H
NMR (400 MHz, CDCl3) of cis-isomer / 10.17 (br.s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.73 (dd, J =
7.6, 1.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 (td, J = 7.5, 1.4
Hz, 1H), 7.04 (td, J = 7.6, 1.3 Hz, 1H), 5.94 (d, J = 5.9 Hz, 1H), 5.35 (d, J = 5.9 Hz, 1H), 3.92 –
3.84 (m, 1H), 3.83 (s, 3H), 3.05 (qd, J = 7.3, 4.8 Hz, 6H), 1.42 (d, J = 6.7 Hz, 3H), 1.27 (t, J =
7.3 Hz, 9H), 1.17 (d, J = 6.7 Hz, 3H).
2-(trans-1-(2-Methoxy-2-oxoethyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-
benzenesulfonic acid triethylammonium salt (trans-20j). Eluent for chromatography
EtOAc/MeOH/Et3N (75 : 20 : 5); yield 130 mg (66%); colorless solid, mp 151–153 °C. 1H NMR
(400 MHz, CDCl3) / 9.82 (s, 1H), 8.00 (dd, J = 7.8, 1.4 Hz, 1H), 7.77 (dd, J = 7.8, 1.2 Hz, 1H),
7.46 (td, J = 7.6, 1.5 Hz, 1H), 7.30 – 7.22 (m, 3H), 6.86 (d, J = 8.7 Hz, 2H), 5.64 (d, J = 2.2 Hz,
1H), 4.76 (d, J = 2.3 Hz, 1H), 4.46 (d, J = 18.1 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.45 (d, J =
18.1 Hz, 1H), 2.95 (qd, J = 7.3, 4.4 Hz, 6H), 1.16 (t, J = 7.3 Hz, 9H). 13C NMR (101 MHz,
CDCl3) / 170.0, 168.9, 159.7, 144.4, 133.2, 130.6, 128.7, 128.6, 128.1, 127.5, 127.1, 114.1, 65.1,
61.5, 55.3, 52.4, 46.1, 41.0, 8.5. HRMS m/z [M–H]– calcd for C19H18NO7S 404.0809, found
404.0807.
2-(trans-1-Methyl-2-(3-nitrophenyl)-4-oxoazetidin-3-yl)benzene
sulfonic
acid
triethylammonium salt (trans-20k). Eluent for chromatography EtOAc/MeOH/Et3N (80 : 15 :
5); yield of trans/cis-isomers mixture 92 mg (50%), dr 4:1; yield of trans-20k after additional
1
column chromatography 56 mg (30%); colorless amorphous solid. H NMR (400 MHz, CDCl3)
/ 9.64 (br.s, 1H), 8.20 – 8.17 (m, 1H), 8.12 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.96 (dd, J = 7.8, 1.4
Hz, 1H), 7.70 (dt, J = 7.5, 1.2 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.46 (dd, J = 7.7, 1.4 Hz, 1H),
7.40 (td, J = 7.5, 1.5 Hz, 1H), 7.28 (td, J = 7.5, 1.5 Hz, 1H), 5.45 (dd, J = 2.1, 1.0 Hz, 1H), 4.48
(d, J = 2.1 Hz, 1H), 2.96 (q, J = 7.3 Hz, 6H), 2.84 (d, J = 0.9 Hz, 3H), 1.15 (t, J = 7.3 Hz, 9H).
13C NMR (101 MHz, CDCl3) / 169.1, 148.3, 144.2, 140.1, 133.8, 132.8, 130.6, 129.6, 127.7,
127.5, 127.5, 123.1, 122.1, 65.6, 62.3, 46.2, 27.0, 8.5. HRMS m/z [M–H]– calcd for
C16H13N2O6S 361.0500, found 361.0499.
