Stereospecific synthesis of β-lactams from heterocyclic imines using the staudinger reaction

Article abstract of DOI:10.1002/jhet.1688

The reactions of the heterocyclic imines 5,6-dihydro-2H-[1,3]oxazines and 2H-1,4-benzothiazines with different substituted acetyl chlorides in the presence of triethylamine forming β-lactams were examined focusing on the stereochemistry of the Staudinger

Full text of DOI:10.1002/jhet.1688

654
Stereospecific Synthesis of b-Lactams from Heterocyclic Imines
Vol 50
Using the Staudinger Reaction
*
T. Stalling, K. Johannes, S. Polina, and J. Martens
Carl von Ossietzky Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg, Germany
*
E-mail: juergen.martens@uni-oldenburg.de
Received December 13, 2011
DOI 10.1002/jhet.1688
Published online in Wiley Online Library (wileyonlinelibrary.com).
The reactions of the heterocyclic imines 5,6-dihydro-2H-[1,3]oxazines and 2H-1,4-benzothiazines with
different substituted acetyl chlorides in the presence of triethylamine forming b-lactams were examined
focusing on the stereochemistry of the Staudinger reaction.
J. Heterocyclic Chem., 50, 654 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
The b-lactam skeletal structure is the key component
of the widespread antimicrobial agents mainly represented
by the b-lactam antibiotics. The family of b-lactam
antibiotics includes penicillins, cephalosporins, penems,
carbapenems, and monolactams, amongst others [1].
In this article, we report on the Staudinger reaction
of the 5,6-dihydro-2H-[1,3]oxazines 1a–c and especially
of the annulated 2H-1,4-benzothiazines 2a–d and observed
the stereoselectivity of the prepared b-lactams 4 in
accordance with 3 (Scheme 1).
As
a
consequence of the increased resistance
The oxazines 1 were achieved by a multicomponent
reaction from the b-hydroxy aldehyde 2-ethyl-2-
(hydroxymethyl)butanal, ammonia, and a variable carbonyl
compound in dichloromethane. The benzothiazines 2 were
synthesized from 2-aminothiophenol, an a-bromoaldehyde
and sodium hydride in anhydrous tetrahydrofuran [11,12].
The imines 1 and 2 were treated with different ketenes,
which were generated in situ from the respective
substituted acetyl chloride with triethylamine in anhydrous
dichloromethane, to prepare the new b-lactams 3a–c and
4a–j. The b-lactams were obtained in moderate yields
(up to 82%) excepting the ones based on chiral starting
materials (Table 1).
against the common antibiotics [2,3], the interest in
creating new b-lactam antibiotics characterized by a
more specific antibacterial activity is rising. Besides
the antibacterial activity, the b-lactam antibiotics are
adequate for possible applications in inhibiting enzymes
[4,5]. In addition, the b-lactam antibiotics take place as
intermediates in the synthesis of other compounds of
biological interest, for example, a-amino acids and b-amino
acids [6].
As a result of the great interest in b-lactams, different
ways of syntheses were developed. Among the most
important of these methods is the Staudinger reaction [7].
It can be described as a stepwise [2 + 2]-cycloaddition
reaction of an imine and a ketene to form a b-lactam
showing two new stereocenters at the ring. Nowadays,
the relative stereoselectivity of the Staudinger reaction is
still in focus of many investigations [8].
A few years back, we performed the Staudinger
reaction using a special type of heterocyclic imines,
namely 5,6-dihydro-2H-[1,3]oxazines [9]. In the course
of our interest in the synthesis of new heterocyclic
imines [10], we developed a new method for the
synthesis of various types of 2H-1,4-benzothiazines
[11,12]. In the recent past, we focused our attention
on reactions based on this substance class [11–13].
Thus, we were successful in the synthesis of different
types of lactam structures offering opportunities for
many functionalizations.
1
The structures of the products were confirmed by H
NMR, 13C NMR, IR, MS, elemental analyses, and X-ray
structures in certain cases. Particularly, the 1H NMR
spectra of the b-lactam oxazine derivatives 3 show a
characteristic shift of the b-lactam ring proton HA at
3.61–3.67 ppm and 5.05–5.10 ppm of the proton HB
(assignment see Scheme 2). The b-lactam benzothiazine
derivatives 4 show a proton shift for HA at 3.86–4.88 ppm
and 3.95–5.39 ppm for HB. Furthermore, the coupling
constants, situated between 1.5 and 2.7 Hz, are characteristic
for trans b-lactams [14].
According to the 1H NMR spectra, only a single
diastereomer was found in case of the products 3a, 3b, 4a,
4b, 4d, 4e, 4g, and 4h (dr ≥ 95:5) starting from prochiral
imines. We were able to obtain single crystals of 3b and
determined the proposed structure by X-ray analysis (Fig. 1).
© 2013 HeteroCorporation

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b-Lactams from Heterocyclic Imines
655
Scheme 1. Diastereoselective synthesis of the b-lactams 3 and 4 starting
from the heterocyclic imines 1 and 2 (only one enantiomer of the racemic
b-lactams is shown). Reagents and conditions: (a) (i) CH2Cl2, 0ꢀC, (ii) RT,
overnight; (b) (i) NaH, THF, 0ꢀC, (ii) RT, 2 h, (iii) THF, 0ꢀC (iv) RT,
overnight; (c) (i) CH2Cl2, 0ꢀC, (ii) RT, overnight.
The structure documents the postulated trans configura-
tion between the described protons HA and HB. This fact
could be explicated by the proposed mechanism of the
Staudinger reaction [16] of heterocyclic imines (Scheme 2).
