A convenient CeCl3·7H2O/NaI-promoted synthesis of structurally novel and strained tricyclic β-lactams from hydrazines

Article abstract of DOI:10.1016/j.tetlet.2008.07.068

A convenient synthetic protocol for structurally novel and strained highly derivatized tricyclic β-lactams has been developed. The synthesis involves CeCl₃·7H₂O/NaI catalyzed addition-condensation of mercaptoacetic acid and N-aroyl-N′-arylidenehydrazines followed by intramolecular cyclodehydration to afford bicyclic 5H-thiazolo[4,3-b][1,3,4]-oxadiazoles, which on treatment with acid chlorides in the presence of triethylamine furnish highly derivatized tricyclic 3H-azetidino[2,1-b]-thiazolo[3,4-d][1,3,4]-oxadiazol-6-ones in 80-93% yields. The process presents an excellent illustration of Ce(III)-catalyzed C-C, C-N and C-S bond formation in a one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2008.07.068

Tetrahedron Letters 49 (2008) 5553–5556
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A convenient CeCl3ꢀ7H2O/NaI-promoted synthesis of structurally
novel and strained tricyclic b-lactams from hydrazines
*
Lal Dhar S. Yadav , Vijai K. Rai
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthetic protocol for structurally novel and strained highly derivatized tricyclic b-lactams
has been developed. The synthesis involves CeCl3ꢀ7H2O/NaI catalyzed addition–condensation of mercap-
toacetic acid and N-aroyl-N0-arylidenehydrazines followed by intramolecular cyclodehydration to afford
bicyclic 5H-thiazolo[4,3-b][1,3,4]-oxadiazoles, which on treatment with acid chlorides in the presence of
triethylamine furnish highly derivatized tricyclic 3H-azetidino[2,1-b]-thiazolo[3,4-d][1,3,4]-oxadiazol-6-
ones in 80–93% yields. The process presents an excellent illustration of Ce(III)-catalyzed C–C, C–N and
C–S bond formation in a one-pot procedure.
Received 7 June 2008
Revised 9 July 2008
Accepted 12 July 2008
Available online 16 July 2008
Keywords:
b-Lactams
Antibiotics
Ó 2008 Elsevier Ltd. All rights reserved.
Trinems
CeCl3ꢀ7H2O/NaI catalysis
Hydrazines
1,3,4-Oxadiazoles
Thiazoles
b-Lactam antibiotics have occupied a central role in the fight
against bacterial infections over the past several decades.1 Bacte-
rial resistance to b-lactam antibiotics by producing b-lactamase
is a serious concern, which has motivated a growing interest in
the synthesis of new types of b-lactams. An attractive strategy to
overcome this problem consists of the co-administration of an
antibiotic and suicide inhibitor2 of the enzyme, which restores
the activity of sensitive antibiotics by selectively inactivating b-
lactamase. The easy opening of the b-lactam ring is a prerequisite
for the design of new suicide inhibitors of b-lactamase.
Recently, tricyclic b-lactam antibiotics, generally referred to as
trinems, have been the subject of considerable study owing to their
broad spectrum of antibacterial activity, resistance to b-lactamase
and stability to renal dehydropeptidases.3 Amongst the most
remarkable of these are GV104326 and GV143253A (Fig. 1). The
ever-growing new applications of 2-azetidinones in fields such as
enzyme inhibition4 to the use of these products as starting materi-
als to develop new synthetic methodologies5 has triggered
renewed interest in the construction of new polycyclic b-lactam
systems in an attempt to move away from classical b-lactam anti-
biotic structures.6 Thus, tricyclic b-lactams have become interest-
ing targets for synthesis in modern synthetic organic chemistry.
Trivalent rare earth compounds7 such as Ce(III) salts exhibit
characteristic Lewis acid properties. After the pioneering work by
H
HO
HO
H
N
H
H
H
N
N
OMe
CO2Na
GV104326
O
O
CO2Na
GV143253A
Figure 1.