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2-(trans-2-(3-(Benzyloxy)phenyl)-1-(furan-2-ylmethyl)-4-oxoazetidin-3-yl)-benzenesulfonic
acid triethylammonium salt (trans-20l). Eluent for chromatography EtOAc/MeOH/Et3N (80 :
1
15 : 5); yield 189 mg (64%); colorless amorphous solid. H NMR (400 MHz, CDCl3) / 10.0
(br.s, 1H), 8.2 – 8.0 (m, 1H), 7.5 – 7.4 (m, 2H), 7.4 – 7.4 (m, 5H), 7.4 – 7.3 (m, 1H), 7.3 – 7.2
(m, 2H), 7.0 – 6.9 (m, 2H), 6.9 – 6.8 (m, 1H), 6.3 (dd, J = 3.2, 1.8 Hz, 1H), 6.1 (d, J = 3.2 Hz,
1H), 5.6 (d, J = 2.3 Hz, 1H), 5.1 (s, 2H), 4.9 (d, J = 15.8 Hz, 1H), 4.4 (d, J = 2.1 Hz, 1H), 3.9 (d,
J = 15.7 Hz, 1H), 2.9 (q, J = 7.3 Hz, 6H), 1.2 (t, J = 7.3 Hz, 9H). 13C NMR (101 MHz, CDCl3) /
169.3, 158.9, 149.3, 144.3, 142.6, 139.2, 137.0, 133.3, 130.5, 129.6, 128.6, 127.9, 127.8, 127.6,
127.4, 127.1, 119.9, 114.8, 113.5, 110.5, 108.5, 70.0, 64.7, 61.0, 46.0, 37.1, 8.4. HRMS m/z [M–
H]– calcd for C27H24NO6S 488.1173, found 488.1159.
2-(trans-1-Cyclopropyl-2-oxo-4-(thiophen-2-yl)azetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans-20m). Eluent for chromatography EtOAc/MeOH/Et3N (80 : 15 :
1
5); yield 133 mg (59%); colorless solid, mp 134–136 °C. H NMR (400 MHz, CDCl3) / 9.65
(br.s, 1H), 8.09 – 7.92 (m, 1H), 7.37 (td, J = 7.5, 1.4 Hz, 1H), 7.31 – 7.21 (m, 3H), 7.17 (dd, J =
3.6, 1.1 Hz, 1H), 6.95 (dd, J = 5.1, 3.5 Hz, 1H), 5.56 (d, J = 2.1 Hz, 1H), 4.69 (d, J = 2.1 Hz,
1H), 2.96 (qd, J = 7.3, 4.7 Hz, 6H), 1.15 (t, J = 7.3 Hz, 9H), 1.02 – 0.92 (m, 1H), 0.81 – 0.70 (m,
3H), 0.70 – 0.60 (m, 1H). 13C NMR (101 MHz, CDCl3) / 169.6, 144.4, 141.9, 132.9, 130.5,
127.8, 127.3, 127.1, 127.0, 126.8, 125.3, 61.1, 60.5, 46.2, 23.1, 8.6, 5.7, 5.0. HRMS m/z [M–H]–
calcd for C16H14NO4S2 348.0370, found 348.0369.
2-(trans-1-(4-Methoxybenzyl)-2-(5-nitrofuran-2-yl)-4-oxoazetidin-3-yl)-benzenesulfonic
acid triethylammonium salt (trans-20n). Eluent for chromatography EtOAc/MeOH/Et3N (75 :
20 : 5); yield 58 mg (21%); colorless solid, mp 167–169 °C. 1H NMR (400 MHz, CDCl3) / 9.79
(br.s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.45 – 7.36 (m, 2H), 7.33 – 7.29 (m, 1H), 7.20 – 7.09 (m,
3H), 6.85 – 6.76 (m, 2H), 6.62 (d, J = 3.7 Hz, 1H), 5.80 (d, J = 2.3 Hz, 1H), 4.66 (d, J = 14.9 Hz,
1H), 4.38 (d, J = 2.3 Hz, 1H), 4.20 (d, J = 14.7 Hz, 1H), 3.77 (s, 3H), 3.04 (q, J = 7.3 Hz, 6H),
1.24 (t, J = 7.4 Hz, 9H). 13C NMR (101 MHz, CDCl3) / 167.8, 159.3, 155.3, 151.7, 144.2, 132.0,
131.1, 130.7, 129.9, 128.6, 127.7, 127.5, 127.0, 114.1, 113.7, 113.1, 112.8, 58.4, 56.8, 55.3,
46.2, 44.9, 8.5. HRMS m/z [M–H]– calcd for C21H17N2O8S 457.0711, found 457.0729.