The lone electron pair at the nitrogen atom of the C═N
bond of the heterocyclic imine attacks nucleophilicly the
carbonyl group of the ketene that is generated in situ from
the respective substituted acetyl chloride by the use of
triethylamine. A zwitterionic intermediate results from this
process. The attack occurs on the unsubstituted side of the
ketene directing the cyclic moiety of the imine and the
voluminous substituent of the ketene in opposite orienta-
tions. Consequently, the steric hindrance is minimized.
The following ring closure is analog to an intramolecular
nucleophilic addition of the enolate moiety to the iminium
ion moiety. This step proceeds diastereoselectively forming
only the trans b-lactam. The result is consistent with
comparable synthetic results of the Staudinger reaction [17].
Starting from the chiral imines 1c and 2c–d, we obtained
two diastereomers in some cases. For the b-lactam 4c
and 4f, respectively, a dr = 62:38 and a dr = 83:17 were
calculated in the crude product. In case of the racemic
major diastereomer (2S*,2aR*,3R*)-4c, we were able to
obtain single crystals and determined the proposed structure
by X-ray analysis (Fig. 2).
The X-ray structure verifies the postulated trans configu-
ration at the b-lactam ring once more. Furthermore, it is
shown that the voluminous phenyl substituent and the
lactam ring are in trans configuration because of steric
hindrance. As a result, the minor racemic diastereomer
(2S*,2aR*,3S*)-4c shows a cis configuration between the
phenyl substituent and the b-lactam ring. Analogously, the
relative configuration of the b-lactams 3c, 4f, 4i, and 4j
according to chiral starting materials was assigned.
Table 1
b-Lactams 3 and 4.
Imine
Lactam
R1
R2
R3
Yielda (%)
drb
1a
1b
1c
2a
2b
2c
2a
2b
2c
2a
2b
2c
2d
3a
3b
3c
4a
4b
4c
4d
4e
4f
CH3
CH3
-(CH2)5-
H
CH3
-(CH2)5-
C6H5
CH3
-(CH2)5-
C6H5
CH3
-(CH2)5-
C6H5
OC6H5
OC6H5
OC6H5
OCH3
OCH3
OCH3
OC6H5
OC6H5
OC6H5
NPhthd
NPhthd
NPhthd
NPhthd
64
54
19
82
74
28
35
40
18
42
37
23
25
≥95:5
≥95:5
≥95:5c
≥95:5
≥95:5
62:38c
≥95:5
≥95:5
83:17c
≥95:5
≥95:5
≥95:5c
≥95:5c
CH3
CH3
CH3
CH3
CH3
CH3
4g
4h
4i
CH3
CH3
4j
n-C3H7
aAll yields are isolated yields.
bDiastereomeric ratio according to the 1H NMR of the crude product.
cThe diastereomeric ratio implies trans configuration at the b-lactam ring (see further discussion), so dr means the ratio between the b-lactam ring and the
substituent at the six-membered imine ring.
dNPhth means phthalimido.
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T. Stalling, K. Johannes, S. Polina, and J. Martens
Vol 50
Scheme 2. Mechanism of the Staudinger reaction of heterocyclic imines [16].
CONCLUSIONS
Starting from the cyclic imines 1 und 2, we succeeded in
the stereoselective synthesis of the b-lactams 3 and 4 by
the means of the Staudinger reaction. We observed the
diastereoselectivity at the b-lactam ring in all cases. The trans
configuration at the b-lactam ring was verified by X-ray struc-
tures and NMR data. In addition to the imines 1, we applied
the procedure successfully to the annulated benzothiazines 2,
a rarely investigated class of heterocyclic imines.
EXPERIMENTAL
Synthetic procedures, performed under argon atmosphere, were
performed on a vacuum line using standard Schlenk techniques.
Melting points were obtained on a melting point apparatus of
1
laboratory devices and are uncorrected. H and 13C NMR spectra
were recorded with a Bruker AM 300 or a Bruker AMX R 500
spectrometer (Bruker AXS GmbH D-76187, Karlsruhe, Germany)
with TMS as an internal standard in CDCl3 solution. Assignments
of the signals were supported by measurements applying DEPT
and COSY techniques. Mass spectra were obtained on a Finnigan-
MAT 212 mass spectrometer with isobutane as reagent gas. The
IR spectra were recorded with a Bruker Vector 22 spectrometer as
film between NaCl plats or in KBr or with a Bruker Tensor 27 spec-
trometer (Thermo Fisher Scientific, Waltham, MA) equipped with a
“Golden Gate” diamond-ATR (attenuated total reflection) unit.
General procedure for the preparation of the 5,6-dihydro-2H-
1,3-oxazines 1a–c (GP A). A solution of the oxocomponent
(250.0 mmol in case of ketones or 50.0 mmol in case of aldehydes)
and 25% solution of ammonia (3.8 mL, 50.0 mmol) was cooled
down to 0ꢀC. While constantly stirring, 2-ethyl-2-(hydroxymethyl)
butanal (6.51 g, 50.0 mmol), dissolved in 50 mL dichloromethane,
was added dropwise. After having been stirred overnight at room
temperature, 50 mL water was added, and the phases were
separated. The aqueous phase was extracted with dichloromethane
(3 ꢁ 20 mL). The recombined organic phases were dried over
magnesium sulfate, and the solvent was removed under reduced
pressure. The crude product was purified by distillation.
Figure 1. X-ray crystal structure of the racemic b-lactam 3b (only one
enantiomer is shown) [15]. The atom numbering in the X-ray structure
does not follow the IUPAC nomenclature.
5,5-Diethyl-2,2-dimethyl-5,6-dihydro-2H-1,3-oxazine (1a).
