An unexpected isomerization of 1,3-benzothiazine and isoquinoline-condensed β-lactams

Article abstract of DOI:10.1016/j.molstruc.2010.08.030

A series of novel aryl-substituted β-lactams condensed with 1,3-benzothiazines, isoquinolines or 1,4-benzothiazepine were obtained by means of the Staudinger reaction and isomerized in the presence of sodium methoxide to the thermodynamically more stable

Full text of DOI:10.1016/j.molstruc.2010.08.030

Journal of Molecular Structure 983 (2010) 54–61
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
An unexpected isomerization of 1,3-benzothiazine and isoquinoline-condensed
b-lactams
c,d,
Lajos Fodor a,b, , Péter Csomós a,b, Ferenc Fülöp b, Antal Csámpai c, , Pál Sohár
⇑
⇑⇑
⇑⇑⇑
a Central Laboratory, County Hospital, H-5701 Gyula, POB 46, Hungary
b Institute of Pharmaceutical Chemistry, University of Szeged and Research Group of Stereochemistry of the Hungarian Academy of Sciences, H-6720, Szeged, Eötvös u. 6., Hungary
c Institute of Chemistry, Eötvös Loránd University, H-1518 Budapest, POB 32, Hungary
d Protein Modelling Research Group, Hungarian Academy of Sciences and Eötvös Loránd University, H-1518 Budapest, POB 32, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2010
Received in revised form 13 August 2010
Accepted 13 August 2010
Available online 25 August 2010
A series of novel aryl-substituted b-lactams condensed with 1,3-benzothiazines, isoquinolines or 1,4-
benzothiazepine were obtained by means of the Staudinger reaction and isomerized in the presence of
sodium methoxide to the thermodynamically more stable form. The structures of the new molecules
were determined by NMR spectroscopy. Theoretical calculations corroborate the experimentally
observed structure–reactivity relationships.
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Sulfur nitrogen heterocycles
Isoquinoline
Staudinger reaction
Cis–trans-b-lactams
NMR spectroscopy
DFT analysis
1. Introduction
nucleophilic reagents usually take place at the N1–C2 bond. Further,
some b-lactam derivatives (e.g. a-halo-b-lactams) are versatile syn-
Since the discovery of penicillin, b-lactams (including penicillins,
cephalosporins, monobactams, and carbapenems) have become a
major class of antibacterial agents. Because of their widespread
use, bacterial resistance has developed into a major health problem
worldwide during the past few decades [1]. This has motivated
growing interest in the preparation and biological evaluation of
new types of b-lactams [2]. Moreover, some derivatives possess var-
ious other useful pharmacological effects. They include, for example,
inhibitors of human leucocyte elastase [3a,b], cholesterol acyl trans-
ferase [3c] and thrombin [3d]. From a synthetic aspect, azetidin-
2-one derivatives are versatile intermediates in the construction of
complex heterocycles [4], non-proteogenic amino acid derivatives,
peptides and peptide turn mimetics [5]. They can be utilized in the
synthesis of different natural compounds, such as apiosporamide
or taxol derivatives [6]. In the former compounds, which contain a
relatively strained b-lactam structural unit, the reactions with
thons that furnish a wide variety of functionalized lactams [7].
Thereactionmostwidelyusedfortheconstructionofazetidinone
rings is the [2 + 2] ketene-imine cycloaddition known as the
Staudinger reaction [2]. Several variants of this reaction have been
described, in which the ketene is formed in situ from precursors
[2,8]. The reactions of monosubstituted ketene with imines furnish
two new stereogenic centres, and thus cis-, trans- or a mixture of
cis-andtrans-azetidinonescanbe obtainedasproducts. Theselectiv-
ityisthereforeoneofthecriticalissuesintheStaudingerreaction[9].
For acyclic imines, a mixture of cis- and trans-azetidinones can be
formed, via isomerization of the zwitterionic intermediate, whereas
in the case of cyclic imines, most often only one product (cis or trans)
can be isolated selectively, depending on the imine [9].
From a pharmacological aspect, there are examples where the
Staudinger product is the biologically active isomer [3a]. In contrast,
however, there are many examples where the Staudinger product is
not the effective isomer. When penicillins or cephalosporins are
prepared by the cycloaddition of protected glycines to thiazoline
or thiazine rings, the newly created stereochemistry of the lactam
Hatomsis transratherthancis, asinthenaturalsubstances. Thetrans
isomers are biologically inactive. Isomers with antibacterial activity
can be prepared only by different methods or in rare cases by
epimerization [10].
⇑
Corresponding author at: Central Laboratory, County Hospital, H-5701 Gyula,
POB 46, Hungary. Tel.: +36 66 463763; fax: +36 66 526539.
⇑⇑
Corresponding author. Tel.: +36 1 3722911; fax: +36 1 3722592.
Corresponding author at: Institute of Chemistry, Eötvös Loránd University,
⇑⇑⇑
H-1518 Budapest, POB 32, Hungary. Tel.: +36 1 3722911; fax: +36 1 3722592.
E-mail addresses: fodor@pandy.hu (L. Fodor), csampai@chem.elte.hu (A. Csámpai),
sohar@chem.elte.hu (P. Sohár).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.08.030

L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
55
In an earlier paper [11], we reported on the mechanisms of the
reactions between differently substituted 4-thia analogues of iso-
quinolines, 4H- and 2H-1,3-benzothiazine derivatives and substi-
tuted acetyl chlorides. The selectivities of the reactions and the
stereochemistry of the linearly or angularly condensed b-lactams
formed were also extensively studied [12]. In our model systems,
the substituents in the newly formed stereocentres were found
in the cis position to each other in all cases.