2-(trans-2-Oxo-1-(pyridin-3-ylmethyl)-4-(thiophen-3-yl)azetidin-3-yl)-benzenesulfonic acid
triethylammonium salt (trans-20o). Eluent for chromatography EtOAc/MeOH/Et3N (75 : 20 :
1
5); yield 72 mg (29%); colorless amorphous solid. H NMR (400 MHz, DMSO-d6+CDCl3) /
10.42 (br.s, 1H), 8.61 – 8.30 (m, 2H), 7.93 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H),
7.43 (s, 1H), 7.36 – 7.26 (m, 2H), 7.26 – 7.15 (m, 3H), 7.01 (dd, J = 4.9, 1.4 Hz, 1H), 5.68 (d, J
= 2.2 Hz, 1H), 4.69 (d, J = 15.4 Hz, 1H), 4.49 (d, J = 2.3 Hz, 1H), 4.01 (d, J = 15.4 Hz, 1H), 2.98
(qd, J = 7.3, 4.7 Hz, 6H), 1.21 (t, J = 7.3 Hz, 9H). 13C NMR (101 MHz, DMSO-d6+CDCl3) /
173.9, 153.0, 152.5, 152.4, 152.3, 144.1, 142.7, 138.3, 138.3, 134.3, 132.2, 132.1, 131.8, 131.7,
129.5, 129.3, 65.6, 64.0, 50.8, 47.0, 13.8. HRMS m/z [M–H]– calcd for C19H15N2O4S2 399.0479,
found 399.0476.
2-(trans-2-Oxo-1-propyl-4-(pyridin-3-yl)azetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans-20p). Eluent for chromatography EtOAc/MeOH/Et3N (75 : 20 :
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5); yield of trans/cis-20p mixture 109 mg (61%), dr 2.8:1; after additional column
1
chromatography: yield of trans-20p 50 mg (28%); colorless amorphous solid. H NMR (400
MHz, CDCl3) / 9.99 (br.s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 4.9, 1.6 Hz, 1H), 8.01 (dd,
J = 7.8, 1.4 Hz, 1H), 7.79 (dd, J = 8.0, 1.9 Hz, 1H), 7.51 (dd, J = 7.7, 1.3 Hz, 1H), 7.44 (td, J =
7.5, 1.4 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.29 (d, J = 6.1 Hz, 1H), 5.51 (d, J = 1.9 Hz, 1H), 4.47 (d,
J = 2.0 Hz, 1H), 3.56 (dt, J = 14.0, 7.7 Hz, 1H), 2.97 (q, J = 7.3 Hz, 6H), 2.80 (dt, J = 13.6, 6.3
13
Hz, 1H), 1.64 – 1.44 (m, 2H), 1.19 (t, J = 7.3 Hz, 9H), 0.95 (t, J = 7.4 Hz, 3H). C NMR (101
MHz, CDCl3) / 169.0, 149.0, 149.0, 144.2, 135.3, 134.0, 133.2, 130.6, 127.6, 127.5, 127.4,
123.7, 62.7, 61.1, 46.0, 42.1, 21.2, 11.6, 8.5. HRMS m/z [M–H]– calcd for C17H17N2O4S
345.0915, found 345.0916.
2-(cis-2-Oxo-1-propyl-4-(pyridin-3-yl)azetidin-3-yl)benzenesulfonic acid triethylammonium
salt (cis-20p). Isolated after additional column chromatography: yield 18 mg (10%); colorless
amorphous solid. 1H NMR (400 MHz, CDCl3) / 10.43 (br.s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.26
(dd, J = 4.9, 1.7 Hz, 1H), 7.74 (dd, J = 7.7, 1.4 Hz, 1H), 7.64 (dt, J = 8.0, 1.9 Hz, 1H), 7.29 (dd,
J = 7.8, 1.2 Hz, 1H), 7.18 (td, J = 7.5, 1.4 Hz, 1H), 7.06 (td, J = 7.6, 1.3 Hz, 1H), 7.00 (dd, J =
7.9, 4.8 Hz, 1H), 6.02 (d, J = 5.6 Hz, 1H), 5.30 (d, J = 5.6 Hz, 1H), 3.65 (dt, J = 13.9, 7.8 Hz,
1H), 3.09 (q, J = 7.3 Hz, 6H), 2.94 (ddd, J = 13.7, 7.7, 5.8 Hz, 1H), 1.67 – 1.51 (m, 2H), 1.30 (t,
J = 7.3 Hz, 9H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) / 168.8, 149.0, 148.2,
143.9, 136.5, 131.6, 130.4, 130.2, 129.7, 127.1, 126.9, 122.7, 59.2, 59.0, 46.2, 42.6, 21.0, 11.6,