Colorless oil; yield: 39%; bp: 70–81ꢀC, 14 mbar; IR (film): n 1650
(C═N) cmꢂ1; 1H NMR (300 MHz, CDCl3): d = 0.91 (t, 3J = 7.5 Hz,
3
6H, 2 ꢁ CH2CH3), 1.40 (2s, 6H, (C(CH3)2), 1.46 (q, J = 7.5 Hz,
3
2H, CH2CH3), 1.47 (q, J = 7.5 Hz, 2H, CH2CH3,), 3.62 (s, 2H,
CH2O), 7.44 (s, 1H, N═CH); 13C NMR (76 MHz, CDCl3):
d = 8.06 (2 ꢁ CH2CH3), 27.19 (C(CH3)2, 2 ꢁ CH2CH3), 38.08
(C(CH2CH3)2), 63.96 (CH2O), 86.33 (C(CH3)2), 164.39
(N═CH); MS (CI, isobutane): m/z (%): 170.2 (15) [MH]+;
HRMS (EI): m/z Calcd for C10H19NO [M]+: 169.1467; found:
169.1467.
3,3-Diethyl-1-oxa-5-azaspiro[5.5]undec-4-ene (1b). Colorless oil;
yield: 65%; bp: 88–92ꢀC, 0.06 mbar; IR (film): n 1650 (C═N) cmꢂ1
;
1H NMR (300 MHz, CDCl3): d =0.66 (t, 3J=7.6Hz, 6H,
2ꢁ CH2CH3), 1.22 (q, 3J=7.6Hz, 4H, 2ꢁ CH2CH3), 1.32–1.50
(m, 10H, 5ꢁ CH2,Cy), 3.35 (s, 2H, CH2O), 7.23 (s, 1H, N═CH);
13C NMR (76 MHz, CDCl3): d =8.63 (2ꢁ CH2CH3), 27.85
(2 ꢁ CH2CH3), 22.55, 25.91, 36.22 (5 ꢁ CH2,Cy), 39.07 (C
CH2CH3)2), 63.72 (CH2O), 87.15 (C(CH2,Cy)5), 165.09 (N═CH);
MS (CI, isobutane): m/z (%): 210.2 (100) [MH]+; HRMS (EI): m/z
Calcd for C13H23NO [M]+: 209.1780; found: 209.1780.
Figure 2. X-ray crystal structure of the racemic major diastereomer
b-lactam (2S*,2aR*,3R*)-4c (only one enantiomer is shown) [15].
The atom numbering in the X-ray structure does not follow the
IUPAC nomenclature.
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(RS)-5,5-Diethyl-2-methyl-5,6-dihydro-2H-1,3-oxazine (1c).
Colorless oil; yield: 60%; bp: 70–79ꢀC, 15mbar; IR (film):
n 1652 (C═N) cmꢂ1; 1H NMR (500MHz, CDCl3): d = 0.87–0.89
(m, 3H, CH2CH3), 0.92–0.94 (m, 3H, CH2CH3), 1.38
(q, 3J = 7.6 Hz, 2H, CH2CH3), 1.41 (d, 3J = 5.8 Hz, 3H, CCH3),
m/z (%): 206.0 (100) [MH]+; HRMS (CI, isobutane): m/z Calcd
for C12H15NS [MH]+: 206.1003; found: 206.1003.
General procedure for the preparation of the b-lactams 3a–c
and 4a–j (GP C). The heterocyclic imine 1 or 2 (5.0mmol) and
anhydrous triethylamine (1.01g, 10.0mmol) were dissolved in
anhydrous dichloromethane (20 mL) and cooled down to 0ꢀC.
The respective acid chloride (5.0mmol), dissolved in anhydrous
dichloromethane (10 ml), was added dropwise. After having been
stirred overnight at room temperature, aqueous saturated
ammonium chloride solution (20mL) was added. The organic
phase was removed and washed with water. The aqueous
phases were extracted with dichloromethane (3ꢁ 20mL). The
recombined organic phases were dried over magnesium sulfate.
After removal of the solvent on a rotary evaporator, the resulting
residue was purified by recrystallization from dichloromethane/
diethyl ether. The obtained solid compound was dried in vacuo.
(6S*,7S*)-5,5-Diethyl-2,2-dimethyl-7-phenoxy-3-oxa-1-azabicyclo
[4.2.0]octan-8-one (3a). Analysis of the crude product by 1H NMR
spectroscopy showed a single diastereomer, indicating a dr≥ 95:5.
After recrystallization, the product was obtained as colorless
crystals. Yield: 64%; mp: 144ꢀC; IR (KBr): n 1740 (C═O), 1235
2
1.50–1.61 (m, 2H, CH2CH3), 3.55 (d, J = 11.4Hz, 1H, CH2O),
3.73 (d, 2J = 11.4Hz, 1H, CH2O), 4.82–4.86 (m, 1H, CHCH3),
7.52 (s, 1H, N═CH); 13C NMR (126 MHz, CDCl3): d = 7.69,
8.43 (2ꢁ CH2CH3), 22.27 (CCH3), 26.51, 28.16 (2ꢁ CH2CH3),
38.96 (C(CH2CH3)2), 68.85 (CH2O), 84.95 (CCH3), 166.34
(N═CH); MS (CI, isobutane): m/z (%): 156.2 (100) [MH]+;
HRMS (EI): m/z Calcd for C9H17NO [M]+: 155.1310; found:
155.1311.
