2,2′-dibenzothiazolyl disulfide: A versatile reagent for the synthesis of 2-azetidinones

Article abstract of DOI:10.1055/s-2004-835628

2,2′-Dibenzothiazolyl disulfide has been found to be a versatile reagent that provides a convenient and efficient route for the synthesis of β-lactams from Schiffs bases and alkoxy/aryloxy acetic acids. The process involves the formation of thioester of the corresponding acid. Finally, condensation of titanium enolates, derived from these esters, with imines completes the synthesis of 2-azetidinones.

Full text of DOI:10.1055/s-2004-835628

2824
LETTER
2,2¢-Dibenzothiazolyl Disulfide: A Versatile Reagent for the Synthesis of
2-Azetidinones
Synthesis of
2
.
-Azetidinone
D
s
. Sharma,* Seema Kanwar
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India
Fax +91(172)2545074; E-mail: sdsharmapu@yahoo.com
Received 7 July 2004
conditions employed collapses to yield thioester 4 and
triphenyl phosphine oxide (Scheme 1).
Abstract: 2,2¢-Dibenzothiazolyl disulfide has been found to be a
versatile reagent that provides a convenient and efficient route for
the synthesis of b-lactams from Schiff’s bases and alkoxy/aryloxy
acetic acids. The process involves the formation of thioester of the
corresponding acid. Finally, condensation of titanium enolates,
derived from these esters, with imines completes the synthesis of 2-
azetidinones.
The thioester was isolated and characterized through
spectroscopic analysis in order to use it for b-lactam for-
mation through the ester enolate–imine condensation re-
action. The potential of various thioesters for b-lactam
synthesis has already been reported.11,12 The thioester 4
was transformed in situ into the titanium enolate at –78 °C
in dichloromethane and then reacted with N-benzylidene
aniline for 6 hours at –78 °C, a 60:40 mixture of trans-
and cis-b-lactams 6b and 6a was obtained in 70%
yield. Optimization of the reaction parameters (enoliza-
tion at –78 °C, condensation at –78 °C to 0 °C) gave 85%
yield and a slightly improved diastereoselectivity (6a/
6b = 75:25).
Key words: 2,2¢-dibenzothiazolyl disulfide, MBTS/TPP, thiol
ester enolate-imine condensation, 2-azetidinones
The b-lactam is an essential structural motif for a number
of medicinally important natural and unnatural products.1
Considerable efforts have been focused on strategies for
the de novo construction of the 4-membered system.2,3
Among some conceptual approaches to accomplish high-
ly stereospecific azetidinone formation, the annulation of
imino compounds with activated acetic acids has received
considerable attention.4 The key to this synthetic route is
the use of an efficient acid activating agent and the efforts
in this direction continues unabated.
Further, we explored the scope and generality of this
methodology and as shown in Table 1. It is a general
method which could be extended to sterically hindered
compound 4c and heterosubstituted S-thioesters 4a,e,g as
well to aromatic 5a,b and unsaturated 5h imines.13,14
To rationalize the stereochemical outcome of these reac-
tions some information about the structures of enolates as
well as imines was required. From S-thioesters 4d,e,g the
Z-enolates such as 7 are predominantly formed which
avoid unfavorable steric interactions between the R group
and the ligands at the metal. Formation of a 6-membered
chelate between the thiazolyl nitrogen, the carbonyl oxy-
gen, and the titanium atom is likely to account for one of
the adducts (Figure 1).
In continuation of our work towards the development of
such reagents,5,6 we explored the versatility of the title
compound as acid activating agent for the construction of
2-azetidinones. Among the disulfides which have been