In contrast with the growing interest in investigations of b-lac-
tam transformations [2], only few examples are known of the
cis–trans isomerization of the Staudinger products [13]. As a con-
tinuation of our investigations on S- and N-containing con-
densed-skeleton heterocycles [14] and azetobenzothiazines [12],
it seemed worthwhile to study the Staudinger reactions of various
2H-1,3-benzothiazines and to devise an isomerization procedure
for the b-lactams obtained. A further aim was to extend our inves-
tigations to model compounds such as azetoisoquinolines and aze-
to-1,4-benzothiazepines.
one of the rare transformations of b-lactams. Thus, 6a–d could be
prepared after separation from the starting 5a–d by colomn chro-
matography in 28–45% yields (Scheme 2). When equivalent
amounts of sodium methoxide were used in the latter isomeriza-
tion reactions, mainly 4 could be isolated as decomposition
product.
In the case of azeto[2,1-d][1,4]benzothiazin-2-one 8, obtained
from thiazepine 7, no isomerization was observed under different
basic conditions. After several days reflux only the starting 8 b-lac-
tam could be isolated from the reaction mixture (Scheme 3).
2.2.1. General procedure for the preparation of cis-azetobenzothiazines
(2b–d) and cis-azetobenzothiazepine (8)
To a stirred solution of 6,7-dimethoxy-4-phenyl-1,3(2H)-benzo-
thiazine 1 (2.85 g, 10 mmol) or 6,7-dimethoxy-4-phenyl-1,4-ben-
zothiazepine 7 (2.99 g, 10 mmol) in anhydrous toluene (30 mL),
the appropriate acid chloride derivative (10 mmol) was added.
The solution was refluxed and triethylamine (1.4 mL, 10 mmol)
in anhydrous toluene (50 mL) was added dropwise during 1 h un-
der reflux. The reaction mixture was then cooled and extracted in
turn with 5% Na2CO3 solution (20 mL), 5% HCl (20 mL) and brine
(20 mL), and the organic layer was dried with Na2SO4. After evap-
oration, the residue was taken up in ethanol, and the crystalline
product was filtered off and recrystallized.
2. Experimental
2.1. Materials and methods
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were per-
formed with a Perkin–Elmer 2400 CHNS elemental analyser. Merck
Kieselgel 60F254 plates were used for TLC, and Merck Silica gel 60
(0.063–0.100) for column chromatography. Azeto-1,3-benzothia-
zines (2a and 3a) [11,12b], and azetoisoquinoline (5a) [15] were
prepared by literature methods.
The structures of the simplified models optimized by the B3LYP/
6-31 G(d) method collected on (Fig. 1) are available from the
authors on request. All calculations were carried out with the
Gaussian 03 suite of programs [16].
IR spectra were recorded in KBr pellets with a Bruker IFS 55 FT-
spectrometer. The 1H and 13C NMR spectra were recorded in CDCl3
solution in 5 mm tubes at room temperature, on a Bruker DRX 500
spectrometer at 500.13 (1H) and 125.76 (13C) MHz, with the deute-
rium signal of the solvent as the lock and TMS as internal standard.
The standard Bruker microprogram NOEMULT.AU was used to gen-
erate NOE. DEPT spectra were run in a standard manner, using only
*
*
2.2.1.1. (1R ,9bS )-7,8-dimethoxy-1-(4-chlorophenyl)-9b-phenyl-1,9b
-dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one (2b). A white
crystalline powder; mp 198–201 °C (from ethanol); 4.10 g, 94%;
Rf (80%, toluene:ethanol 9:1). Anal. Calcd. for C24H20ClNO3S
(437.94): C, 65.82; H, 4.60; N, 3.20; S, 7.32. Found: C, 65.67; H,
4.48; N, 3.12; S, 7.11%.
*
*
2.2.1.2. (1R ,9bS )-7,8-dimethoxy-1-(4-fluorophenyl)-9b-phenyl-1,9
b-dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one (2c). A white
crystalline powder; mp 174–176 °C (from ethanol); 4.05 g, 96%;
Rf (82%, toluene:ethanol 9:1). Anal. Calcd. for C24H20FNO3S
(421.48): C, 68.39; H, 4.78; N, 3.32; S, 7.61. Found: C, 68.24; H,
4.71; N, 3.51; S, 7.83%.
*
*
2.2.1.3. (1R ,9bS )-7,8-dimethoxy-1-(4-methoxyphenyl)-9b-phenyl-1,
9b-dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one (2d). A white
crystalline powder; mp 167–169 °C (from ethanol); 3.90 g, 90%; Rf
(75%, toluene:ethanol 9:1). Anal. Calcd. for C25H23NO4S (433.52): C,
69.26; H, 5.35; N, 3.23; S, 7.40. Found: C, 69.47; H, 5.55; N, 12; S,
7.55%.
the
H = 135° pulse to separate CH/CH3 and CH2 lines phased ‘‘up”
and ‘‘down”, respectively. The 2D-HMQC and 2D-HMBC spectra
were obtained by using the standard Bruker pulse programs.
*
*
2.2. Synthesis
2.2.1.4. (1R ,9bS )-8,9-dimethoxy-1,10b-diphenyl-1,4,5,10b-tetrahy
dro-2H-azeto[2,1-d][1,4]benzothiazepin-2-one (8). A white crystal-
line powder; mp 206–207 °C (from ethanol; Lit. [12d] mp 205–
206 °C); 3.60 g, 87%; Rf (85%, toluene:ethanol 9:1). Anal. Calcd.
for C25H23NO3S (417.52): C, 71.92; H, 5.55; N, 3.35; S, 7.68. Found:
C, 72.14; H, 5.42; N, 3.51; S, 7.54%.