General procedure for the preparation of 2H-1,4-
benzothiazines 2a–c (GP B). Under argon atmosphere, a solution
of 2-aminothiophenol (6.00 g, 48.0 mmol) in anhydrous THF
(20 mL) was added to a suspension of sodium hydride (2.00 g,
50.0 mmol, 60% in oil) in anhydrous THF (70 mL) at 0ꢀC. The
resulted foamy white/violet colored reaction mixture was stirred for
2 h at room temperature. The respective a-bromoaldehyde
(50.5 mmol), dissolved in anhydrous THF (15 mL), was added
dropwise. After having been stirred overnight at room temperature,
molecular sieves were added, and the reaction mixture was stirred
for 3 h. After filtration, the solvent was removed on a rotary
evaporator. The crude product was purified by recrystallization from
petroleum ether 40/60 or by distillation in certain cases.
1
(C-N) cmꢂ1; H NMR (500 MHz, CDCl3): d = 0.83–0.85 (m, 3H,
CH2CH3), 0.88–0.90 (m, 3H, CH2CH3), 1.04–1.11, 1.34–1.44,
1.66–1.72 (3m, 4H, 2 ꢁ CH2CH3), 1.46, 1.76 (2s, 3H, C(CH3)2),
3.35 (d, 2J = 12.5 Hz, 1H, CH2O), 3.60 (d, 2J = 12.5Hz, 1H,
CH2O), 3.62 (d, 3J = n.s., 1H, NCH), 5.07 (d, 3J = n.s., 1H,
CHOC6H5), 7.01–7.03, 7.14–7.16, 7.26–7.31 (3m, 5H, 5 ꢁ Ar-H);
13C NMR (76MHz, CDCl3): d = 7.27, 7.53 (2 ꢁ CH2CH3), 17.96,
22.06, 25.04, 26.30 (C(CH3)2, 2ꢁ CH2CH3), 37.27 (C(CH2CH3)2),
62.21 (NCH), 65.14 (CH2O), 82.66 (CHOC6H5), 83.08
(C(CH3)2), 116.48, 122.42, 129.53, 157.81 (6ꢁ Ar-C), 162.35
(C═O); MS (CI, isobutane): m/z (%): 304.3 (100) [MH]+;
HRMS (CI, isobutane): m/z Calcd for C18H26NO3 [MH]+:
304.1913; found: 304.1913.
2,2-Dimethyl-2H-1,4-benzothiazine (2a) [18]. After recrystallization,
the product was obtained as a colorless solid. Yield: 57%;
1H NMR (500 MHz, CDCl3): d =1.40 (2s, 6H, 2ꢁ CH3), 7.15
(ddd, 3J=7.5Hz, 3J=9.1Hz, 4J= 1.4 Hz, 1H, Ar-H), 7.21 (ddd,
3J=7.8Hz, 3J=9.1Hz, 4J= 1.4 Hz, 1H, Ar-H), 7.25 (dd, 3J=7.5Hz,
4J= 1.4 Hz, 1H, Ar-H), 7.43 (dd, 3J=7.8Hz, 4J= 1.4 Hz, 1H, Ar-H),
7.57 (s, 1H, N═CH); 13C NMR (126 MHz, CDCl3): d = 25.29
(2 ꢁ CH3), 37.10 (C(CH3)2), 123.29, 126.25, 127.37, 127.60,
127.76, 140.94 (6 ꢁ Ar-C), 160.85 (N═CH).
(6S*,7S*)-5,5-Diethyl-7-phenoxy-3-oxa-1-azaspiro[bicyclo[4.2.0]
Spiro[1,4-benzothiazine-2,10-cyclohexane] (2b) [13]. After
recrystallization, the product was obtained as red solid. Yield:
octane-2,10-cyclohexa-ne]-8-one (3b). Analysis of the crude
1
product by H NMR spectroscopy showed a single diastereomer,
1
53%; H NMR (500MHz, CDCl3): d = 1.38–1.44 (m, 1H, CH2,
indicating a dr ≥95:5. After recrystallization, the product was
obtained as colorless crystals. Yield: 54%; mp: 128ꢀC; IR (KBr):
Cy), 1.54–1.65 (m, 3H, 2 ꢁ CH2,Cy), 1.68–1.80 (m, 6H, 3 ꢁ CH2,
Cy), 7.12 (ddd, 3J = 7.5 Hz, 3J = 9.0 Hz, 4J = 1.4 Hz, 1H, Ar-H),
7.20 (ddd, 3J = 7.7 Hz, 3J = 9.2 Hz, 4J = 1.4 Hz, 1H, Ar-H), 7.26
(dd, 3J = 7.5 Hz, 4J = 1.4 Hz, 1H, Ar-H), 7.41 (dd, 3J = 7.8 Hz,
4J = 1.4 Hz, 1H, Ar-H), 7.59 (s, 1H, N═CH); 13C NMR
(126MHz, CDCl3): d = 21.09, 25.58, 33.20 (5 ꢁ CH2,Cy), 42.17
(C(CH2,Cy)5), 122.98, 126.21, 127.70, 127.62, 127.78, 141.78
(6ꢁ Ar-C), 160.73 (N═CH).
n
1739 (C═O), 1247 (C-N) cmꢂ1 1H NMR (500 MHz,
;
CDCl3): d =0.82–0.84 (m, 3H, CH3), 0.87–0.89 (m, 3H, CH3),
1.02–1.09, 1.34–1.45, 1.48–1.55, 1.59–1.65, 1.69–1.75, 1.81–1.88,
2.05–2.08, 2.34–2.39 (8m, 14H, 5 ꢁ CH2,Cy, 2 ꢁ CH2CH3), 3.32
(d, 2J = 12.5Hz, 1H, CH2O), 3.58 (d, 2J = 12.5Hz, 1H, CH2O),
3
3
3.61 (d, J = n.s., 1H, NCH), 5.05 (d, J = n.s., 1H, CHOC6H5),
7.00–7.03, 7.15–7.16, 7.27–7.30 (3m, 5H, 5 ꢁ Ar-H); 13C NMR
(76 MHz, CDCl3): d = 7.32, 7.55 (2 ꢁ CH3), 18.07, 21.50, 21.73,
25.07, 25.15, 30.12, 34.84 (9ꢁ CH2), 37.35 (C(CH2CH3)2), 61.72
(NCH), 64.31 (CH2O), 82.46 (CHOC6H5), 84.51 (C(CH2,Cy)5),
116.48, 122.35, 129.51, 157.84 (6ꢁ Ar-C), 162.41 (C═O); MS
(CI, isobutane): m/z (%): 344.3 (100) [MH]+.