Luche8 and Imamoto,9 numerous reactions and methodologies
employing Ce(III) derivatives as key components have been devel-
oped.10 Amongst these, commercially available CeCl3ꢀ7H2O has
attracted much attention as a Lewis acid in organic synthesis due
to its special attributes, which include water tolerance, non-toxi-
city and easy handling.11 It has been reported that the Lewis acid
character of CeCl3ꢀ7H2O increases very strongly in conjunction
with an iodine source such as NaI.12 The CeCl3ꢀ7H2O/NaI system
is active towards the cleavage of carbon–oxygen and silicon–
oxygen bonds under neutral conditions,13 and new reactions
for nitrogen–carbon14 and oxygen–carbon15 bond formation
promoted by this system have also been developed.
Along with various reports16 on the synthesis of trinems, we
have also described the synthesis of b-lactam antibiotics.17 Most
of these trinems have been prepared by annulation of 2-azetidi-
none with carbocyclic rings, whereas in the present study we have
fused the 2-azetidinone motif with heterocyclic rings of biological
potential. The continued interest of synthetic chemists in tricyclic
* Corresponding author. Tel.: +91 5322500652; fax: +91 5322460533.
E-mail address: ldsyadav@hotmail.com (L. D. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.068

5554
L. D. S. Yadav, V. K. Rai / Tetrahedron Letters 49 (2008) 5553–5556
Table 1
b-lactams and our ongoing efforts to develop new, one-pot hetero-
cyclization processes,18 especially for small rings,17,19 prompted us
to design and realize the annulation of 2-azetidinone with a biolog-
ically versatile thiazolo-oxadiazole framework, which is hitherto
unreported and appears to offer an attractive scaffold for exploiting
chemical diversity and generating a drug-like library to screen lead
candidates. In the present Letter, we disclose the straightforward
synthesis of trinem antibiotics, namely, highly derivatized 3H-
azetidino[2,1-b]-thiazolo[3,4-d][1,3,4]-oxadiazol-6-ones 3 starting
from N-aroyl-N0-arylidenehydrazines 1 (Scheme 1). A probable
mechanism for the facile ring opening of strained tricyclic b-lac-
tams 3, which is a prerequisite for the design of new suicide inhib-
itors of b-lactamase, is shown in Scheme 2.
Optimization of the Lewis acid catalyst for the synthesis of 6a
Entry
Catalysta
Timeb (h)
Yieldc,d (%)
1
2
3
4
5
6
Ce2(SO4)3ꢀ8H2O
Ce2(SO4)3ꢀ8H2O/NaI (1:1)
CeCl3ꢀ7H2O
10
9
8
6
8
29
71
51
83
17
13
CeCl3ꢀ7H2O/NaI (1:1)
Cu(OTf)2
Zn(ClO4)2
8
a
Catalyst loading was 25 mol %.
Time for completion of the reaction at 60 °C as indicated by TLC.
Yield of isolated and purified product 6a.
b
c
d
For the experimental procedure, see Ref. 19.
In our initial experimentation for the synthesis of compounds 6,
we used anhydrous ZnCl2 as catalyst with reagents 1 and 2; how-
ever, compounds 5, rather than 6, were isolated in 69–72% yields,
which on further treatment with concd H2SO4 afforded thiazolo-
1,3,4-oxadiazoles 6 in 57–64% yields (Scheme 3). In order to
improve the yields and synthesize thiazolo-1,3,4-oxadiazoles 6
expeditiously from compounds 1 in a one-pot procedure, we exam-
ined various Lewis acid catalysts (Table 1). Amongst these, the best
result was obtained with CeCl3ꢀ7H2O/NaI (1:1) (Table 1, entry 4).
This is in conformity with the earlier observation that the catalytic
activity of CeCl3ꢀ7H2O increases dramatically in the presence of an
iodide source, such as NaI,12 owing to the formation of a complex
which exhibits stronger Lewis acid character than CeCl3ꢀ7H2O.
We also tested the effect of solvents on the formation of 6a and
found that amongst MeOH, EtOH, 1,4-dioxane and THF, EtOH was
the best solvent in terms of the yield.
The present optimized synthesis is accomplished by stirring a
mixture of N-aroyl-N0-arylidenehydrazine 1, mercaptoacetic acid
2 and CeCl3ꢀ7H2O/NaI in ethanol with a few drops of water at
60 °C for 6–9 h to afford 5H-thiazolo[4,3-b][1,3,4]-oxadiazoles 6
in 79–85% yields.19 Compounds 6 on stirring with an acid chloride
and triethylamine in dioxane at room temperature for 4–6 h affor-
ded the target b-lactams 320 in 80–93% yields (Table 2). The
CeCl3ꢀ7H2O/NaI-catalyzed one-pot synthesis of compounds 6 from
N-aroyl-N0-arylidenehydrazines 1 is postulated via intermediate
formation of compounds 5 and 9 (Scheme 4). This conclusion is
based on the observation that the representative intermediate
compound 5a could be isolated in 42% yield,21 and that this could
be converted into the corresponding thiazolo-1,3,4-oxadiazole 6a
in quantitative yield. The formation of trinems 3 was entirely dia-
stereoselective. The relative stereochemistry of 3 was established
by NOE experiments. For example, an 8.5% NOE was observed
between 3-H and 7-H; 6.7% between 7-H and the Me of 4-MeOC6H4
at position 7a in the case of compound 3e, whereas a 9.2% NOE was
observed between 3-H and 7-Me; 7.9% between 7-Me and the Me
of 4-MeOC6H4 at position 7a in the case of compound 3k (Fig. 2).
This indicates that 3-H, 7-H/Me and 4-MeOC6H4 at position 7a
Ar2
O
CO2H
HS
S
2
O
Ar2
N
N
N
Ar1
N
H
1. CeCl3.7H2O
NaI
R1
O
R2 Ar1
1
2. Et3N
3
R1R2CHCOCl
3
Ar1
Ph
4-MeOC6H4
4-ClC6H4
Ar2
3
Ar1
Ar2
R1
R1
R2
R2
a
b
c
d
e
f
g
h
i
j
k
l
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
Cl Ph
Cl 4-MeOC6H4
Cl 4-ClC6H4
H
H
H
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me Cl Ph
Me Cl 4-MeOC6H4
Me Cl 4-ClC6H4
Cl Ph
Cl 4-MeOC6H4
Cl 4-ClC6H4
Scheme 1. Formation of tricyclic b-lactams 3.
Table 2
H
H
Ar2
Ar2
CeCl3ꢀ7H2O/NaI-promoted synthesis of compounds 3 and 6
O
O
S
S
OH
O
Product
Timea (h)
Yieldb,c (%)
N
O
N
N
N
R1
R1
β-lactamase
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
6a
6b
6c
6d
6e
6f
4
4
6
4
5
5
5
6
4
5
5
6
6
7
8
6
9
7
85
81
80
83
83
91
80
80
88
93
82
88
83
80
85
79
84
82
O
Ar1
R2
Ar1
R2
4
3
Scheme 2. Probable mechanism for the ring opening of strained tricyclic b-lactams
3.
Ar2
Ar2
O
Conc.
2
H2SO4
N
O
Ar1
N
1
N N
H
Ar1
S
anhyd.
ZnCl2
S
O
6
5
Ar1
Ph
4-MeOC6H4
4-ClC6H4
Ar2 5,6
5,6
Ar1
Ph
Ar2
a
b
c
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
d
e
f
a
4-MeOC6H4
4-ClC6H4
Time for oil-bath heating at 60 °C.
Yield of isolated and purified products.
All compounds gave C, H and N analyses within 0.36% and satisfactory spectral
b
c
(IR, 1H NMR, 13C NMR and EIMS) data.
Scheme 3. Synthesis of compounds 6 from 1 using anhyd ZnCl2.

L. D. S. Yadav, V. K. Rai / Tetrahedron Letters 49 (2008) 5553–5556
5555
Ar2
O
HS
CO2H
O
Ar2
2
O
EtOH
-H2O
Ar2CHO
HN
N
Ar1
N
H
NH2
Ar1
N
H
S
Ar1
CeCl3.7H2O/NaI
N
HO
H
8
1
9
7
O
Ar2
Ar2
S
Ar2
O
S
O
N
Et3N
N
O
Ar1
N
N
N N
H
O
Ar1
-H2O
S
R1
R1R2CHCOCl
-H2O
O
R2
Ar1
3
5
6
Scheme 4. Postulated intermediates leading to the formation of strained tricyclic b-lactams 3.
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3e; NOE 8.5%
3k; NOE 9.2%
3e; NOE 6.7%
3k; NOE 7.9%
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R1
7
O
6
Cl
Me
O
7a
5
N
O
8a
N4
H
Ar2
8
3
S 2
1
Figure 2. Observed NOE’s in compounds 3e and 3k.
5. (a) Alcaide, B.; Almendros, P. Synlett 2002, 381; (b) Alcaide, B.; Almendros, P.
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are located on the same face of the molecule, that is, cis to one an-
other, and thus the 4-MeOC6H4 and Ar2 groups are trans to each
other.
In the preliminary in vitro antibacterial assay of compounds 3
and 6 against Escherichia coli and Staphylococcus aureus, it was
found that trinems 3 bearing a b-lactam ring were much more
active against both the tested bacteria than their precursors 6. Of
these, 3i and 3l exhibited antibacterial activity comparable with
amoxicillin at 1000 ppm concentration. A detailed study on the
antibacterial potential of trinems 3, including their co-administra-
tion as a suicide inhibitor with an antibiotic, is in progress and will
be published elsewhere.
In summary, we have developed a general, Lewis acid-promoted
and straightforward synthetic protocol for structurally novel and
strained tricyclic b-lactams using readily available substrates. The
protocol is conceptually new as it offers an easy access to the
trinem class of antibiotics incorporating a 2-azetidinone motif
fused with heterocyclic rings of biological potential instead of
carbocyclic rings.
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Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002, 468.
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Acknowledgement
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra.
References and notes
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L. D. S. Yadav, V. K. Rai / Tetrahedron Letters 49 (2008) 5553–5556
19. General procedure for the synthesis of 2,5-diaryl-5H-thiazolo-[4,3-b][1,3,4]-
oxadiazoles 6: A solution of CeCl3ꢀ7H2O (1.25 mmol) and NaI (1.25 mmol) in
ethanol (15 mL) and a few drops of water was stirred at 60 °C for 15 min. Then,
N-aroyl-N0-arylidenehydrazine 1 (5 mmol) and mercaptoacetic acid 2 (6 mmol)
were added with stirring at 60 °C. The reaction mixture was further stirred at
60 °C for 6–9 h. After completion of the reaction (monitored by TLC), the
reaction mixture was cooled to room temperature and treated with a saturated
solution of sodium bicarbonate to neutralize the unreacted acid. Water (10 mL)
was added, the mixture was extracted with dichloromethane (3 ꢁ 20 mL),
dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.
The crude product 6 thus obtained was crystallized from ethanol to afford an
analytically pure sample of 6. Physical data of representative compound 6a:
Yellowish solid, yield 83%, mp 130–131 °C. IR (KBr) mmax 3011, 1763, 1635,
PhCHS), 7.09–7.81 (m, 10Harom). 13C NMR (100 MHz; CDCl3/TMS) d: 48.2, 57.9,
72.5, 102.6, 124.5, 125.8, 126.9, 127.5, 128.3, 129.2, 130.5, 131.4, 152.1, 172.3.
EIMS (m/z): 322 (M+). Anal. Calcd for C18H14N2O2S: C, 67.06; H, 4.38; N, 8.69.
Found: C, 67.27; H, 4.59; N, 8.55. Compound 3f: Yellowish solid, yield 91%, mp
174–176 °C. IR (KBr) mmax 3008, 1765, 1601, 1585, 1451 cmꢂ1 1H NMR
.
(400 MHz; CDCl3/TMS) d: 4.38 (s, 1H, @CH), 4.63 (s, 1H, HC@O), 5.61 (s, 1H,
PhCHS), 7.07–7.68 (m, 7Harom), 7.73–7.89 (m, 2Harom). 13C NMR (100 MHz;
CDCl3/TMS) d: 58.1, 73.0, 73.5, 103.7, 125.3, 126.1, 126.9, 128.5, 129.8, 130.7,
131.5, 132.9, 152.5, 172.6. EIMS (m/z): 390, 392 (M, M+2). Anal. Calcd
for C18H12Cl2N2O2S: C, 55.25; H, 3.09; N, 7.16. Found: C, 55.03; H, 2.97;
N, 7.33.
21. Isolation of the intermediate compound 5a and its conversion into the
corresponding product 6a: The procedure followed was the same as described
above for the synthesis of 6 except that the time of stirring in this case was 3 h
instead of 6–9 h. Compound 5a was recrystallized from ethanol to give an
analytically pure sample. To a well-stirred solution of CeCl3ꢀ7H2O and NaI
(each 25 mol% with respect to 5a) in ethanol containing a few drops of water
was added 5a and the stirring continued for 5 h at 60 °C. Then, the reaction
mixture was cooled to rt, water (10 mL) was added, the mixture extracted with
dichloromethane (3 ꢁ 20 mL), dried over anhydrous magnesium sulfate,
filtered and evaporated to dryness. The crude product 6a thus obtained was
crystallized from ethanol to afford an analytically pure sample in quantitative
yield. Physical data of isolated intermediate compound 5a: Yellowish solid,
yield 42%, mp 188–190 °C. IR (KBr) mmax 3368, 3015, 1743, 1710, 1608, 1588,
1608, 1587, 1449 cmꢂ1 1H NMR (400 MHz; CDCl3/TMS) d: 4.32 (s, 1H, @CH),
.
5.54 (s, 1H, PhCHS), 7.13–7.85 (m, 10Harom). 13C NMR (100 MHz; CDCl3/TMS) d:
58.5, 73.2, 122.8, 124.2, 125.9, 127.5, 128.8, 129.9, 130.8, 131.5, 152.1, 161.3.
EIMS (m/z): 280 (M+). Anal. Calcd for C16H12N2OS: C, 68.55; H, 4.31; N, 9.99.
Found: C, 68.21; H, 4.45; N, 9.87.
20. General procedure for the synthesis of 3H-azetidino[2,1-b]-thiazolo[3,4-d][1,3,4]-
oxadiazol-6-ones 3: To a well-stirred solution of thiazolo-oxadiazole 6 (5 mmol)
and triethylamine (10 mmol) in dioxane (15 mL) was added dropwise
a
solution of acetyl chloride (5 mmol) in dioxane (15 mL) with stirring at room
temperature. After the addition was complete, the solution was further stirred
at rt for 4–6 h. The precipitated material (Et3NꢀHCl) was filtered off, the solvent
evaporated under reduced pressure and the residue was purified by column
chromatography using AcOEt and n-hexane as eluent to afford an analytically
pure sample of 3. Physical data of representative compounds: Compound 3a:
Yellowish solid, yield 85%, mp 150–152 °C. IR (KBr) mmax 3011, 1761, 1605,
1453 cmꢂ1 1H NMR (400 MHz; CDCl3/TMS) d: 3.05 (d, 1H, J = 14.5 Hz, 5-Ha),
.
3.19 (d, 1H, J = 14.5 Hz, 5-Hb), 6.21 (s, 1H, 2-H), 7.19–7.92 (m, 10Harom), 8.43
(br s, 1H, NH, exchangeable with D2O). 13C NMR (100 MHz; CDCl3/TMS) d: 42.8,
55.7, 125.5, 126.8, 127.9, 128.8, 129.7, 130.5, 131.8, 133.0, 172.2, 173.8. EIMS
(m/z): 298 (M+). Anal. Calcd for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39. Found:
C, 64.19; H, 4.68; N, 9.51.
1583, 1455 cmꢂ1 1H NMR (400 MHz; CDCl3/TMS) d: 3.35 (d, 1H, J = 15.7 Hz,
.
HaC@O), 3.67 (d, 1H, J = 15.7 Hz, HbC@O), 4.31 (s, 1H, @CH), 5.57 (s, 1H,