The cycloadditions of 4-phenyl-1,3-benzothiazine
1 with
substituted phenylacetyl chlorides in refluxing toluene in the pres-
ence of triethylamine stereoselectively provided lactams 2a–d, in
which the 9b-phenyl is cis to the 1-phenyl group (Scheme 1)
[17]. Interestingly, the treatment of 2a–d with an equivalent
amount of sodium methoxide in refluxing methanol furnished
3a–d; in the latter compounds, the 9b-phenyl proved to be trans
to the 1-phenyl group. The isomerization proceeded almost
quantitatively.
In most reports on the azetoisoquinolines, the Staudinger reac-
tion yields only one isomer; the stereochemistry or transforma-
tions of these azetidinone derivatives have been investigated in
only a few cases [18]. In our case, when the reaction was carried
out in refluxing toluene, azeto[2,1-a]isoquinolin-2-one derivatives
(5a–d) were obtained in good yields (Scheme 2).
2.2.2. General procedure for the preparation of trans-
azetobenzothiazines (3b–d)
To a stirred solution of cis-azetobenzothiazines (2a–d) (5 mmol)
in anhydrous methanol (30 mL), NaOMe (0.27 g, 5 mmol) was
added. The reaction mixture was refluxed for 3 h. After evaporation
of the solvent to 5 ml, the product crystallized out.
*
*
2.2.2.1.
(1S ,9bS )-7,8-dimethoxy-1-(4-chlorophenyl)-9b-phenyl-
(3b). A
1,9b-dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one
white crystalline powder; mp 145–147 °C (from ethanol); 1.84 g,
84%; Rf (85%, toluene:ethanol 9:1). Anal. Calcd. for C24H20ClNO3S
(437.94): C, 65.82; H, 4.60; N, 3.20; S, 7.32. Found: C, 65.67; H,
4.65; N, 3.08; S, 7.11%.
Similarly to azetobenzothiazines, the treatment of 5a–d with
catalytic amount of sodium methoxide (0.25 equiv.) in refluxing
methanol led to partial isomerization. The latter isomerization is

56
L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
IIa
IIIa
Xa
XIa
Va
XIIa
XIIIa
VIa
VIII
XIV
XV
IX
Fig. 1. Optimized structures [B3LYP/6-31 G(d)] of the simplified models of cis and trans diphenyl-substituted b-lactams and the possible intermediates involved in the
epimerizations.
Scheme 1. Preparation and isomerization of azeto[1,2-c][1,3]benzothiazin-2-one
Scheme 2. Preparation and isomerization of azeto[2,1-a]isoquinolin-2-one deriv-
derivatives 3a–d.
atives 5a–d.
*
*
2.2.2.2. (1S ,9bS )-7,8-dimethoxy-1-(4-fluorophenyl)-9b-phenyl-1,9b-
dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one (3c). A white
crystalline powder; mp 168–171 °C (from ethanol); 1.94 g, 92%;
Rf (87%, toluene:ethanol 9:1). Anal. Calcd. for C24H20FNO3S
(421.48): C, 68.39; H, 4.78; N, 3.32; S, 7.61. Found: C, 68.21; H,
4.61; N, 3.53; S, 7.45%.

L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
57
*
*
2.2.2.3. (1S ,9bS )-7,8-dimethoxy-1-(4-methoxyphenyl)-9b-phenyl-
1,9b-dihydro-2H,4H-azeto[2,1-a][1,3]benzothiazin-2-one (3d). A
white crystalline powder; mp 172–173 °C (from ethanol); 1.67 g,
77%; Rf (80%, toluene:ethanol 9:1). Anal. Calcd. for C25H23NO4S
(433.52): C, 69.26; H, 5.35; N, 3.23; S, 7.40. Found: C, 69.47; H,
5.18; N, 3.39; S, 7.61%.
2.2.3. General procedure for the preparation of cis-azetoisoquinolines (
5b–d)
To a stirred solution of 1-phenyl-6,7-dimethoxy-3,4-dihydroiso-
quinoline 4 (1.0 mmol) in anhydrous toluene (30 mL), triethylamine
(0.14 mL, 1.0 mmol) was added. The solution was refluxed and the
appropriate acid chloride derivative (1.0 mmol) in anhydrous tolu-
ene (50 mL) was added dropwise during 3 h under reflux. The addi-
tion of the appropriate acid chloride derivative (1.0 mmol) and
triethylamine (0.14 mL, 1.0 mmol) was repeated once under the
same conditions as above. The reaction mixture was then cooled
and extracted in turn with 5% Na2CO3 solution (20 mL), 5% HCl
(20 mL) and brine (20 mL), and the organic layer was dried with
Na2SO4. After evaporation, the residue was taken up in diisopropyl
ether, and the crystalline product was filtered off and recrystallized.
Scheme 3. Preparation of azeto[1,2-d][1,4]benzothiazepine derivative 8.
Scheme 4. Possible pathways of the base-catalysed isomerization of cis b-lactams IIa, Va and VIII.
Table 1
Energetic data on the model cis and trans b-lactams (IIa, IIIa, Va, VIa, VIII, IX) and the possible intermediates (Xa, XIa, XIIa, XIIIa, XIV, XV) calculated on the optimized structures
by the B3LYP-6-31 G(d) method.