found application in synthesis, 2,2¢-dipyridyl disulfide is
the only one which finds an important place in the arsenal
of b-lactam chemistry.7,8 In this paper, we report the use
of another disulfide, 2,2¢-dibenzothiazolyl disulfide (MB-
TS), for the formation of the b-lactam ring, mainly be-
cause it is a low priced chemical. It is also worth
mentioning here that this reagent has been utilized for pre-
paring amides,9 S-thiobenzoyl derivatives,10 and in the
rubber industry as an accelerator.
Cl
Cl
Cl
S
Ti
S
R
ArO
N
O
First, we tried the construction of b-lactam ring by react-
ing MBTS-TPP with phenoxyacetic acid and benzylidine
aniline in dichloromethane in the presence of triethyl-
amine. In this one-pot reaction, we anticipated the forma-
tion of reactive intermediate 3 which could react with
imine 5 to furnish the corresponding b-lactam 6. Howev-
er, using various reaction conditions we were not success-
ful in creating the four-membered ring system. It is
therefore obvious that such an intermediate under the
N
R1
Cl
Cl
O
Ti
S
R1
S
Cl
8
If R = OAr
7
Figure 1
However, compound 4a could equally well react to yield
a 5-membered chelate involving the carbonyl and the aryl-
oxy oxygen, involving E-enolate 8 in which the oxophilic
titanium atom prefers oxygen to nitrogen in the coordina-
tion.22,23 The aromatic and unsaturated imines such as
SYNLETT 2004, No. 15, pp 2824–2826
0
7
.1
2
.2
0
0
4
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835628; Art ID: D18104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Azetidinones
2825
N
N
S
N
S
P+Ph3
1
PPh3
+
-S R'
O
R' =
R'
S
S S
S
(MBTS)
R
OH
Ph
R1
2
Ph
O
O
Ph
P
+
HS R'
R
R
a
+ O
P
+
R'
R'SH
S
O
S R'
Ph
Ph
R1
R1
a
Ph
4
3
–S R'
TiCl4
R2
NR3
–78 °C
R2
NR3
+
O–TiCl3
R
5
b
N
R1
(C2H5)3N
5
S
S
(C2H5)3N
R1
R
R2
+
Ph
R1
H
R1
H
R2
R3
O
P
R'SH
R2
+
R
R
Ph
+
N
R3
Ph
O
N
N
R3
O
O
6b
(trans)
6
6a
(cis)
Scheme 1
5a,b,h existed in E-configuration and were likely to react S-thioesters such as 4b can be explained by model 10,
in their E-configuration.24
where the E-enolate reacts with an E-imine in a boat-like
transition state (Figure 2).
In proposing models of stereoselection, we thought that
cyclic rather than acyclic transition states should be con- In conclusion, we have shown that condensation between
sidered, since in poorly coordinating dichloromethane the the titanium enolates of thioesters, derived from 2,2¢-
imine nitrogen should bind a good Lewis acid such as dibenzothiazolyl disulfide (MBTS), and imines represents
trichlorotitanium enolate. On this basis, the formation of a convenient and versatile entry to monocyclic b-lactams.
trans-b-lactams from S-thioesters such as 4d,e,g can be The low price and convenience of handling of this reagent
considered process via a chair-like model 9, which should can surpass the use of 2,2¢-dipyridyl disulfide for b-lactam
be particularly favored when R and R2 are both bulky formation enabling the present process to become the
groups and that is the case when maximum trans selec- method of choice for large-scale preparations.
tivity is observed. The formation of cis-azetidinones from
Table 1 b-Lactams Prepared Using 2,2¢-Dibenzothiazolyl Disulfide
Entry
a15
R
R1
H
R2
R3
Config. cis:trans Yield (%)a
PhO
PhO
CH3
CH3
PhS
PhS
Phth
PhO
C6H5
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
C6H4OCH3 (p)
75:25
100:0
–
85
70
69
65
72
75
70
75
b16
c17
H
Piperonyl
Piperonyl
Piperonyl
C6H5
CH3
H
d18
e19
20:80
0:100
0:100
0:100
100:0
H
f20
H
Piperonyl
C6H5
g21
h15
H
H
Cinnamyl
a Yield refers to isolated product; all products were identified by comparing FT-IR, NMR, analytical data and TLC with those of authentic
samples.
Synlett 2004, No. 15, 2824–2826 © Thieme Stuttgart · New York

2826
S. D. Sharma, S. Kanwar
LETTER
R1
R2
PMP
S
S
C6H5
R
N
Ti
Cl
S
N
O
Ti
Cl
N
N
S
Cl
Cl
Cl
Cl
O
R1
O
PMP
R2
10
9
(E)-enolate + (E)-imine
3,4-cis
(Z)-enolate + (E)-imine
3,4-trans
Figure 2
the addition of sat. NH4Cl solution and filtered through
celite. The aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried over anhyd Na2SO4 and
concentrated under pressure. The unreacted thioester was
removed by 1 N KOH hydrolysis in THF at r.t. for 2–12 h,
and the remained mixture was flash chromatographed over
silica gel using Et2O–hexane (40:60) as eluent to give the
required b-lactam.
Acknowledgment
Financial support of this work from the CSIR New Delhi (India) is
gratefully acknowledged.
References
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(s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 4.4 (s, 1 H, C4H), 6.70–
7.50 (m, 9 H, ArH). IR (CHCl3): 1748.1 cm–1. Anal. Calcd
for C18H19NO2: C, 76.86; H, 6.76; N, 4.98. Found: C, 76.66;
H, 6.90; N, 5.05.
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(13) General Procedure for the Formation of Thioesters: To
the solution of phenoxy acetic acid (0.1 mmol) and PPh3
(0.12 mmol) in CH2Cl2, MBTS (0.11 mmol) was added and
the contents were stirred for 24 h at r.t. The reaction was
quenched by the addition of H2O and the organic layer
separated, washed with H2O and dried over anhyd Na2SO4.
The excess solvent was removed under vacuum to get
phenoxythioacetic acid S-benzothiazol-2-yl ester.
(14) General Procedure for the Formation of 2-Azetidinones:
To the thioester solution (0.05 M) of phenoxyacetic acid (0.1
mmol) in dry CH2Cl2 cooled at –78 °C, under nitrogen
atmosphere, was added dropwise a TiCl4 solution (0.1
mmol) in CH2Cl2. The solution was stirred for 30 min at this
temperature. To this solution Et3N (0.11 mmol) was added
dropwise at –78 °C and stirred for 15 min. Then, the solution
of benzylidene(4-methoxy-phenyl)amine (0.05 mmol) in dry
CH2Cl2 was added dropwise at –78 °C and the reaction
mixture was stirred for 5 h, and finally at r.t. overnight
(reaction monitored by TLC). The reaction was quenched by
(20) 4-Benzo[1,3]dioxol-5-yl-3-thiophenyl-1-(4-methoxy-
phenyl)-azetidin-2-one (f).
1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 4.05
(d, 1 H, C3H, J = 1.0 Hz), 4.25 (d, 1 H, C4H, J = 1.0 Hz),
5.99 (s, 2 H, OCH2O), 6.75–7.57 (m, 12 H, ArH). IR
(CHCl3): 1751.7 cm–1. Anal. Calcd for C23H19NO4S: C,
68.15; H, 4.69; N, 3.46. Found: C, 68.00; H, 4.60; N, 3.44.
(21) 2-[1-(4-Methoxy-phenyl)-2-oxo-4-phenyl-azetidin-3-yl]-
isoindole-1,3-dione (g).
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H, OCH3), 5.41
(d, 1 H, C3H, J = 3.0 Hz), 5.56 (d, 1 H, C4H, J = 3.0 Hz),
6.63–8.13 (m, 13 H, ArH). IR (CHCl3): 1770 cm–1. Anal.
Calcd for C24H18N2O4: C, 72.36; H, 4.52; N, 3.52. Found: C,
72.00; H, 4.36; N, 4.69.
(22) Reetz, M. T. Organotitanium Reagents in Organic
Synthesis; Springer: Berlin, 1986.
(23) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.;
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Ponzini, F.; Raimondi, L. Tetrahedron 1994, 50, 2939.
Synlett 2004, No. 15, 2824–2826 © Thieme Stuttgart · New York