8.6. HRMS m/z [M–H]– calcd for C17H17N2O4S 345.0915, found 345.0903.
2-(trans/cis-1-Cyclohexyl-2-ethyl-4-oxoazetidin-3-yl)benzenesulfonic
acid
triethylammonium salt (trans/cis-20q). Eluent for chromatography EtOAc/MeOH/Et3N (85 :
10 : 5); yield of trans/cis-20q mixture 24 mg (11%), dr 8:1; colorless amorphous solid. 1H NMR
(400 MHz, CDCl3) of major trans-isomer / 8.02 (dd, J = 7.8, 1.3 Hz, 1H), 7.34 (td, J = 7.3, 1.3
Hz, 1H), 7.28 (d, J = 7.1 Hz, 1H), 7.21 (td, J = 7.6, 1.4 Hz, 1H), 6.41 (br.s, 1H), 5.24 (d, J = 2.1
Hz, 1H), 3.58 (ddd, J = 6.8, 3.8, 2.1 Hz, 1H), 3.49 (tt, J = 11.5, 3.7 Hz, 1H), 2.87 (q, J = 7.3 Hz,
6H), 2.09 – 1.91 (m, 2H), 1.89 – 1.61 (m, 5H), 1.60 – 1.45 (m, 2H), 1.38 – 1.20 (m, 3H), 1.17 (t,
J = 7.3 Hz, 9H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) of major trans-isomer /
169.0, 144.6, 134.4, 130.2, 127.7, 127.2, 126.6, 63.1, 54.6, 52.2, 46.2, 32.1, 31.1, 26.1, 25.4,
25.4, 25.3, 9.6, 8.9. HRMS m/z [M–H]– calcd for C17H22NO4S 336.1275, found 336.1285.
2-(cis-1-Cyclohexyl-2-ethyl-4-oxoazetidin-3-yl)benzenesulfonic acid triethylammonium salt
1
(cis-20q). Next was isolated cis-20q; yield 115 mg (53%); colorless amorphous solid. H NMR
(400 MHz, CDCl3) / 10.18 (br.s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 4.2 Hz, 2H), 7.32 –
7.21 (m, 1H), 5.58 (d, J = 5.4 Hz, 1H), 4.06 – 3.91 (m, 1H), 3.48 (tt, J = 11.8, 3.8 Hz, 1H), 3.13
– 2.98 (m, 6H), 2.01 – 1.88 (m, 2H), 1.86 – 1.71 (m, 3H), 1.71 – 1.62 (m, 1H), 1.62 – 1.49 (m,
13
1H), 1.49 – 1.35 (m, 2H), 1.34 – 1.11 (m, 12H), 0.70 (t, J = 7.5 Hz, 3H). C NMR (101 MHz,
CDCl3) / 168.6, 144.7, 132.0, 130.4, 129.7, 127.4, 126.9, 58.9, 54.6, 52.7, 46.3, 32.2, 30.8, 25.5,
25.4, 25.4, 24.1, 10.8, 8.7. HRMS m/z [M–H]– calcd for C17H22NO4S 336.1275, found
336.1272.
2-(trans/cis-1-Butyl-2-isopropyl-4-oxoazetidin-3-yl)benzenesulfonic acid triethylammonium
salt (trans/cis-20r). Eluent for chromatography EtOAc/MeOH/Et3N (85 : 10 : 5); yield 103 mg
1
(48%), dr 1:1.1; colorless amorphous solid. H NMR (400 MHz, CDCl3) signals of cis-isomer /
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9.84 (br.s, 1H), 8.00 – 7.98 (m, 1H), 7.40 – 7.31 (m, 2H), 7.27 – 7.23 (m, 1H), 5.62 (d, J = 5.6
Hz, 1H), 3.79 (dd, J = 7.7, 5.6 Hz, 1H), 3.70 – 3.54 (m, 1H), 3.09 – 2.99 (m, 7H), 1.77 (dq, J =
13.8, 6.9 Hz, 1H), 1.70 – 1.51 (m, 2H), 1.47 – 1.29 (m, 2H), 1.22 (t, J = 7.3 Hz, 9H), 0.88 (d, J
13
= 6.7 Hz, 3H), 0.93 (t, J = 6.6 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3)
signals of cis-isomer / 170.1, 144.9, 131.8, 130.6, 129.5, 127.4, 127.0, 63.7, 54.8, 46.3, 42.1,
30.2, 29.1, 20.3, 20.2, 19.8, 13.69, 8.6.
1H NMR (400 MHz, CDCl3) signals of trans-isomer / 9.84 (br.s, 1H), 8.03 – 8.00 (m, 1H), 7.35
– 7.32 (m, 1H), 7.26 (dd, J = 7.6, 1.4 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.36 (s, 1H), 3.70 – 3.54
(m, 1H), 3.50 (dd, J = 4.6, 2.2 Hz, 1H), 3.09 – 2.99 (m, 7H), 2.24 – 2.10 (m, 1H), 1.70 – 1.51 (m,
2H), 1.47 – 1.29 (m, 2H), 1.22 (t, J = 7.3 Hz, 9H), 1.03 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz,
3H), 0.97 (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) signals of trans-isomer / 169.7,
144.5, 134.0, 130.3, 127.8, 127.5, 126.7, 67.7, 53.0, 46.3, 40.9, 29.8, 29.7, 20.4, 18.1, 18.0,
13.68, 8.6. The stereoisomers signals assignment is based on HMBC and HSQC spectra.
HRMS m/z [M–H]– calcd for C16H22NO4S 324.1275, found 324.1269.
General procedure for the preparation of sulfonamides 24a-b from compound trans-20b
To a stirred ice-cooled suspension of compound trans-20b (323 mg, 0.6 mmol) in dry DMF (3
mL) thionyl chloride (300 mg, 2.5 mmol) was added. The mixture was stirred for 20 min under
cooling and then at ambient temperature for 16 hours. The resulting mixture was concentrated in
vacuo at 35 °C, triturated with ice water (10 mL) and extracted with EtOAc (2×20 mL). Organic
phases were dried over MgSO4 and evaporated to dryness to give 300 mg of crude sulfonyl
1
chloride 23 which was used for preparation of sulfonamides without further purification. H
NMR (400 MHz, CDCl3) / 8.09 (dd, J = 8.1, 1.4 Hz, 1H), 7.74 (td, J = 7.7, 1.4 Hz, 1H), 7.55
(dd, J = 7.9, 1.2 Hz, 1H), 7.52 (ddd, J = 8.0, 7.5, 1.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.19 (d, J
= 8.3 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.32 (d, J = 2.4 Hz, 1H), 4.92
(d, J = 14.8 Hz, 1H), 4.23 (d, J = 2.2 Hz, 1H), 3.82 (s, 3H), 3.73 (d, J = 14.7 Hz, 1H), 2.40 (s,
3H). HRMS m/z [M+H]+ calcd for C24H22ClNO4S 456.1031, found 456.1052.
2-(trans-1-(4-Methoxybenzyl)-2-oxo-4-(p-tolyl)azetidin-3-yl)benzenesulfon-amide (24a). The
crude sulfonyl chloride 23 from previous step (100 mg) was dissolved in THF (3 mL) and under
stirring and ice-cooling gaseous ammonia was passed through the solution for 2 hours. The
mixture was stirred at ambient temperature for 2 hours, then evaporated and subjected to column
chromatography on silica gel (eluent – CHCl3); yield 65 mg (75% for 2 steps); pale beige solid,
mp 195–197 °C. 1H NMR (400 MHz, CDCl3) / 8.14 (dd, J = 7.9, 1.2 Hz, 1H), 7.56 (td, J = 7.6,
1.3 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.27 – 7.20 (m, 4H), 7.08 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6
Hz, 2H), 5.85 (s, 2H), 5.53 (d, J = 2.3 Hz, 1H), 4.83 (d, J = 2.6 Hz, 1H), 4.80 (d, J = 15.0 Hz,
1H), 3.83 (s, 3H), 3.83 (d, J = 14.8 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) / 168.5,
159.3, 141.4, 139.1 133.0, 132.8, 132.0, 129.9, 129.8, 129.2, 128.2, 128.1, 127.1, 126.9, 114.3,
61.1, 58.7, 55.3, 44.2, 21.2. HRMS m/z [M+H]+ calcd for C24H24N2O4S 437.1530, found
437.1520.
N-(3,4-Dimethoxyphenethyl)-2-(trans-1-(4-methoxybenzyl)-2-oxo-4-(p-tolyl)-azetidin-3-
yl)benzenesulfonamide (24b). The solution of crude sulfonyl chloride 23 (100 mg) in dry DCM
(2 mL) was added to the stirred solution of 2-(3,4-dimethoxyphenyl)ethanamine (36 mg, 0.2
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mmol) and pyridine (20 mg, 0.25 mmol) in dry DCM (2 mL). The mixture was stirred for 3
hours at ambient temperature, then it was washed with water (3 mL), evaporated and subjected to
column chromatography on silica gel (eluent – CHCl3); yield 68 mg (57% for 2 steps); pale
yellow solid, mp 171–173 °C; 1H NMR (400 MHz, CDCl3) / 8.00 (dd, J = 7.9, 1.2 Hz, 1H), 7.53
(td, J = 7.6, 1.2 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.38 (td, J = 7.8, 1.0 Hz, 1H), 7.18 (s,
4H),7.06 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.66 – 6.61 (m,
2H), 5.96 (t, J = 6.1 Hz, 1H), 5.45 (d, J = 2.3 Hz, 1H), 4.77 (d, J = 14.8 Hz, 1H), 4.64 (d, J = 2.6
Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.78 (d, J = 14.7 Hz, 1H), 3.15 – 3.03 (m, 1H),
3.00 – 2.90 (m, 1H), 2.76 – 2.58 (m, 2H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) / 168.2,
159.3, 148.9, 147.7, 139.0, 138.5, 133.0, 132.9, 132.6, 130.8, 130.3, 129.9, 129.8, 128.6, 127.6,
127.2, 126.9, 120.7, 114.2, 112.1, 111.3, 60.9, 59.8, 55.9, 55.8, 55.2, 44.8, 44.0, 35.6, 21.2.
HRMS m/z [M+Na]+ calcd for C34H36N2NaO6S 623.2186, found 623.2194.
trans-3-(2-((3,4-Dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-1-(4-methoxy-benzyl)-4-(p-
tolyl)azetidin-2-one (24c). The solution of crude sulfonyl chloride 23 (100 mg) in dry DCM (2
mL) was added to the stirred solution of 1,2,3,4-tetrahydroisoquinoline (27 mg, 0.2 mmol) and
pyridine (20 mg, 0.25 mmol) in dry DCM (2 mL). The mixture was stirred for 3 hours at ambient
temperature, then it was washed with water (3 mL), evaporated and subjected to column
chromatography on silica gel (eluent – CHCl3); yield 68 mg (62% for 2 steps); pale beige
amorphous solid. 1H NMR (400 MHz, CDCl3) / 8.02 (dd, J = 7.9, 1.3 Hz, 1H), 7.60 (td, J = 7.7,
1.4 Hz, 1H), 7.49 – 7.42 (m, 2H), 7.17 (s, 4H), 7.16 – 7.11 (m, 4H), 7.07 – 7.01 (m, 1H), 6.87 (d,
J = 8.7 Hz, 2H), 6.87 – 6.83 (m, 1H), 5.38 (d, J = 1.9 Hz, 1H), 4.90 (d, J = 14.8 Hz, 1H), 4.22 (d,
J = 2.1 Hz, 1H), 4.10 (d, J = 15.4 Hz, 1H), 4.01 (d, J = 15.4 Hz, 1H), 3.83 (s, 3H), 3.68 (d, J =
14.7 Hz, 1H), 3.20 (ddd, J = 12.1, 6.8, 5.2 Hz, 1H), 3.15 – 3.09 (m, 1H), 2.82 – 2.65 (m, 2H),
2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) / 167.6, 159.2, 138.6, 136.2, 135.4, 133.7, 133.5,
133.1, 131.5, 130.7, 129.9, 129.6, 129.1, 128.8, 127.79, 127.78, 127.1, 126.6, 126.3, 126.2,
114.2, 64.1, 60.2, 55.3, 46.3, 43.7, 42.8, 28.5, 21.3. HRMS m/z [M+Na]+ calcd for
C33H32N2NaO4S 575.1975, found 575.1982.
Supporting Information
1
Electronic supplementary information (ESI) available: Figures of H, 13C NMR spectra for
compounds 14, 20a-r, 24a-c and X-ray data for compound trans-20h (CCDC 1548177). For ESI
and crystallographic data in CIF or other electronic format see DOI: .
Acknowledgments
This research was supported by the Russian Science Foundation (project grant 14-50-00069).
NMR, mass-spectrometry studies and X-ray studies were performed at the Research Centre for
Magnetic Resonance, the Centre for Chemical and Materials Research and the Centre for X-ray
Diffraction Methods of Saint Petersburg State University Research Park.
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