Model compound
Total energy [au] in vacuo
D
E(cis–trans) [kJ/mol]
Total energy in MeOH [au]a
D
E(cis–trans) in MeOH [kJ/mol]a
IIa (cis)
IIIa (trans)
Va (cis)
VIa (trans)
VIII (cis)
IX (trans)
ꢀ1376.731408
ꢀ1376.732492
ꢀ1017.862317
ꢀ1017.863600
ꢀ1416.045720
ꢀ1416.042638
2.81
ꢀ1376.749351
ꢀ1376.751329
ꢀ1017.879344
ꢀ1017.880963
ꢀ1416.063936
ꢀ1416.062743
5.13
3.33
4.20
ꢀ7.99
ꢀ3.09
Possible intermediate
Total energy [au] in vacuo
D
E(lactam–ketene) [kJ/mol]
Total energy in MeOH [au]a
D
E(lactam–ketene) in MeOH [kJ/mol]a
Xa (lactam)
XIa (ketene)
XIIa (lactam)
XIIIa (ketene)
XIV (lactam)
XV (ketene)
ꢀ1538.443885
ꢀ1538.412427
ꢀ1179.574782
ꢀ1179.469196
ꢀ1577.755379
ꢀ1577.652130
ꢀ81.61
ꢀ1538.498663
ꢀ1538.460053
ꢀ1179.626656
ꢀ1179.501688
ꢀ1577.804674
ꢀ1577.691714
ꢀ100.17
ꢀ324.21
ꢀ296.58
ꢀ273.92
ꢀ271.08
a
Obtained with the IEFPCM solvent model, using the dielectric constant
e = 32.63.

58
L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
Table 2
Calculated lengths of the potential coordination bonds in models XIa, XIIIa and XV and the atomic charges (Mulliken) on the donor atoms obtained with the B2LYP/6-31 G(d)
method.
0
0
0
0
Compound
q(S)
q(C)
q(O)
q(N)
d(S–Na) [ÅA]
d(C–Na) [ÅA]
d(O–Na) [ÅA]
d(N–Na) [ÅA]
XIa
XIIIa
XV
2.576
–
2.752
–0.371
–
+0.084
–
–
2.443
2.581
2.392
–0.455
–0.445
–0.473
2.421
2.531
4.459
–0.364
–0.355
–0.323
2.361
2.392
–0.599
–0.664
*
*
2.2.3.1.
(1R ,9bR )-7,8-dimethoxy-1-(4-chlorophenyl)-9b-phenyl-
matography with n-hexane:ethyl acetate 3:2, followed by n-hex-
1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (5b). A white
crystalline powder; mp 208–211 °C (from diisopropyl ether–ethyl
acetate); 0.30 g, 72%; Rf (48%, n-hexane:ethyl acetate 1:1). Anal.
Calcd. for C25H22ClNO3 (419.90): C, 71.51; H, 5.28; N, 3.34. Found:
C, 71.38; H, 5.21; N, 3.19%.
ane:ethyl acetate 1:1 as eluent.
*
*
2.2.4.1. (1S ,9bR )-7,8-dimethoxy-1,9b-diphenyl-1,4,5,9b-tetrahydro-
2H-azeto[2,1-a]isoquinolin-2-one (6a). A white crystalline powder;
mp 219–221 °C; 78 mg, 34%; Rf (52%, n-hexane:ethyl acetate 1:1).
Anal. Calcd. for C25H23NO3 (385.46): C, 77.90; H, 6.01; N, 3.63.
Found: C, 77.79; H, 5.95; N, 3.77%.
* *
(1R ,9bR )-7,8-dimethoxy-1-(4-fluorophenyl)-9b-phenyl-
2.2.3.2.
1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (5c). A white
crystalline powder; mp 210–212 °C (from diisopropyl ether–ethyl
acetate); 0.31 g, 78%; Rf (55%, n-hexane:ethyl acetate 1:1). Anal.
Calcd. for C25H22FNO3 (403.45): C, 74.43; H, 5.50; N, 3.47. Found:
C, 74.33; H, 5.39; N, 3.62%.
*
*
2.2.4.2. (1S ,9bR )-7,8-dimethoxy-1-(4-chlorophenyl)-9b-phenyl-1,4,
5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (6b). A white
crystalline powder; mp 188–190 °C; 113 mg, 45%; Rf (53%, n-hex-
ane:ethyl acetate 1:1). Anal. Calcd. for C25H22ClNO3 (419.90): C,
71.51; H, 5.28; N, 3.34. Found: C, 71.46; H,5.22; N, 3.52%.
*
*
2.2.3.3. (1R ,9bR )-7,8-dimethoxy-1-(4-methoxyphenyl)-9b-phenyl-
1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (5d). A white
crystalline powder; mp 205–207 °C (from diisopropyl ether–ethyl
acetate); 0.35 g, 83%; Rf (50%, n-hexane:ethyl acetate 1:1). Anal.
Calcd. for C26H25NO4 (415.48): C, 75.16; H, 6.06; N, 3.37. Found:
C, 74.97; H, 6.27; N, 3.52%.
*
*
2.2.4.3. (1S ,9bR )-7,8-Dimethoxy-1-(4-fluorophenyl)-9b-phenyl-1,4,
5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (6c). A white
crystalline powder; mp 216–217 °C; 77 mg, 32%; Rf (60%, n-hex-
ane:ethyl acetate 1:1). Anal. Calcd. for C25H22FNO3 (403.45): C,
74.43; H, 5.50; N, 3.47. Found: C, 74.23; H, 5.42; N, 3.61%.