(RS)-2-Methyl-2-phenyl-2H-1,4-benzothiazine (2c) [18].
Purification was not necessary. The product was obtained as
1
brown oil. Yield: 100%; H NMR (500 MHz, CDCl3): d = 1.78
(s, 3H, CH3), 7.10–7.51 (m, 9H, 9 ꢁ Ar-H), 7.86 (s, 1H, N═CH);
13C NMR (126 MHz, CDCl3): d = 24.41 (CH3), 43.76 (CCH3),
122.97, 126.43, 126.88, 127.07, 127.73, 127.78, 127.84, 128.55,
140.42, 141.82 (12 ꢁ Ar-C), 159.48 (N═CH).
(2S*,6S*,7S*)-5,5-Diethyl-2-methyl-7-phenoxy-3-oxa-1-azabicyclo
[4.2.0]octan-8-one (3c). Analysis of the crude product by 1H NMR
spectroscopy showed a single diastereomer, indicating a dr≥ 95:5.
After recrystallization, the product was obtained as colorless
crystals. Yield: 19%; mp: 95–96ꢀC; IR (KBr): n 1744 (C═O),
(RS)-2-Methyl-2-propyl-2H-1,4-benzothiazine (2d). After
distillation, the product was obtained as yellow oil. Yield: 68ꢂ%1;
bp: 152–154ꢀC, 0.07mbar; IR (film): n 1595 (C═N) cm
;
1H NMR (300 MHz, CDCl3): d = 0.89–0.91 (m, 3H, CH2CH3),
1.36 (s, 3H, CCH3), 1.41–1.68 (m, 4H, 2 ꢁ CH2), 7.10–7.43
(m, 4H, 4 ꢁ Ar-H), 7.54 (s, 1H, N═CH); 13C NMR (76 MHz,
CDCl3): d = 14.25 (CH2CH3), 17.39 (CH2CH3), 23.13 (CCH3),
40.29 (CCH2), 41.05 (CCH3), 123.08, 125.98, 127.29, 127.43,
127.66, 140.74 (6 ꢁ Ar-C), 160.52 (N═CH); MS (CI, isobutane):
1244 (C-N) cmꢂ1 1H NMR (500 MHz, CDCl3): d = 0.83–0.85
;
(m, 3H, CH2CH3), 0.85–0.87 (m, 3H, CH2CH3,), 1.10–1.17,
1.39–1.44, 1.62–1.70 (3m, 4H, 2 ꢁ CH2CH3), 1.42 (d, 3J = 6.2 Hz,
3H, CCH3), 3.41 (d, 2J= 12.4 Hz, 1H, CH2O), 3.51
2
3
(d, J= 12.4 Hz, 1H, CH2O), 3.67 (d, J=n.s., 1H, NCHCH), 5.10
(d, 3J= n.s., 1H, CHOC6H5), 5.44 (q, 3J= 6.2 Hz, 1H, CHCH3),
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7.00–7.03, 7.14–7.16, 7.28–7.31 (3m, 5H, 5 ꢁ Ar-H); 13C NMR
(126 MHz, CDCl3): d = 7.27, 7.47 (2 ꢁ CH2CH3), 17.54, 18.86
(2 ꢁ CH2CH3), 25.53 (CCH3), 37.69 (C(CH2CH3)2), 61.58
(NCHCH), 64.67 (CH2O), 74.26 (CCH3), 82.79 (CHOC6H5),
116.33, 122.44, 129.57, 157.71 (6 ꢁ Ar-C), 163.28 (C═O); MS
(CI, isobutane): m/z (%): 290.2 (100) [MH]+.
126.92, 127.97, 128.52, 130.31, 140.53 (12 ꢁ Ar-C), 162.38
(C═O). IR (ATR): n 1748 (C═O) cmꢂ1; MS (CI, isobutane):
m/z (%): 312.1 (100) [MH]+; HRMS (CI, isobutane): m/z Calcd
for C18H18NO2S [MH]+: 312.1058; found: 312.1061.
(2S*,2aR*)-3,3-Dimethyl-2-phenoxy-2a,3-dihydroazeto[1,2-d]
benzo[1,4]thiazin-1(2H)-one (4d). Analysis of the crude product
(2S*,2aR*)-2-Methoxy-3,3-dimethyl-2a,3-dihydroazeto[1,2-d]
benzo[1,4]thiazin-1(2H)-one (4a). Analysis of the crude product
by 1H NMR spectroscopy showed a single diastereomer,
indicating a dr ≥ 95:5. After recrystallization, the product was
obtained as colorless crystals. Yield: 82%; mp: 107–108ꢀC; IR
by 1H NMR spectroscopy showed
a single diastereomer,
indicating a dr≥ 95:5. After recrystallization, the product was
obtained as colorless crystals. Yield: 35%; mp: 120–122ꢀC; IR
1
(KBr): n 1745 (C═O), 1301 (C-N) cmꢂ1; H NMR (500MHz,
CDCl3): d = 1.40, 1.49 (2s, 6H, 2 ꢁ CH3), 4.21 (d, 3J = 1.5 Hz,
1H, NCH), 5.09 (d, 3J = 1.5 Hz, 1H, CHOC6H5), 6.97–7.82
(4m, 9H, 9 ꢁ Ar-H); 13C NMR (126MHz, CDCl3): d = 23.07,
24.87 (2 ꢁ CH3), 40.19 (C(CH3)2), 64.98 (NCH), 83.01
(CHOC6H5), 116.71, 119.02, 121.29, 122.99, 124.41, 126.23,
127.65, 129.74, 130.42, 157.44 (12ꢁ Ar-C), 162.21 (C═O);
MS (CI, isobutane): m/z (%): 312.0 (100) [MH]+; HRMS
(CI, isobutane): m/z Calcd for C18H18NO2S [MH]+: 312.1058;
found: 312.1057.