*
*
2.2.4. General procedure for the preparation of trans-
2.2.4.4. (1S ,9bR )-7,8-Dimethoxy-1-(4-methoxyphenyl)-9b-phenyl-
1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (6d). A white
crystalline powder; mp 152–154 °C; 70 mg, 28%; Rf (55%, n-hex-
ane:ethyl acetate 1:1). Anal. Calcd. for C26H25NO4 (415.48): C,
75.16; H, 6.06; N, 3.37. Found: C, 75.22; H, 6.30; N, 3.46%.
azetoisoquinolines (6a–d)
To
a
stirred solution of cis-azetoisoquinoline (5a–d)
(0.60 mmol) in anhydrous methanol (30 mL), NaOMe (8 mg,
0.15 mmol; for compound 5d, 12 mg, 0.22 mmol) was added. The
reaction mixture was refluxed for 24 h, after which the solvent
was evaporated off and the residue was purified by column chro-
Table 4
Measured (upper rows) and calculated [GIAO/B3LYP/6-311+G(2d,p) (lower rows in
italics)] values of 1H NMR chemical shifts which are most relevant for conformation.
Table 3
a
b
OCH3 Pos. 7 OCH3 Pos. 8 SCH2
NCH2
H-6 H-9
Energetic data on the experimentally studied cis and trans b-lactams (2a, 3a, 5a, 6a, 8,
9) calculated on the structures optimized by B3LYP-6-31 G(d) method with IEFPCM
solvent model (CHCl3,
2a (meas.) 4.04
2a (calc.) 3.86
3a (meas.) 3.83
3a (calc.) 3.74
6a (meas.) 3.83
3.90
3.94
3.20
3.11
3.25
3.12
4.02
3.93
4.46, 5.05
4.22, 5.06
4.37, 5.07
4.80, 5.00
2.68, 3.04 3.42, 4.08 6.63 5.84
2.65, 3.54 3.44, 4.26 6.60 5.63
2.77, 2.79 3.48, 4.60 7.15 7.25
2.51, 2.98 3.32, 4.59 7.26 7.30
–
–
–
–
6.84 7.29
6.60 7.25
6.63 5.81
6.59 5.67
e
= 4.90).
Studied b-lactam
Total energy in CHCl3 [au]
D
E(cis–trans) [kJ/mol]
2a (cis)
3a (trans)
5a (cis)
6a (trans)
8 (cis)
9 (trans)
ꢀ1605.783978
ꢀ1605.785174
ꢀ1246.914963
ꢀ1246.915725
ꢀ1645.099582
ꢀ1645.092659
3.10
6a (calc.)
8 (meas.)
8 (calc.)
3.77
3.95
3.88
1.98
–17.97
a
For 6a C(Ar)–CH2.
For 2a and 3a NCH2 is equivalent to SCH2.
b
8 (HOMO-4)
8 (HOMO-3)
Fig. 2. Contour plots of HOMO-3 and HOMO-4 disclosing some
p electron delocalisation between the two cis-oriented phenyl substituents calculated [B3LYP/6-31 G(d)] for 8
of pronounced stability.

L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
59
Table 5
Characteristic IR frequenciesa and 1H NMR datab on compounds 2a–d, 3a–d, 5b–d, 6a–d, and 8.c
g
h
Compound
m
C@O
m
C–O
c
CAr
bandd bande and
CArCAr
H
c
CAr
H
c
CAr
H
OCH3
Pos. 7
OCH3
Pos. 8
SCH2 NCH2 CH s H–6 s H–9 s H–20,60 Ar H–30,50
2 ꢁ d 2 ꢁ m to C@O) Ar ( to N)
H–20,60 H–30,50 H–40
band band
(a
a
f
c
2a*
2b
2c
2d
3a*
3b
3c
3d
5b
5c
5d
6a
6b
6c
6d
8l
1748 1262, 854
1216
–
746,
698
721,
699
759,
699
758,
701
741,
697
744,
698
726,
698
740,
701
761,
700
760,
700
752,
699
769,
699
757,
703
757,
704
755,
701
745,k
699
4.04
4.03
4.04
4.03
3.83
3.85
3.84
3.83
3.90
3.90
3.89
3.83
3.85
3.84
3.84
3.95
3.90
3.90
3.90
3.89
3.20
3.27
3.27
3.26
4.04
4.05
4.04
3.25
3.32
3.32
3.31
4.02
4.46,
5.05
4.45,
5.03
4.46,
5.04
4.46,
5.05
4.37,
5.07
4.36,
5.06
4.35,
5.05
4.36,
5.06
2.65, 3.71,
2.79 3.83
2.66, 3.73,
2.80 3.84
2.67, 3.73,
2.79 3.84
2.68, 3.42,
3.04 4.08
2.68, 3.39,
3.05 4.07
2.68, 3.38,
3.06 4.08
2.68, 3.42,
3.02 4.06
2.77, 3.48,
2.90 4.60
–
–
–
–
–
–
–
–
4.99 6.84
4.93 6.84
4.94 6.84i
4.93 6.83
5.11 6.63
5.08 6.64
5.10 6.64
5.05 6.64
4.87 6.72
4.88 6.72
4.86 6.71
4.89 6.63
4.85 6.64
4.89 6.65
4.83 6.64
5.36 7.15
7.29
7.23
7.24
7.26
5.81
5.82
5.82
5.85
7.17
7.18
7.19
5.84
5.82
5.84
5.82
7.25
ꢂ7.1 m
(10H)i
7.03
1757 1212
852
819
819
810
–
7.12
7.11 ꢂ s
(5H)
1745 1161
853
7.07
7.01
6.93
6.88
6.89
6.84
7.02
7.05i
7.00
6.93
6.86
ꢂ6.9
6.84
7.20
6.84i
6.68
7.17i
7.16
6.91
6.70
7.09
6.82
6.65
ꢂ7.2i
7.18
7.47
6.74
7.08i
7.11 ꢂ s
(5H)
1746 1219, 852
1026
1752 1246, 862
1209
1756 1247, 843
1038
1752 1247, 854
1038
1743 1246, 849
1027
1738 1221, 856
1023
1739 1220, 858
1023
1740 1222, 877
1023
1732 1234, 869
1026
1740 1231, 865
1028
1739 1231, 869
1027
1740 1237, 866
1026
ꢂ7.1 m
(5H)
7.50
7.49
7.48
7.48
7.14
7.16
7.16
7.48
7.46
7.38
7.47
6.75
7.42
7.43
7.42
7.41
7.09
7.10
7.09
7.38
7.38
7.32
7.38
7.37
7.38
7.38
7.37
7.09i
7.05i
7.04
7.31
7.32
814
814
834
818
817
836
826
826
829
830
–
i
7.31
1746 1213, 863
1045
ꢂ7.08
m (6H)i
a
In KBr discs (cmꢀ1).
b
In CDCl3 solution at 500 MHz. Chemical shifts in ppm (dTMS = 0 ppm), coupling constants in Hz. Further signals: OCH3: 3.71 (2d): 3.72 (3d), 3.70 (5d), 3.74 (6d); H-40 Ar (
a
to C@O): ꢂ7.1i (2a), 7.16i (3a), ꢂ7.2i (6a), 7.08 m (6H)[i] (8).
c
Assignments were supported by HMQC and HMBC (except for 3a, c), for compound 8 also by DIFFNOE measurements.
Condensed benzene ring.
d
e
p-Disubstituted ring.
Monosubstituted ring.
f
G
J: 10.9 (2a), 10.7 (2b–d), 12.3 (3a, b, d), 12.7 (3c). [C(sp2)]CH2 group, 2 ꢁ m (2 ꢁ 1H) for 5b–d, 6a–d and 8.
h
2 m (2 ꢁ 1H).
i
Overlapping signals.
k
Split band with the other maximum at 769 cmꢀ1
.
l
The numbering of the other compounds was used also for 8.
Previously published compounds, c.f. Ref. [11] (2a) and Ref. [12b] (3a).
*
(representing 8) is more stable than its trans counterpart IX (repre-
3. Results and discussion
senting 9) both in vacuo and in solution [
D
E (VIII–IX) = ꢀ7.99 kJ/
mol and ꢀ3.09 kJ/mol, respectively]. It is also noteworthy that, de-
spite similar energetics for the overall processes IIa ? IIIa and
Va ? VIIa, the experiments showed that the isomerization of cis-
azetobenzothiazine 2a is much faster than that of cis-azetoisoquin-
oline 5a. The enhanced tendency of 2a to undergo isomerization
may be interpreted in terms of the relatively significant contribu-
tion of the pathway involving a thiophenolate intermediate analo-
gous to XIa, which contains a tricoordinated Na ion, as disclosed by
geometry optimisation (Fig. 1, Table 2). On the other hand, the low-
er stability of XIa relative to that of the amidate salt Xa indicates a
major contribution of the alternative pathway with the simple
base-catalysed epimerization of the cis-azetobenzothiazine ring
system. The slower isomerization of cis-azetoisoquinoline 5a may
be due to a negligible contribution of the pathway proceeding via
a ketene intermediate analogous to XIIIa, with the sodium-coordi-
nated benzylate moiety being much less stable than amidate salt
XIIa (Table 1) involved in the alternative epimerization pathway.
It should be noted here that, in spite of the thermodynamically
unfavoured isomerization of 8, the equilibrium formation of an
amidate salt analogous to XIV can not be ruled out. The calculated
3.1. Theoretical calculations
To explain the significant substrate dependence observed
experimentally in the course of the base-catalysed isomerization
of cis b-lactams 2a, 5a and 8, we considered two pathways, involv-
ing a simple deprotonation-protonation sequence and a base-med-
iated simultaneous fission of the condensed rings with the
formation of a ketene intermediate, respectively, as illustrated in
the simplified models IIa, Va and VIII (Scheme 4). To obtain the
energetics of the studied epimerizations and the assumed elemen-
tary steps, DFT analysis [19] was carried out at the B3LYP level of
theory [20], using the 6-31G(d) basis set [21] on the cis–trans coun-
terparts IIa–IIIa, Va–VIa and VIII–IX, and the possible intermediate
Na salts Xa–XIIIa, XIV and XV (Scheme 4). Total energy values ob-
tained in vacuo were recalculated with the IEFPCM solvent model
[22] (eMeOH = 32.63) representing the experimental conditions
(Scheme 4, Table 1). The computed differences in the total energy
values of the cis and trans b-lactams were in agreement with the
data from the preparative experiments, showing that, in contrast
with the cis b-lactams IIa and Va (representing 2a and 5a), VIII

60
L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
Table 6
13C NMR chemical shiftsa of compounds 2a–d, 3a–d, 5b–d, 6a–d, and 8.b
Compound OCH3
Pos. 7, 8
CH C@O Benzothiazine or isoquinoline moietyc
Aryl groups attached to the lactam ring
d
C-5a C-6 C-7 C-8 C-9 C-9a
C-9b SCH2
Csubst.
(10)
Cortho
Cmeta
Cpara
2a*
2b
2c
2d
3a*
3b
3c
3d
5b
5c
5d
6a
6b
6c
6d
8
56.6, 57.0 69.0 168.5 123.0 112.9 149.6 148.3 112.1 132.7 67.7 40.6
132.8,
137.5
131.5,
137.2
128.8f
137.4
124.9,
137.6
133.3,
142.2
132.3,
141.9
129.7,f
142.0
125.4,
141.9
132.1,
138.7
129.4,f
138.8
125.6,
139.1
133.8,
143.5
132.4,
143.0
129.8,f
143.2
125.8,
143.5
133.2,
137.8
127.81,e 127.83, 128.1, 128.8,
129.2, 128.8, 129.2
127.7, 128.4, 129.0, 130.5, 129.2 128.1,
133.8
56.6, 57.1 68.1 168.0 123.1 113.0 148.8 148.4 112.1 132.5 67.6 40.6
56.6, 57.1 68.1 168.3 123.1 113.0 149.7 148.4 112.1 132.6 67.7 40.7
56.6, 57.0 68.5 168.9 123.9 112.9 149.6 148.3 112.1 132.8 67.7 40.6
56.3, 56.0 69.3 169.2 123.9 109.9 148.9 146.2 114.8 122.1 64.8 37.2
56.3, 56.1 68.5 168.7 124.1 110.0 149.1 146.3 114.9 121.7 64.8 37.2
56.3, 56.1 68.3 169.1 124.1 110.0 149.1 146.3 114.9 121.7 64.8 37.2
55.9, 55.7 68.5 169.3 123.5 109.5 148.5 145.8 114.6 121.9 64.4 36.8
56.5, 57.1 67.4 169.7 127.9 112.5 149.3 148.4 110.6 133.1 66.5 26.9
56.5, 57.1 67.4 170.0 127.9 112.5 149.2 148.4 110.6 133.2 66.6 26.9
56.5, 57.0 67.8 170.7 127.9 112.4 149.1 148.4 110.6 133.5 66.7 26.9
56.2, 55.9 69.7 171.4 127.2 111.8 148.4 146.8 112.6 127.9 64.3 27.2
56.2, 55.9 68.9 170.8 128.0 111.9 148.6 146.9 112.7 128.3e 64.3 27.2
56.2, 55.9 68.8 171.2 128.0 111.9 148.6 146.9 112.7 128.2e 64.3 27.3
56.2, 55.9 69.2 171.8 127.9 111.7 148.4 146.8 112.8 127.4 64.3 27.2
56.6, 56.8 67.0 167.9 127.7 118.6 148.4 148.7 115.0 138.6 74.9 33.4
130.8,f127.7g
127.79, 130.4
127.6, 130.3
127.6, 131.6
127.6, 131.9f
127.1, 131.0
127.3, 130.7
127.3, 131.0f
127.35, 130.5
126.7, 130.2
126.7, 131.5
126.7,f 126.8
126.6, 131.3
128.3, 128.6
115.7,f
128.3g
114.2,
128.2
129.3,
128.84
129.0,
129.3
115.8,f
129.3
113.9,
128.8
128.4,
128.8
115.6,f
128.3
114.1,
128.2
128.9,
129.1
129.0,
129.2
115.8,f
129.1
114.3,
129.1
128.2,
128.5
128.0,
162.4f
127.81,
159.2
128.75,
128.4
128.9,
134.5
128.9,
162.8f
128.3,
159.4
127.7,
133.5
127.6,
162.3f
127.42,
159.1
128.12,
128.17
128.3,e
134.3
128.2,e
162.8f
128.0,
159.7
127.3,
127.8
a
In ppm (dTMS = 0 ppm) at 125.7 MHz. Solvent: CDCl3. Further signals, OCH3 (Pos. 4, disubstituted benzene): 55.6 (2d, 5d and 6d), 55.3 (3d); NCH2: 39.6 (5b–d), 37.6 (6a, d),
37.4 (6b, c).
b
Assignments were supported by DEPT (except for 3b), HMQC and HMBC (except for 3a, c) measurements.
This numbering was also used for compound 8.
c
d
e
f
ArCH2 for 5b–d, 6a–d.
Two overlapping lines.
Due to C, F-coupling d [Hz], 1J: 246.7 (2c), 248.2 (3c), 246.4 (5c), 247.9 (6c), 2J: 21.4 (2c), 21.6 (3c, 5c and 6c), 3J: 8.2 (2c, 3c and 5c), 4J: 3.5 (2c and 3c), <1 (5c), 3.0 (6c).
g
Reversed assignments are also possible.
*
Previously published compounds, c.f. Ref. [11] (2a) and Ref. [12b] (3a).
relative energy values of the simplified models XIV and XV repre-
senting the two isomerization pathways are similar to those of
model pairs XIIa/XIIIa (Table 1) and associated with the weakly
stabilized carbanion present in ketene XV. In this complex, the so-
dium ion is also tricoordinated by the carbanionic centre, the ke-
tene O and the S atom, but is not coordinated by the distant
imine-N atom. The view concerning the different coordination pat-
terns in XIa, XIIIa and XV discussed above is supported by the
distances between the sodium ion and the potential coordinating
sites (Table 2) calculated for these models. The relative strength
of the N ? Na coordination may also be estimated from the Mullik-
en charge on the N atom, which seems to correlate with the atomic
distance. Its shortening increases the electron-density on the N
centre approaching the Na ion (Table 2). A similar tendency can
be observed for the ketene O atom, but, besides coordination, the
charges on the S and C atoms are also influenced by their different
positions in the anionic ligands.
Finally, it must be pointed out that, although relatively small
energy differences emerged for the overall isomerization processes
and quite large energy differences were obtained for the possible
intermediate pairs in the alternative pathways, the tendencies in
the calculated values corroborate the experimentally observed
structure–reactivity relationships sufficiently to support the pro-
posed mechanisms.
In order to obtain more sophisticated energetics for the actually
studied molecules we performed the geometry optimisation and sub-
sequent energy calculation on cis–trans counterparts 2a–3a, 5a–6a
and 8–9 placed in chloroform by means of B3LYP-6-31 G(d) method
using IEFPCM solvent model which represents the conditions of
NMR measurements (Table 3) giving information on conformation.
The calculated energetics and the relative stability of cis–trans
counterparts obtained by modelling more realistic conditions are
again in keeping with the experimental observations. Although
diastereomer pairs 2a–3a and 5a–6a are very similar in relative
stability, cis-azetothiazepine 8 with complete resistance to epimer-
isation proved to be significantly more stable than trans isomer 9.
The pronounced stability of 8 can at least partly be attributed to p-
stacking interaction as evidenced by the calculated contour plots of
HOMO-3 and HOMO-4 (Fig. 2) showing some delocalisation be-
tween the two cis-oriented phenyl groups.
The reality of conformations resulted by geometry optimisation
in chloroform gains support from the comparison of the chemical
shifts of skeletal protons measured and calculated by GIAO method
[23] at B3LYP/6-311+G(2d,p) level [24] of DFT, respectively (Table
4). As it will be discussed in the next session, the most spectacular
characteristics reflected from both the measured and calculated
values is the significant anisotropic shield exerted by the phenyl
group [25a] attached to C-1 atom on H-9 and on the methoxy

L. Fodor et al. / Journal of Molecular Structure 983 (2010) 54–61
61
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[5] F. Fülöp, Chem. Rev. 101 (2001) 2181.
protons in Pos. 8 in trans isomers 3a and 6a. Such shielding effect
causing upfield shifts on the aforementioned signals was not de-
tected in cis isomers 2a, 5a and 8.
[6] (a) D.R. Williams, D.C. Kammler, A.F. Donnel, W:R:F. Goundry, Angew. Chem.
Int. Ed. 44 (2005) 6715;
3.2. NMR spectroscopy
(b) H. Ge, J.T. Spletstoser, Y. Yang, M. Kayser, G.I. Georg, J. Org. Chem. 72 (2007)
756.
The IR, 1H and 13C NMR data on the new compounds presented
in this paper are given in Tables 5 and 6. They provide unambigu-
ous proof of the presumed structures. The following additional re-
marks are necessary.
[7] (a) W. Van Brabant, Y. Dejaegher, R. Van Landeghem, N. De Kimpe, Org. Lett. 8
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Comprehensive Heterocyclic Chemistry II, vol. 1B, Pergamon Press, Oxford,
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ThepresenceoftheazetidinoneringfollowsfromthehighIRmC@O
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frequencies (1732–1757 cmꢀ1) characteristic of strained b-lactams
[26] and also from the appearance of the 13C NMR carbonyl lines
(167.9–171.8 ppm) in the expected chemical shift interval [25b].
As concerns the cis–trans isomerism, the most uncommon phe-
nomenonis thestrikingdifferencein thechemicalshiftsof themeth-
oxy H atoms in Pos. 8, which lie between 3.89 and 4.05 ppm for the
cis compounds 2a–d, 5b–d and 8, and in the interval 3.20–3.32 ppm
for the trans isomers.
[10] N. Fu, T.T. Tidwell, Tetrahedron 64 (2008) 10465.
[11] L. Fodor, J. Szabó, P. Sohár, Tetrahedron 37 (1981) 963.
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(2000) 3453;
Similarly, the H-9 singlet is significantly upfield-shifted for the
transisomers(5.83 0.02 ppmfor3a–d and6a–d)ascomparedwith
their cis counterparts: 6.84 0.01 ppm (2a–d), 7.18 0.01 ppm (5b–
d) and 7.25 ppm (8).
(c) R. Alcázar, P. Ramírez, R. Vicente, M.J. Mancheño, M.A. Sierra, M. Gómez-
Gallego, Heterocycles 55 (2001) 511;
These observations can be explained by the anisotropic shield-
ing of the benzene ring [25a] in Pos. 1, which lies near H-9 and the
methyl H atoms in the 8-methoxy group in the preferred confor-
mation, containing the thiazine ring in a boat-like form with
out-of-plane S and C-9b. The other conformation (half-boat-like
form with out-of-plane C-4) is unfavourable because of steric hin-
drance between the 9b-phenyl ring and one of the non-bonded
electron pair on the S atom.
(d) L.W.A. vanBerkom, G.J.T. Kuster, R. deGelder, H.W. Scheeren, Eur. J. Org.
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Pihlaja, Tetrahedron 64 (2008) 1002.
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Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery, T. Vreven, Jr., K.N.
Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, M. Klene, H. Li, J.E. Knox, H. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo,
R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W.
Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G.
Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D.
Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S.
Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A.
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[17] The studied compounds were racemates. The term cis or trans refers to the
relative position of the 1-phenyl to the 9b-phenyl (10b-phenyl for compound
8) group throughout the text. In Schemes 1–4, C-1 (for 2a–d and 5a–d, 8) is
A further fact in support of the configuration is the 13C NMR
chemical shift of C-9b. This line is upfield-shifted for the more
crowded trans isomers 3a–d and 6a–d (at 64.3–64.8 ppm) due to
the field effect [25c], while it appears in the interval 66.5–
67.7 ppm for the cis compounds 2a–d and 5b–d.
The cis position of the two phenyl substituents in 8 was proved by
DIFFNOEmeasurements. On saturation of the orthoH atoms of oneof
the benzene rings, the analogous ortho H-signal of the other ring
underwent an intensity enhancement. These results confirm the
near (cis) position of these groups relative to the azetidinone ring.
*
drawn in R .
Acknowledgements
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