(ATR): n 1748 (C═O) cmꢂ1 1H NMR (500 MHz, CDCl3):
;
d = 1.35, 1.53 (2s, 6H, C(CH3)2), 3.58 (s, 3H, OCH3), 3.98
3
3
(d, J = 1.5 Hz, 1H, NCH), 4.44 (d, J = 1.5 Hz, 1H, CHOCH3),
6.99 (ddd, 3J = 8.0 Hz, 3J = n.s., 4J = 1.0Hz, 1H, Ar-H), 7.12–7.15
3
4
(m, 2H, 2 ꢁ Ar-H), 7.78 (dd, J = 8.5 Hz, J = 1.0 Hz, 1H, Ar-H);
13C NMR (126 MHz, CDCl3): d = 22.89, 24.87 (C(CH3)), 40.11
(C(CH3)2), 57.98 (OCH3), 64.27 (NCH), 85.49 (CHOCH3),
118.91, 121.17, 124.24, 126.10, 127.62, 130.26 (6ꢁ Ar-C),
162.97 (C═O); MS (CI, isobutane): m/z (%): 250.1 (100) [MH]+;
HRMS (CI, isobutane): m/z Calcd for C13H16NO2S [MH]+:
250.0902; found: 250.0903.
(2S*,2aR*)-2-Phenoxy-2,2a-dihydro-1H-spiro[azeto[1,2-d]
benzo[1,4]thiazine-3,10-cyclohexane]-1-one (4e). Analysis of the
crude product by 1H NMR spectroscopy showed a single
diastereomer, indicating a dr≥ 95:5. After recrystallization, the
product was obtained as colorless crystals. Yield: 40%; mp:
118–119ꢀC; IR (KBr): n 1733 (C═O) cmꢂ1; 1H NMR (500MHz,
CDCl3): d = 1.19–1.89 (m, 10H, 5 ꢁ CH2,Cy), 4.25 (d, 3J = 1.5 Hz,
1H, NCH), 5.27 (d, 3J = 1.5 Hz, 1H, CHOC6H5), 6.99–7.79
(5m, 9H, 9 ꢁ Ar-H); 13C NMR (126MHz, CDCl3): d = 21.43,
21.46, 25.88, 28.88, 33.74 (5ꢁ CH2,Cy), 46.10 (C(CH2,Cy)5),
65.28 (NCH), 82.12 (CHOC6H5), 116.54, 118.81, 120.49, 122.81,
124.34, 126.13, 128.11, 129.69, 130.87, 157.38 (Ar-C), 162.03
(C═O); MS (CI, isobutane): m/z (%): 352.2 (100) [MH]+.
(2S*,2aR*)-2-Methoxy-2,2a-dihydro-1H-spiro[azeto[1,2-d]benzo
[1,4]thiazine-3,10-cyclohexane]-1-one (4b). Analysis of the crude
1
product by H NMR spectroscopy showed a single diastereomer,
indicating a dr≥ 95:5. After recrystallization, the product was
obtained as brown solid. Yield: 74%; mp: 127–131ꢀC; IR (ATR):
n 1749 (C═O) cmꢂ1; 1H NMR (500MHz, CDCl3): d = 1.19–1.29
(m, 1H, CH2,Cy), 1.39–1.44 (m, 1H, CH2,Cy), 1.54–1.92 (m, 8H,
4 ꢁ CH2,Cy), 3.58 (s, 3H, OCH3), 3.98–3.99 (m, 1H, NCH),
4.60 (d, 3J = 2.0 Hz, 1H, CHOCH3), 6.96–6.99 (m, 1H, Ar-H),
7.11–7.14 (m, 1H, Ar-H), 7.16–7.17 (m, 1H, Ar-H), 7.75–7.77
(m, 1H, Ar-H); 13C NMR (126 MHz, CDCl3): d = 21.48, 21.49,
25.95, 28.71, 33.95 (5 ꢁ CH2,Cy), 46.12 (C(CH2,Cy)5), 57.94
(OCH3), 64.92 (NCH), 84.84 (CHOCH3), 118.76, 120.48, 124.14,
126.05, 128.09, 130.94 (6ꢁ Ar-C), 162.70 (C═O); MS (CI,
isobutane): m/z (%): 290.1 (100) [MH]+; HRMS (CI, isobutane):
m/z Calcd for C16H20NO2S [MH]+: 290.1215; found: 290.1214.
(2S*,2aR*,3R*)- and (2S*,2aR*,3S*)-2-Methoxy-3-methyl-
3-phenyl-2a,3-dihydroazeto[1,2-d]benzo[1,4]thiazin-1(2H)-one
(4c). Analysis of the crude product by 1H NMR spectroscopy
revealed a 62:38 mixture of diastereomers. The diastereomers
were separated by recrystallization from dichloromethane/diethyl
ether. The major diastereomer (2S*,2aR*,3R*)-4c was obtained
as colorless crystals. Yield: 20%; mp: 114–116ꢀC; 1H NMR
(500MHz, CDCl3): d = 1.69 (s, 3H, CCH3), 3.35 (s, 3H, OCH3),
4.48–4.49 (m, 2H, NCH, CHOCH3), 7.02–7.05 (m, 1H, Ar-H),
7.18–7.22 (m, 2H, 2 ꢁ Ar-H), 7.36–7.39 (m, 1H, Ar-H), 7.44–7.47
(m, 2H, 2 ꢁ Ar-H), 7.58–7.59 (m, 2H, 2 ꢁ Ar-H), 7.86–7.88
(m, 1H, Ar-H); 13C NMR (126 MHz, CDCl3): d = 21.85 (CCH3),
46.65 (CCH3), 57.91 (OCH3), 63.54 (CHOCH3), 85.83
(NCH), 118.98, 121.87, 124.25, 126.30, 126.37, 127.70, 128.43,
129.20, 130.40, 140.23 (12 ꢁ Ar-C), 163.12 (C═O). The minor
diastereomer (2S*,2aR*,3S*)-4c was obtained as yellow solid.
Yield: 8%; mp: 107–109ꢀC; 1H NMR (500 MHz, CDCl3): d =1.90
(s, 3H, CCH3), 3.44 (s, 3H, OCH3), 3.86 (d, 3J= 2.0 Hz, 1H, NCH),
3.95 (d, 3J= 2.0 Hz, 1H, CHOCH3), 6.99 (ddd, 3J=7.5Hz,
3J=8.5Hz, 4J= 1.0 Hz, 1H, Ar-H), 7.10 (ddd, 3J=7.5Hz,
(2S*,2aR*,3R*)- and (2S*,2aR*,3S*)-3-Methyl-2-phenoxy-
3-phenyl-2a,3-dihydroazeto[1,2-d]benzo[1,4]thiazin-1(2H)-one
(4f). Analysis of the crude product by 1H NMR spectroscopy
revealed an 83:17 mixture of diastereomers. The diastereomers
were separated by recrystallization from dichloromethane/diethyl
ether. The major diastereomer (2S*,2aR*,3R*)-4f was obtained
as brown solid. Yield: 10%; mp: 141–143ꢀC; IR (KBr): n 1746
1
(C═O), 1239 (C-N) cmꢂ1; H NMR (300 MHz, CDCl3): d =1.75
3
3
(s, 3H, CH3), 4.74 (d, J= 1.8 Hz, 1H, NCH), 5.11 (d, J=1.8Hz,
1H, CHOC6H5), 6.90–7.92 (m, 14H, 14 ꢁ Ar-H); 13C NMR
(126 MHz, CDCl3): d = 21.83 (CH3), 46.53 (CCH3), 64.01 (NCH),
83.11 (CHOC6H5), 116.14, 119.04, 121.86, 122.62, 124.41,
126.30, 126.42, 127.54, 128.48, 129.15, 129.49, 130.22, 139.77,
157.08 (12 ꢁ Ar-C), 162.13 (C═O). The minor diastereomer
(2S*,2aR*,3S*)-4f was obtained as colorless solid. Yield: 8%; mp:
1
107–109ꢀC; H NMR (500 MHz, CDCl3): d = 1.90 (s, 3H, CH3),
4.24 (d, 3J= 1.9 Hz, 1H, NCH), 4.62 (d, 3J= 1.9 Hz, 1H,
CHOC6H5), 7.01–7.82 (m, 14H, 14 ꢁ Ar-H); 13C NMR (126 MHz,
CDCl3): d = 25.37 (CH3), 46.60 (C(CH3)), 63.47 (NCH), 83.77
(CHOC6H5), 116.33, 119.26, 122.82, 123.57, 124.62, 125.46,
125.89, 126.81, 128.13, 128.63, 129.67, 130.26, 140.53, 157.06
(18 ꢁ Ar-C), 161.40 (C═O). IR (KBr): n 1746 (C═O), 1239 (C-N)
cmꢂ1; MS (CI, isobutane): m/z (%): 374.0 (100) [MH]+.
2-((2S*,2aR*)-3,3-Dimethyl-1-oxo-1,2,2a,3-tetrahydroazeto[1,2-d]
benzo[1,4]thiazin-2-yl)isoindoline-1,3-dione (4g). Analysis of the
crude product by 1H NMR spectroscopy showed a single
4
3J=8.0Hz, J= 1.5 Hz, 1H, Ar-H), 7.15–7.18 (m, 6H, 6 ꢁ Ar-H),
diastereomer, indicating
the product was obtained as colorless crystals. Yieꢂld1: 42%; mp:
197–198ꢀC; IR (KBr): n 1788, 1729 (C═O) cm 1H NMR
(300 MHz, CDCl3): d = 1.45, 1.51 (2s, 6H, 2 ꢁ CH3), 4.36
a dr≥ 95:5. After recrystallization,
3
7.70 (dd, J=8.0Hz, 4J= 1.0 Hz, 1H, Ar-H); 13C NMR (126 MHz,
CDCl3): d = 25.44 (CCH3), 46.62 (CCH3), 58.02 (OCH3), 62.85
(CHOCH3), 86.77 (NCH), 119.19, 123.54, 124.43, 125.44, 125.81,
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2013
b-Lactams from Heterocyclic Imines
659
(d, 3J = 2.7 Hz, 1H, NCH), 5.23 (d, 3J = 2.7 Hz, 1H, CHC═O),
7.00–7.90 (m, 8H, 8 ꢁ Ar-H); 13C NMR (76 MHz, CDCl3):
d = 22.38, 24.48 (2 ꢁ CH3), 40.31 (C(CH3)2), 56.45 (CHC═O),
63.39 (NCH), 118.80, 120.96, 123.88, 124.26, 126.24, 127.65,
130.53, 131.62, 134.63 (12 ꢁ Ar-C), 160.17 (C═O), 166.68
(C═O); MS (CI, isobutane): m/z (%): 365.2 (100) [MH]+; Anal.
Calcd for C20H16N2O3S (364.4): C, 65.92; H, 4.43; N, 7.69; S,
8.80; found: C, 65.56; H, 4.33; N, 7.55; S, 8.67.
6.99–7.92 (m, 8H, 8 ꢁ Ar-H); 13C NMR (126 MHz, CDCl3):
d = 14.50 (CH2CH3), 17.27 (CH2CH3), 19.71 (CH3), 40.63
(CCH3), 44.49 [CCH3], 56.88 (CHC═O), 62.68 (NCH), 118.69,
120.51, 123.88, 124.22, 126.12, 127.72, 130.53, 131.60, 134.61
(12 ꢁ Ar-C), 160.36 (C═O), 166.69 (C═O); MS (CI, isobutane):
m/z (%): 393.0 (100) [MH]+; Anal. Calcd for C22H20N2O3S
(392.5): C, 67.33; H, 5.14; N, 7.14; S, 8.17; found: C, 67.35; H,
5.33; N, 7.00; S, 8.16.
2-((2S*,2aR*)-1-Oxo-2,2a-dihydro-1H-spiro[azeto[1,2-d]
benzo[1,4]thiazine-3,10-cyclohexane]-2-yl)isoindoline-1,3-dione
(4h). Analysis of the crude product by 1H NMR spectroscopy
showed a single diastereomer, indicating a dr ≥95:5. After
recrystallization, the product was obtained as colorless crystals.
Yield: 37%; mp: 138–139ꢀC; IR (KBr): n 1766, 1728 (C═O)
Acknowledgments. T. S. and K. J. gratefully acknowledged the
Heinz-Neumüller-Stiftung for a doctoral fellowship.
cmꢂ1 1H NMR (500 MHz, CDCl3): d =1.30–1.92 (m, 10H,
;
3 3
5ꢁ CH2,Cy), 4.34 (d, J= 2.7 Hz, 1H, NCH), 5.39 (d, J=2.7Hz,
1H, CHC═O), 6.94–7.88 (m, 8H, 8 ꢁ Ar-H); 13C NMR (126 MHz,
CDCl3): d = 21.37, 21.44, 25.74, 28.00, 33.51 (5 ꢁ CH2,Cy), 46.24
(C(CH2,Cy)5), 55.66 (CHC═O), 63.95 (NCH), 118.58, 120.22,
123.82, 124.15, 126.17, 128.08, 131.09, 131.59, 134.59 (12 ꢁ Ar-
C), 159.85 (C═O), 166.71 (C═O); MS (CI, isobutane): m/z (%):
405.2 (100) [MH]+; Anal. Calcd for C23H20N2O3S (404.5):
C, 68.30; H, 4.98; N, 6.93; S, 7.93; found: C, 68.59; H, 5.14; N,
6.69; S, 7.52.
REFERENCES AND NOTES
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2-((2S*,2aR*,3R*)-3-Methyl-1-oxo-3-phenyl-1,2,2a,3-
tetrahydroazeto[1,2-d]benzo[1,4]thiazin-2-yl)isoindoline-1,3-dione
(4i). Analysis of the crude product by 1H NMR spectroscopy
showed a single diastereomer, indicating a dr ≥95:5. After
recrystallization, the product was obtained as colorless crystals.
Yield: 23%; mp: 192–193ꢀC; IR (KBr): n 1767, 1729 (C═O)
[6] Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr
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1
cmꢂ1; H NMR (500MHz, CDCl3): d =1.86 (s, 3H, CH3), 4.88
(d, 3J = 2.7 Hz, 1H, NCH), 5.38 (d, 3J= 2.7 Hz, 1H, CHC═O),
7.07–7.96 (m, 13H, 13 ꢁ Ar-H); 13C NMR (126 MHz, CDCl3):
d = 21.27 (CH3), 46.89 (CCH3), 57.18 (CHC═O), 62.68 (NCH),
118.81, 121.43, 123.86, 124.28, 126.08, 126.38, 127.69, 128.32,
129.08, 130.47, 131.45, 134.56, 139.49 (18 ꢁ Ar-C), 160.44
(C═O), 166.51 (C═O); MS (CI, isobutane): m/z (%): 427.2 (100)
[MH]+; Anal. Calcd for C25H18N2O3S (426.5): C, 70.40; H, 4.25;
N, 6.57; S, 7.52; found: C, 70.82; H, 4.35; N, 6.55; S, 7.57.
2-((2S*,2aR*,3R*)-3-Methyl-1-oxo-3-propyl-1,2,2a,3-
tetrahydroazeto[1,2-d]benzo[1,4]thiazin-2-yl)isoindoline-1,3-dione
(4j). Analysis of the crude product by 1H NMR spectroscopy
showed a single diastereomer, indicating a dr ≥95:5. After
recrystallization, the product was obtained as brown crystals.
Yield: 25%; mp: 198–200ꢀC; IR (KBr): n 1755, 1728 (C═O)
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ccdc.cam.ac.uk/data_request/cif.
cmꢂ1 1H NMR (500MHz, CDCl3): d =0.92–0.94 (m, 3H,
;
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CH2CH3), 1.49 (s, 3H, CCH3), 1.36–1.77 (m, 4H, 2 ꢁ CH2), 4.43
(d, 3J = 2.7 Hz, 1H, NCH), 5.24 (d, 3J= 2.7 Hz, 1H, CHC═O),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet