Inter-and intra-molecular cyclisation reactions of azoacetates derived from aryl hydrazones of ethyl acetoacetate and acetoacetanilides

Article abstract of DOI:10.3987/COM-08-11433

The base induced cyclisations of azoacetates to azetidinones were investigated. In addition to the isolation of the desired products, it was found that 2-iminopyrrolidine-5-one derivatives as well as N-acyl hydrazides could be isolated when metal cyanides were employed as base. These entities were further modified to form pyrrolidine-2,5-diones and diazetidinones respectively. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11433

HETEROCYCLES, Vol. 75, No. 11, 2008
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HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2681 - 2701. © The Japan Institute of Heterocyclic Chemistry
Received, 8th May, 2008, Accepted, 27th June, 2008, Published online, 2nd July, 2008. COM-08-11433
INTER- AND INTRA- MOLECULAR CYCLISATION REACTIONS OF
AZOACETATES DERIVED FROM ARYL HYDRAZONES OF ETHYL
ACETOACETATE AND ACETOACETANILIDES
Neil O’Halloran, John P. James,* Carol A. Downey, Patrick O’Malley,
Thomas Duff, and Samuel Bertrand
National Institute for Cellular Biotechnology, School of Chemical Sciences,
Dublin City University, Glasnevin, Dublin 9, Ireland
E-mail: paraic.james@dcu.ie
Abstract – The base induced cyclisations of azoacetates to azetidinones were
investigated. In addition to the isolation of the desired products, it was found that
2-iminopyrrolidine-5-one derivatives as well as N-acyl hydrazides could be
isolated when metal cyanides were employed as base. These entities were further
modified to form pyrrolidine-2,5-diones and diazetidinones respectively.
INTRODUCTION
The search for new β-lactam species as antibacterial agents has been in decline in recent times due to
problems encountered with the rapid development of resistant strains of bacteria. However due to the low
levels of toxicity inherent to these compounds there has been a simultaneous surge in interest in any
newly generated species in ancillary roles. Monocyclic β-lactams with non-classical features, bearing
simple aryl and alkyl moieties have been of particular interest recently in a variety of roles ranging from
anti-cancer agents,1 and HIV-1 protease inhibitors,2 to anti-fungal agents.3 The synthesis of some
azetidinones and diazetidinones through the reaction of the appropriate azoacetates with various bases has
been previously reported by this group.4 Herein we report in full the experimental details of these
procedures and the related spectral data. In addition to these published intramolecular ring closures it has
been discovered that products of intermolecular reactions between the azoacetate and the cyanide ion can
be isolated in reasonable yields in some cases. The generation of the 2-iminopyrrolidine-5-ones
derivatives is presumably due to a nucleophilic displacement of the acetate group by the cyanide ion to
form the nitrile entity followed by spontaneous cyclisation. Relatively few examples of synthetic routes to
these molecules can be found in the mainstream literature.5 However it will be shown here that these
compounds provide a valuable route to the synthetically and medicinally versatile pyrrolidine-2,5-dione

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HETEROCYCLES, Vol. 75, No. 11, 2008
(succinimide) molecules.6 The azoacetate derived from α,α-dimethyl ethyl acetoacetate was found to form
an N-acyl hydrazide rearrangement product that could be isolated and subsequently, after hydrolysis of
the ester moiety, cyclised to form a diazetidinone derivative. It was found that azo functionality in the
azetidinones reported here could be easily oxidized to give the corresponding azoxy species. The scope of
this reaction to furnish further compounds is currently under investigation. Also discussed is the
unexpected cyclisation of the α,α-unsubstituted azoacetate derivatives to form pyrazole ring derivatives.
RESULTS AND DISCUSSION
The azoacetates in question were synthesized in several steps from simple inexpensive starting materials
using facile procedures. Where possible commercially available acetoacetanilides were used as starting
materials, the remainder were generated by simply heating the appropriately substituted aniline (2a-e)
º
(1 molar equivalents) with ethyl acetoacetate (1) (5 molar equivalents) to 160 C until the evolution of
ethanol had ceased, after removing the bulk of the remaining ethyl acetoacetate by vacuum distillation the
desired acetoacetanilides could be easily crystallized by scratching the reaction vessel.7
Table 1. Synthesis of acetoacetanilides from ethyl acetoacetate
O
R1
R2
O
+
H2N
R3
O
NH
160 0C
O
OEt
R1
1
2
R2
R3
3
Entry
Substrate
R1
R2
H
R3
Br
OMe
H
Product
3a
Yield (%)
1
2
3
4
5
2a
2b
2c
2d
2e
H
H
90
88
91
85
77
H
3b
Me
H
Me
H
3c
3d
Me
H
H
CO2Et
3e
These were further purified by recrystallization from EtOAc/hexane before being used in the next stage.
Dimethylation of the acetoacetanilides (3a-j) was achieved by refluxing overnight with an excess of
methyl iodide (6 molar equivalents) and potassium carbonate (3 molar equivalents). In the case of the
methyl, benzyl substituted example 7 the substrate acetoacetanilide was initially methylated using methyl
iodide in a 1:1:1.5 ratio of substrate:base:methyl iodide. This resulted in the production of the
mono-methylated species 6 as the major product but also resulted in the production of some of the

HETEROCYCLES, Vol. 75, No. 11, 2008
2683
di-methylated product 5j. It was found that the desired mono-methylated compound could be isolated in
pure form after several recrystallizations from ethanol. The subsequent benzylation was carried out under
similar reaction conditions using an excess of benzyl chloride as alkylating agent.
Table 2. Alkylation of ester and anilides
Me
O
O
X / K2CO3
R'
R4
Y
Y
O
O
R1
R2
Substrate
Y
OEt
NH-Ar
NH-Ar
NH-Ar
X
I
I
I
Cl
R’
Product
R3
Ar =
1
3
3
6
Me
Me
Me
Bn
4
5
6a
7
Entry
Substrate
Y = OEt or NH-Ar
R2
Product
Yield (%)
R1
R3
1
2
1
-
H
-
H
H
Me
H
H
H
H
H
H
H
H
H
-
Br
4
80
79
78
80
83
70
80
67
75
74
69
74
90
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
H
OMe
H
4
Me
H
5
Me
6
H
CO2Et
H
7
H
8b
9b
10b
11b
12b
13
Me
Me
OMe
H
Me
H
H
3j
3j
6
Cl
5j
6
H
Cl
H
Cl
7
a In all entries R4 = CH3, except in entry 12 (Product 6) where, R4 = H, and entry 13 (Product 7) where,
R4 = Bn, bStarting materials were commercially available acetoacetanilides
4-nitrophenylhydrazone derivatives were prepared of the starting materials ethyl acetoacetate (1) and the
acetoacetanilide (3f) along with α,α-disubstituted ethyl acetoacetate (4) and all of the α,α-disubstituted
acetoacetanilides (5a-j and 7) (Table 3) by stirring the substrates in a slight excess (1.1 molar equivalents)
of 4-nitrophenylhydrazine in MeOH under mild acidic conditions (~5% acetic acid).8 This procedure
routinely furnished the desired hydrazones in reasonable yields (50-72%).

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HETEROCYCLES, Vol. 75, No. 11, 2008
Table 3. Synthesis of 4-nitrophenylhydrazone derivatives
NO2
H
R5
N
NO2
R5
NH2
O
N N
R4
O
H
R4
Y
Y
O
Substrate
Y
OEt
NH-Ar
OEt
NH-Ar
NH-Ar
R4
H
H
Me
Me
Me
R5
H
H
Me
Me
Bn
Product
Yield(%)
55
59
65
50-72
39
1
3f a
4
8
9f
10
11a-j
12
5a-j a
7 a
a With reference to aromatic groups Ar, substitutions at R1, R2 and R3 are as shown in Table 2
The synthesis of the azoacetates of these hydrazones was found to be equally facile (Table 4), once again
it was found that merely stirring the substrate hydrazones overnight in a mildly acidic CH2Cl2 solution
(10% acetic acid) containing a slight excess (1.1 molar equivalents) of Pb(OAc)4 was sufficient to effect
the desired transformation.9 After a standard work-up, flash chromatography was used to separate the
azoacetates from any persistent lead salt residues
Table 4. Synthesis of azoacetate derivatives
NO2
NO2
R5
R5 OAc
N N
N N
Pb(OAc)4
H
R4
R4
O
Y
Y
O
Substrate
Y
OEt
NH-Ar
OEt
NH-Ar
NH-Ar
R4
H
H
Me
Me
Me
R5
H
H
Me
Me
Bn
Product
13
14f
15
16a-j
17
Yield(%)
65
68
77
70-89
56
8
9f a
10
11a-ja
12a
a With reference to aromatic groups Ar, substitutions at R1, R2 and R3 are as shown in Table 2
The reactions of the azoacetates with various bases produced the most interesting results (Scheme 1). It
was found that the azoacetates derived from α,α-dimethylated acetoacetanilide or α-methyl-α-benzyl
acetoacetanilide could be cyclised to azetidinones (18f, 18j and 19) upon treatment with K2CO3 under

HETEROCYCLES, Vol. 75, No. 11, 2008
2685
reflux in acetone. It was also found that the cyclisation could be carried out in other conditions;
azetidinones (18a-j) were also isolated when the reaction was carried out in n-propanol using KCN as
base. When the reactions of previously reported azoacetates (16f and 16j) were more closely examined it
was found that in addition to the reported rearrangement products 20f and 20j, an additional cyclised
compound could be isolated in both cases. The isolation of these 2-iminopyrrolidine-5-one products (21f
and 21j) is a relatively rare example of the incorporation of cyanide moiety into a heterocyclic system in a
one step process. It would seem that both the basic and nucleophilic properties of the cyanide species
have an effect on the formation of reaction products in this case. The formation of these products has been
confirmed by spectral analysis (NMR, IR, MS) and in the case of azetidinone (18j) and
2-iminopyrrolidine-5-one derivative (21f) by X-Ray crystal structure determination (Figures 1a and b).
NO2
NO2
R5
R5
OAc
N N
N N
R4
R4
K2CO3/acetone
reflux, 24 h.
H
N
N
O
O
Ar
Ar
substrate
16a-j
17
product
18f and j
19
KCN/PrOH
reflux 30 min.
O
N
N
NO2
H
N
N
18 a-j
+
+
O
O
N
NH
Ar
O
Ar
21f and j
20f and j
Scheme 1
The formation of these three products are clearly as a result of different reaction mechanisms, they do
however all conform to previously postulated reaction pathways. Instances of the base induced
abstraction of the relatively acidic amido-hydrogen, followed by cyclisation through loss of a leaving
group (Scheme 2a) can be commonly found in the literature related to β-lactam formation.10 However the
acetate moiety acting as leaving group in this manner under such mild conditions has, to our knowledge,
not been previously reported. Of note amongst the azetidinone products isolated was compound 18e, it
was found that the transesterification product of the azetidinone was isolated. The action of the
base/propanol media in this case resulted in the isolation of the 4-propyl ester derivative as sole
azetidinone product in this case. Also two diastereomeric forms of azetidinone derivative (19) were

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HETEROCYCLES, Vol. 75, No. 11, 2008
isolated and could be differentiated on the basis of differing chemical shift values for key NMR spectral
values (e.g. benzyl CH2 shift).
NO2
NO2
O
O
N N
N N
N
NH
Ar
16
C
N
O
O
Ar
18
Scheme 2a. Proposed mechanism of formation of azetidinone 18
NO2
NO2
NO2
O
N
O
N
N
N
N
N N
N
C
N
H
NH
Ar
NH
C
N
16
22
O
21
O
O
Ar
Ar
Scheme 2b. Proposed mechanism of formation of 21
OH
C3H7
O
C3H7
N
C
N
C
H
NO2
NO2
NO2
C3H7
O
O
O
O
O
O
N N
N N
N N
NH
NH
Ar
NH
Ar
O
O
O
Ar
16
NO2
O
NO2
NO2
O
H
O
H
N
N N
N
N N
H
NH
Ar
NH
Ar
NH
Ar
O
O
O
20
23
Scheme 2c. Proposed mechanism of formation of 20

HETEROCYCLES, Vol. 75, No. 11, 2008
2687
C9
C10
O1
C8
C7
N1
C11
C2
N2
C1
C6
C3
C4
C12
N3
C18
C13
C14
C17
C16
C5
C15
Cl
N4
O3
O2
Figure 1a. X-Ray crystal structure of azetidinone 18j
C19
O3
C17
C8
C16
N2
C18
C5
C11
C12
C7
C4
C3
N5
C6
C1
C9
N4
N3
C13
C10
C15
O2
N1
O1
C14
C2
Figure 1b. X-Ray crystal structure of 2-iminopyrrolidine-5-one derivative 21f
The α-azo-α-nitrile functionality is a known species and it has been demonstrated that in certain cases, the
nitrile group can be introduced at a position α to an azo-group by reaction of a hydrazone with metal
cyanides.11 The intermolecular nucleophilic displacement of a leaving group by the cyanide species to
form a nitrile followed by cyclisation, as in the case of the formation 2-iminopyrrolidine-5-ones (21f and
21j) has also previously been studied by Nisole et al.12 The isolation 2-iminopyrrolidine-5-ones directly
upon treatment of carbamoylated chloroenamines with metal cyanides in alcohol have similarly been
observed by Vilsmaier et al.13 In that case, the cyclisation took place spontaneously under the action of
the basic reaction media with a similar mechanism proposed; some parallels can be drawn to the
observations made here, in so far as the isolation of the nitrile intermediate was not achieved. Since the
formation of the cyclised product through incorporation of the cyanide ion is evident, it is reasonable to
assume that the intermediate 22 in Scheme 2b, plays a role.
It is proposed that the rearrangement of azoacetates (16f and 16j) to N-acyl hydrazides (20f and 20j) takes
place via an alcoholysis mechanism involving the formation of an azocarbinol species (a.k.a. α-hydroxy

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HETEROCYCLES, Vol. 75, No. 11, 2008
phenylazo compounds) such as intermediate 23 in Scheme 2c. It seems most likely that it is this species
that undergoes the rearrangement. The transformation of azoacetates to azocarbinols in this way has
previously been shown to be possible.14 Barton et al. utilized 2-t-butyl-1,1,3,3-tetramethyl guanidine base
(Barton’s base) to effect this type of transformation in ethanol, however efforts to isolate intermediate 23
in a similar manner failed. The azocarbinol species in general is notoriously unstable, and it would seem
that the formation of the rearrangement product is the favored process in this case.
In order to further investigate the versatility of the compounds synthesized, some supplementary reactions
were carried out on the products mentioned thus far and it was found that a further array of interesting
compounds could be created. In the case of the N-acyl hydrazide derivative (24) isolated from the
reaction of azoacetate (15) with potassium cyanide it was found that the ester moiety could be easily
hydrolyzed to the carboxylic acid 25 and this could then be cyclised to give a diazetidinone product (26).
The structure of the rearrangement product 24 was confirmed by X-Ray crystallography.
NO2
NO2
O
OAc
N N
N
N
H
KCN, n-PrOH
OEt
reflux 30 min
OEt
O
O
24
15
NO2
O
O
NaOH, H2O
DCC, MeCN
N
N
N
N
H
OH
O
O
26
25
NO2
Scheme 3
C8
C7
O3
N2
C10
C5
C6
N3
C9
C11
C4
C14
O4
C1
C12
O5
O1
C3
N1
C2
C13
O2
Figure 2. X-Ray crystal structure of rearrangement product 24

HETEROCYCLES, Vol. 75, No. 11, 2008
2689
Among the many published synthetic routes to the versatile succinimide compounds perhaps the simplest
is the acid catalyzed hydrolysis of 2-iminopyrrolidine-5-ones.15 The appearances of several versions of
the procedure in the literature show it to be a robust high-yielding technique that can be used when a
variety of functional groups are present adjacent to the imino functionality. In the example presented here
a smooth transition with high yield was achieved. 2-iminopyrrolidine-5-one (21f) was converted to the
corresponding succinimide (27f). The substrate 21f was introduced to a refluxing solution of aqueous
acetic acid and allowed to reflux for a further 24 h after which the desired succinimide was easily
extracted into organic solvent (CH2Cl2) and purified by flash chromatography.
NO2
NO2
N
N
N
N
N
N
aqueous acetic acid
reflux 24 h
O
N
H
O
O
21f
27f
Scheme 4
It was found that the azoxy derivative 28h of azetidinone (18h) could be generated through reaction with
hydrogen peroxide in the presence of acetic acid. Although all spectral data supports the formation of the
azoxy functionality at a position adjacent to the phenyl group, since an X-Ray crystal structure of the
product was not obtained in this case this characterization is somewhat tentatively assigned. The
formation of the azoxy functionality is in little doubt; however guidelines to the assignment of the
position of the azoxy oxygen found in the literature were at times contradictory and at best speculative.
Some consensus seems to have been reached on the issue of the increase in the deshielding effect on
groups adjacent to the newly formed azoxy group by comparison to the parent azo compound. The
creation of the azoxy group presented here was indeed accompanied by a large downfield shift by the
aromatic proton signals adjacent to the proposed site of the azoxy oxygen.
O
N
N
NO2
N
N
NO2
acetic acid, H2O2
reflux 24 h
N
N
O
O
18h
28h
Scheme 5

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HETEROCYCLES, Vol. 75, No. 11, 2008
The production of the 2-iminopyrrolidine-5-one derivative (21f) raised the question of what might happen
under similar conditions with an α,α-unsubstitued azoacetate. The investigations of this question led to an
unexpected cyclisation. It was found that when these substrates 13 and 14f were subjected to identical
conditions to those used previously with the α,α-dimethylated azoacetate derivatives, that once again a
cyano unit was incorporated into the cyclic product. However, in this case the absence of alkyl groups at
positions α to the carbonyl allows for the formation of the pyrazole derivatives (29 and 30f) as the
intermolecular reaction products.16
NO2
NO2
N
OAc
H2N
H
N
N
N
KCN, n-PrOH
H
reflux 30 min
Y
Y
O
O
Substrate
13
Product
29
Y=OEt
a14f
Y=NH-Ar
30f
Scheme 6
Confirmation of the structure has been established by X-Ray crystal structure analysis in the case of
compound 30f. Although the isolation of these compounds has been previously reported, different
methodologies were employed in the synthesis. Furthermore, the crystal structure of this species has not
been published to date.
C12
O2
O4
N4
C7
C11
C10
C5
C13
C14
C4
N1
N5
N2
C9
C3
O1
C8
C6
C15
C2
C1
N3
C16
C17
Figure 3. X-Ray crystal structure of pyrazole derivative 30f

HETEROCYCLES, Vol. 75, No. 11, 2008
2691
Scheme 7 depicts a proposed mechanism for the formation of pyrazole derivative (29) from the
corresponding azoacetate derivative (13). In light of the basic reaction conditions, the formation of the
pyrazole is presumably due to initial elimination of a unit of acetic acid aided by stabilization of the
product provided by the neighboring phenylazo group. Nucleophilic addition at this newly formed double
bond provides a cyano substituted hydrazone substrate for cyclisation to the pyrazole ring, as has been
previously proposed by Shawali et al.17 In that case the proposed formation of the hydrazone species was
as a result of the condensation of a hydrazidic halide and ethyl cyanoacetate.
O2N
O2N
O2N
O
N
O
N
N
δ+
δ−
N
N
H
C
H
C
N
H
H
N
H
N
OEt
13
OEt
O
H
O
EtO
O
C
N
NO2
NO2
N
N
H2N
H
N
N
N
H
OEt
OEt
O
O
29
Scheme 7
In conclusion the results presented here, demonstrate the synthetic versatility of these azoacetates derived
from simple, inexpensive starting material. The examples shown here of both endo- and exocyclic
incorporation of the azo functionality into heterocyclic systems demonstrate the value of a previously
unexplored resource in the synthetic sphere. A range of products from established medicinally important
families of compounds have been synthesized through simple modifications using facile procedures. It is
deemed noteworthy to point out that the synthesis of products based solely on 4-nitrophenyl hydrazone
derivatives was due to their inherent stability to the acidic conditions required for condensation. Some
arylhydrazone of β-keto esters are prone to spontaneous cyclisation giving, pyrazoles and pyrazolones.18

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HETEROCYCLES, Vol. 75, No. 11, 2008
Our research has not been based exclusively on arylhydrazones of this type, however these compounds
were chosen for presentation at this time due to the reliability and reproducibility of the results obtained.
EXPERIMENTAL
Ethyl acetoacetate, iodomethane, benzyl chloride and substituted acetoacetanilides were purchased from
the Sigma Aldrich chemical company and were used as received. All solvents were dried or distilled prior
to use. Melting points were determined using a Griffin melting point apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin-Elmer 2000FT-IR spectrometer. NMR spectra were recorded
1
13
using a Bruker AC 400 NMR spectrometer operating at 400 MHz for H NMR and at 100 MHz for C
NMR. The 1H and 13C NMR chemical shifts (ppm) are relative to TMS and all coupling constants (J) are
in Hertz (Hz).
X-Ray crystallographic data
"CCDC 272234 (18j), CCDC 686905 (21f), CCDC 686907 (24), and CCDC 686906 (30f), contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033."
Preparation of acetoacetanilides (3a-e)
These compounds were prepared according to a general procedure a representative example is given.
Synthesis of 4-bromoacetoacetanilide (3a)
Ethyl acetoacetate (65.1 g, 0.5 mol) was heated to 160 oC in a round bottomed flask with reflux condenser
fitted. To this was added 4-bromoaniline (17.0 g, 0.1 mol). When the evolution of EtOH began the
reaction was allowed to reflux for 2-3 h until the reaction was complete (TLC) before the EtOH was
distilled off. The bulk of the remaining ethyl acetoacetate was removed by vacuum distillation at 90o C,
50mbar. The resulting oily residue was scratched with a glass rod to promote precipitation. The
precipitate was filtered and washed with hexane before being recrystallised from an EtOAc:hexane 30:70
mixture. Yield (22.8 g, 90.1 %); mp 132-135 ºC; 1H NMR (400MHz, DMSO-d6): δ =, 2.21 (3H, s, CH3),
13
3.56 (2H, s, CH2), 7.48 (2H, ArH, J = 8.8), 7.55 (2H, d, ArH, J = 8.8) 10.21 (1H, s, NH); C NMR
(100MHz, DMSO-d6) 30.2, 52.3, 114.9, 120.9, 131.5, 138.2, 165.2, 202.7; IR (KBr) 3292, 1718, 1661,
1607, 1554, 1491, 1396, 1162, 1075, 832, 505 cm-1.
Preparation of α,α-dimethylethylacetoacetate (4) and α,α-dimethylacetoacetanilides (5a-j)
These compounds were prepared according to a general procedure a representative example is given.

HETEROCYCLES, Vol. 75, No. 11, 2008
2693
Synthesis of α,α-dimethyl-4-bromoacetoacetanilide (5a)
(6.62 g, 25.9 mmol) of 4-bromoacetoacetanilide was dissolved in 150 mL of acetone, to this was added
K2CO3 (7.8 g, 56.4 mmol) and the reaction was set to reflux. Once the reaction had reached reflux
temperature iodomethane (22.45 g, 158.2 mmol) was added and the reaction was allowed to reflux
overnight. The solvent was reduced to 1/5 of the original volume by rotary evaporation and the entire
contents of the reaction vessel were poured into a beaker containing 200 mL of ice-water. The product
formed an oil and was extracted with CH2Cl2 (5 x 50 mL). The organic extracts were combined, dried
over magnesium sulfate and evaporated to an oil under reduced pressure. A small portion of the oil was
removed and precipitation was induced by scratching, this was then returned to the bulk in order to seed
the crystallization of the remaining oil. The solid was filtered and washed with hexane, this was further
1
recrystallized from an EtOAc:hexane 70:30 mixture. Yield (5.84 g, 79.4%); mp 85-87 ºC; H NMR
(400MHz, DMSO-d6): δ =, 1.37 (6H, s, 2 x CH3), 2.15 (3H, s, CH3), 7.48 (2H, ArH, J = 9.2), 7.61 (2H, d,
13
ArH, J = 8.8), 9.57 (1H, s, NH); C NMR (100MHz, DMSO-d6) 21.8, 25.7, 56.5, 115.3, 122.2, 131.3,
138.2, 171.8, 207.2; IR (KBr) 3361, 1684, 1531, 1490, 1394, 1310, 1239, 1240, 1117, 1071, 818 cm-1.
Preparation
of
α-methyl-4-chloroacetoacetanilide
(6)
and
α-methyl-α-benzyl-4-
chloroacetoacetanilide (7)
Synthesis of α-methyl-4-chloroacetoacetanilide (6)
(10.8 g, 51.2 mmol) of 4-chloroacetoacetanilide (3j) was dissolved in acetone (75 mL) and) K2CO3 (7.2 g,
52.0 mmol) was added and the reaction brought to reflux. Iodomethane (10.66 g, 75.1 mmol) was added
dropwise with stirring to the reaction vessel over 1 h and the reaction was allowed to reflux for a further 2
h. The reaction mixture was cooled and poured into ice-water (150 mL) and allowed to stir for 30 min, a
white precipitate (6) was collected and recrystallized several times from aqueous EtOH to remove any
1
dimethylated product (5j). Yield (8.59 g, 74.4%); mp 125-129 ºC; H NMR (400MHz, DMSO-d6): δ =,
1.23 (3H, d, CH3, J = 6.8), 2.17 (3H, s, CH3), 3.65 (1H, q, CH, J = 6.8), 7.37 (2H, d, ArH, J = 8.8), 7.50
(2H, d, ArH, J = 8.8), 10.34 (1H, s, NH); 13C NMR (100MHz, DMSO-d6) 13.0, 28.2, 54.5, 120.8, 127.1,
128.6, 137.8, 168.9, 204.3. IR (KBr) 3241, 1720, 1654, 1604, 1543, 1494, 1403, 1081, 826 cm-1.
Synthesis of α-methyl-α-benzyl-4-chloroacetoacetanilide (7)
(6.8 g, 30.2 mmol) of α-methyl-4-chloroacetoacetanilide (6) was dissolved in acetone 50 mL and (7.2 g,
52.0 mmol) of K2CO3 was added and the reaction brought to reflux. Benzyl chloride (6.58 g, 52.0 mmol)
was added dropwise with stirring to the reaction vessel over 1 h and the reaction was allowed to reflux
overnight. The reaction mixture was cooled and poured into ice-water (150 mL) and allowed to stir for 30
min, a white precipitate (7) was collected and recrystallized from an EtOAc:hexane 70:30 mixture. Yield:
1
(8.53 g, 89.5%); mp 124-127 ºC; H NMR (400MHz, DMSO-d6): δ =, 1.27 (3H, s, CH3), 2.20 (3H, s,

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HETEROCYCLES, Vol. 75, No. 11, 2008
CH3), 3.07 (1H, d, CH2, J = 13.6), 3.36 (1H, d, CH2, J = 13.6), 7.11-7.23 (5H, m, ArH), 7.77 (2H, d, ArH,
J = 8.8), 7.43 (2H, d, ArH, J = 8.8), 9.68 (1H, s, NH); 13C NMR (100MHz, DMSO-d6) 18.7, 26.3, 39.7,
61.3, 122.3, 126.5, 127.6, 128.0, 128.1, 130.1, 136.7, 137.5, 170.2, 206.3; IR (KBr) 3328, 1720, 1654,
1604, 1543, 1494, 1403, 1081, 826 cm-1.
Preparation of hydrazone derivatives (8, 9a and f, 10, 11a-j, 12)
These compounds were prepared according to a general procedure a representative example is given.
Synthesis of 4-nitrophenyl hydrazone derivative of α,α-dimethyl-4-bromoacetoacetanilide (11a)
(4.0 g, 14.0 mmol) of 2,2-dimethyl-4-bromoacetoacetanilide (5a) was dissolved in MeOH 75 mL, (2.6 g,
16.8 mmol) of 4-nitrophenylhydrazine was dissolved in warm acetic acid (3.25 mL) and added to the
stirring reaction vessel. After 1-2 min a yellow precipitate began to fall from solution, the reaction was
allowed to stir overnight and the precipitate collected and dried. Yield (4.01 g, 68%); mp 197-200 ºC; 1H
NMR (400MHz, DMSO-d6): δ = 1.48 (6H, s, 2 x CH3), 1.96 (3H, s, CH3), 7.27 (2H, d, ArH, J = 8.8),
7.50 (2H, d, ArH, J = 9.2), 7.65 (2H, d, ArH, J = 8.8), 8.12 (2H, d, ArH, J = 8.8), 9.43 (1H, s, NH), 9.97
13
(1H, s, NH); C NMR (100MHz, DMSO-d6) 13.7, 23.5, 51.3, 111.6, 115.1, 122.5, 125.8, 131.2, 138.1,
138.5, 151.8, 151.9, 173.5; IR (KBr) 3322, 1671, 1596, 1492, 1324, 1260, 1113, 1089, 841, 821 cm-1.
Preparation of azoacetate derivatives (13, 14a and f, 15, 16a-j, 17)
These compounds were prepared according to a general procedure a representative example is given.
Synthesis of azoacetate derivative of α,α-dimethyl-4-bromoacetoacetanilide (16a)
(3.0 g, 7.15 mmol) of the hydrazone substrate (11a) was dissolved in CH2Cl2 (100 mL). To this was
added (3.8 g, 8.6 mmol) of lead tetraacetate with stirring. 5 mL of glacial acetic acid was added to aid the
dissolution of the lead tetraacetate and the solution was allowed to stir overnight. When the reaction was
judged complete (TLC) the solvent volume was reduced by 75% and the remaining CH2Cl2 solution was
washed alternately with 5 x 50 mL portions of water and 5% aqueous sodium bicarbonate solution. The
organic portion was dried over magnesium sulfate and evaporated to dryness and any persistent lead
residues were removed by flash chromatography using a 25:75 EtOAc:hexane mixture as eluent. Yield
(2.80 g, 82%); mp 202-205 ºC; 1H NMR (400MHz, DMSO-d6): δ =, 1.28 (3H, s, CH3), 1.40 (3H, s, CH3),
1.86 (3H, s, CH3), 2.18 (3H, s, CH3), 7.48 (2H, d, ArH, J = 8.8), 7.57 (2H, d, ArH, J = 9.2), 7.75 (2H, d,
ArH, J = 8.8), 8.37 (2H, d, ArH, J = 8.8). 9.19 (1H, s, NH); 13C NMR (100MHz, DMSO-d6) 17.2, 20.5,
20.6, 21.5, 51.0, 103.6, 115.5, 123.0, 123.2, 125.0, 131.2, 138.0, 148.5, 153.9, 168.8, 171.1; IR (KBr)
3324, 1731, 1687, 1605, 1539, 1344, 1240, 1175, 868 cm-1.
Preparation of azetidinones derivatives (18f and 19) procedure 1
Synthesis of azetidinone derivative (18f) using procedure 1

HETEROCYCLES, Vol. 75, No. 11, 2008
2695
Anhydrous potassium carbonate (0.5 g, 3.6 mmol) was added to azoacetate 16f (1.2 g, 3 mmol) in 50 mL
of refluxing acetone. The solution was allowed to reflux for 22 h after which time (TLC) showed the
reaction to be complete. The insoluble material was filtered from the solution and the filtrate evaporated
to dryness. The azetidinone product (18f) was isolated after silica gel column chromatography using
CHCl3 as eluent. Yield (0.223 g, 22%); mp 87-89 ºC; 1H NMR (400MHz, CDCl3): δ = 1.08 (3H, s, CH3),
1.50 (3H, s, CH3), 1.92 (3H, s, CH3), 7.15-7.11 (1H, m, ArH), 7.35-7.03 (2H, m, ArH), 7.43 (2H, d, ArH,
J = 8.8), 7.88 (2H, d, ArH, J = 8.8), 8.37 (2H, d, ArH, J = 9.2); 13C NMR (100MHz, CDCl3) 17.3, 19.1,
19.2, 60.5, 90.2, 118.3, 123.4, 124.4, 124.9, 129.1, 137.2, 149.2, 154.1, 170.5; IR (KBr) 1759, 1599, 1527,
1495, 1368, 1346, 862, 756, 690 cm-1.
Synthesis of azetidinone derivative (19) using procedure 1
1
(19a) Yield (8.3%); mp 139-141 ºC; H NMR (400MHz, CDCl3): δ = 0.85 (3H, s, CH3), 1.94 (3H, s,
CH3), 3.01 (1H, d, CH, J = 14.4), 3.32 (1H, d, CH, J = 14.4), 7.27-7.07 (9H, m, ArH,), 7.78 (2H, d, ArH,
13
J = 8.8), 8.29 (2H, d, ArH, J = 8.8); C NMR (100MHz, CDCl3) 16.8, 17.8, 30.6, 64.6, 91.1, 120.0,
125.3, 124.9, 127.2, 128.5, 128.5, 129.1, 129.9 136.1, 136.6, 149.7, 154.2 170.0; IR (KBr) 1745, 1527,
1494, 1383, 1342, 1091, 827, 692 cm-1. Anal. Calcd for C24H21ClN4O3: C, 64.21; H, 4.72; N, 12.48.
Found: C; 64.01, H; 4.84, N; 12.18.
(19b) Yield (11.6%); mp 137-139 ºC; 1H NMR (400MHz, CDCl3): δ = 1.43 (3H, s, CH3), 1.99 (3H, s,
CH3), 2.67 (1H, d, CH, J = 14.4), 2.90 (1H, d, CH, J = 14.8), 7.27-7.10 (9H, m, ArH,), 7.87 (2H, d, ArH,
13
J = 8.8), 8.36 (2H, d, ArH, J = 9.2); C NMR (100MHz, CDCl3) 15.1, 15.9, 36.3, 62.7, 89.2, 118.0,
122.0, 123.3, 125.2, 126.7, 127.5, 127.9, 128.4, 134.2, 134.7,147.8, 152.3, 168.0; IR (KBr) 1757, 1528,
1494, 1367, 1345,1180, 1092, 820, 745 cm-1.
Preparation of azetidinones derivatives (18a-j) procedure 2
Synthesis of azetidinone derivative (18a) using procedure 2
(1g, 2.1 mmol) of the azoacetate derivative (16a) was dissolved in hot propanol (40 mL) to which (0.15 g,
2.3 mmol) of potassium cyanide was added. The solution was allowed to reflux for 30 min, after which
TLC showed development of product spots and total consumption of the starting material, this was
evaporated to dryness. Water (100 mL) was added to the reaction vessel and this was extracted with
EtOAc (2 x 25 mL) followed by CH2Cl2 (2 x 25 mL). The combined extracts were dried over magnesium
sulfate and upon evaporation to dryness an orange oil was collected. The product was isolated after
column chromatography. Yield (0.14 g, 16%); mp 155-158 ºC; 1H NMR (400MHz, CDCl3): δ = 1.19 (3H,
s, CH3), 1.42 (3H, s, CH3), 1.62 (3H, s, CH3), 7.18 (2H, d, ArH, J =8.8), 7.55 (2H, d, ArH, J =8.8), 7.76
(2H, d, ArH, J = 9.2), 8.28 (2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 13.3, 17.8, 24.4, 49.3, 83.0,
122.5, 123.4, 124.9, 127.7, 130.8, 132.4, 153.8, 174.0, 180.1; IR (KBr) 1755, 1520, 1489, 1362, 1347,

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HETEROCYCLES, Vol. 75, No. 11, 2008
827, 753 cm-1. Anal. Calcd for C18H17BrN4O3: C, 51.81; H, 4.11; N, 13.43. Found: C; 52.10, H; 4.28, N;
13.21.
Synthesis of azetidinone derivative (18b) using procedure 2
Yield (0.15 g, 20%); mp 95-98 ºC; 1H NMR (400MHz, CDCl3): δ = 0.98 (3H, s, CH3), 1.40 (3H, s, CH3),
1.77 (3H, s, CH3), 3.71 (3H, s, OCH3), 6.77 (2H, d, ArH, J = 9.2), 7.28 (2H, d, ArH, J = 9.2), 7.79 (2H, d,
ArH, J = 9.2), 8.28 (2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 17.2, 19.1, 19.2, 55.5, 60.4, 90.3,
114.3, 120.3 123.3, 124.8, 130.2, 149.2, 154.1, 156.5, 170.2; IR (KBr) 1759, 1513, 1392, 1346, 1247,
1184, 1164, 1031, 860, 828, 751, 688 cm-1
.
Synthesis of azetidinone derivative (18c) using procedure 2
1
Yield (0.21 g, 25%); mp 112-116 ºC; H NMR (400MHz, CDCl3): δ = 1.08 (3H, s, CH3), 1.45 (3H, s,
CH3), 1.62 (3H, s, CH3), 2.24 (3H, s, CH3), 2.25 (3H, s, CH3), 7.06-6.96 (3H, m, ArH), 7.76 (2H, d, ArH,
J = 9.2), 8.29 (2H, d, ArH, J = 9.2); 13C NMR (100MHz, CDCl3) 15.2, 17.4, 19.3, 19.9, 20.7, 59.6, 91.8,
123.2, 124.3, 124.9, 125.8, 129.8, 132.9, 135.1, 138.5, 149.1, 154.2, 171.6; IR (KBr) 1757, 1526, 1471,
1366, 1345, 1134, 1093, 869,792, 752, 688 cm-1. Anal. Calcd for C20H22N4O3: C, 65.56; H, 6.05; N, 15.29.
Found: C; 65.61, H; 6.02, N; 15.20.
Synthesis of azetidinone derivative (18d) using procedure 2
1
Yield (0.13 g, 15%); mp 103-107 ºC; H NMR (400MHz, CDCl3): δ = 1.07 (3H, s, CH3), 1.49 (3H, s,
CH3), 1.89 (3H, s, CH3), 2.33 (3H, s, CH3), 7.13 (2H, d, ArH, J =8.0), 7.32 (2H, d, ArH, J =8.4), 7.88
(2H, d, ArH, J = 9.2), 8.37 (2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3)17.3, 19.1, 19.2, 21.0, 60.4,
90.1, 118.3, 123.4, 124.9, 129.6, 134.1, 134.6, 149.2, 154.1, 170.3; IR (KBr) 1751, 1523, 1513, 1347,
1164, 1131, 861, 817, 752, 688 cm-1. Anal. Calcd for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C;
64.81, H; 5.73, N; 15.85.
Synthesis of azetidinone derivative (18e) using procedure 2
In the case of azetidinone derivative (18e) it was the propanol transesterification product that was
isolated
1
Yield (0.10 g, 11%); mp 97-100 ºC; H NMR (400MHz, CDCl3): δ = 0.94 (2H, t J =7.6), 1.00 (3H, s,
CH3), 1.29 (2H,m), 1.31 (3H, s, CH3), 1.72-1.67 (1H, m), 1.88 (3H, s, CH3), 4.18 (1H, t, J =6.4), 4.27
(1H, q, J =5.2), 7.38 (2H, d, ArH, J =8.8), 7.78 (2H, d, ArH, J =8.8), 7.91 (2H, d, ArH, J = 9.2), 8.27
(2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 9.5, 13.3, 16.5, 17.9, 18.1, 59.8, 65.5, 89.2, 116.3,
122.4, 123.9, 124.9, 129.7, 140.0, 148.3, 152.9, 165.0, 169.6; IR (KBr) 1749, 1709, 1509, 1352, 1270,
849, 769 cm-1.

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2697
Synthesis of azetidinone derivative (18f) using procedure 2
Azetidinone derivative (18f) was prepared using procedure 2 as outlined above; two additional
compounds were isolated during the chromatographic separation (20f and 21f).
(18f) Yield (0.10 g, 12%). Spectra identical to those reported using procedure 1
1
(20f) Yield (0.14 g, 16%); mp 195-197 ºC H NMR (400MHz, DMSO-d6): δ = 1.49 (3H, s, CH3), 1.53
(3H, s, CH3), 1.92 (3H, s, CH3), 6.96 (1H, s br, ArH),7.07 (1H, t, ArH, J = 7.2), 7.33-7.26 (3H, m, ArH),
13
7.61 (2H, d, ArH, J = 7.6), 8.15 (2H, s br, ArH), 9.06 (1H, s br, NH), 9.48 (1H, s br, NH); C NMR
(100MHz, DMSO-d6) 21.7, 22.9, 24.3, 65.6, 110.5 (d, J = 222), 120.8, 123.5, 126.2 (d, J = 69), 128.3,
138.7, 138.9, 154.2, 171.8, 172.8. IR (KBr) 3338, 3288, 1647, 1592, 1522, 1329, 1272, 1108, 750, 695
cm-1.
1
(21f) Yield (0.17 g, 18%); mp 142-145 ºC H NMR (400MHz, DMSO-d6): δ = 1.19 (3H, s, CH3), 1.42
(3H, s, CH3), 1.61 (3H, s, CH3), 7.34-7.28 (2H, m, ArH), 7.41-7.39 (1H, m, ArH), 7.52-7.47 (2H, m,
ArH, ), 7.76 (2H, d, ArH, J = 8.8), 8.26 (2H, d, ArH, J = 9.2); 9.00 (1H, s NH); 13C NMR (100MHz,
DMSO-d6) 13.3, 17.9, 24.4, 49.3, 83.1, 123.4, 124.8, 126.3, 128.7, 129.2, 131.9, 149.3, 153.9, 174.3,
180.5; IR (KBr) 1661, 1528, 1377, 1346, 1161, 1107, 862 cm-1
Synthesis of azetidinone derivative (18g) using procedure 2
1
Yield (0.21 g, 25%); orange oil; H NMR (400MHz, CDCl3): δ = 1.06 (3H, s, CH3), 1.44 (3H, s, CH3),
1.63 (3H, s, CH3), 2.23 (3H, s, CH3), 2.32 (3H, s, CH3), 6.88 (1H, d, ArH, J =8.0), 7.02 (2H, d, ArH, J
=8.0), 7.75 (2H, d, ArH, J = 9.2), 8.28 (2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 17.5, 18.9,
19.3, 19.8, 21.1, 59.5, 91.7, 123.1, 124.9, 126.3, 127.1, 130.5, 131.9, 136.2, 138.1, 149.1, 154.2, 171.5. IR
(liquid film) 1762, 1527, 1504 1370, 1347, 1139, 862, 753, 739 cm-1.
Synthesis of azetidinone derivative (18h) using procedure 2
1
Yield (0.18 g, 22%); mp 108-110 ºC; H NMR (400MHz, CDCl3): δ = 1.06 (3H, s, CH3), 1.45 (3H, s,
CH3), 1.65 (3H, s, CH3), 2.37 (3H, s, CH3), 7.22-7.06 (4H, m, ArH,), 7.76 (2H, d, ArH, J = 8.8), 8.29 (2H,
d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 17.6, 19.1, 19.3, 19.9, 59.6, 91.8, 128.2, 124.9, 126.2,
126.4, 128.2, 131.3, 133.3, 136.4, 149.1, 154.1, 171.3; IR (KBr) 1761, 1530, 1493, 1346, 1133, 874, 769
cm-1. Anal. Calcd for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C; 64.66, H; 5.69, N; 15.83.
Synthesis of azetidinone derivative (18i) using procedure 2
Yield (0.14 g, 16%); mp 98-100 ºC; 1H NMR (400MHz, CDCl3): δ = 1.04 (3H, s, CH3), 1.44 (3H, s, CH3),
1.60 (3H, s, CH3), 3.67 (3H, s, OCH3), 6.89-6.85 (2H, m, ArH,), 7.19-7.15 (1H, m, ArH,), 7.60-7.58 (1H,
m, ArH,), 7.79 (2H, d, ArH, J = 9.2), 8.29 (2H, d, ArH, J = 8.8); 13C NMR (100MHz, CDCl3) 16.9, 18.9,

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19.9, 55.6, 59.8, 91.5, 112.0, 120.8, 123.1, 123.9, 124.9, 127.6, 128.4, 149.0, 153.9, 154.4, 172.4; IR
(KBr) 1761, 1524, 1497, 1390, 1345, 1242, 1106, 1025, 858, 770, 752.
Synthesis of azetidinone derivative (18j) using procedure 2
(18j) Yield (0.17 g, 20%); mp 132-134 ºC; 1H NMR (400MHz, CDCl3): δ = 0.98 (3H, s, CH3), 1.42 (3H,
s, CH3), 1.82 (3H, s, CH3), 7.18 (2H, d, ArH, J =8.8), 7.29 (2H, d, ArH, J =9.2), 7.78 (2H, d, ArH, J =
8.8), 8.28 (2H, d, ArH, J = 9.2); 13C NMR (100MHz, CDCl3) 17.3, 19.0, 19.1, 60.7, 90.3, 119.5, 123.4,
124.9, 129.1, 129.5, 135.8, 149.3, 154.0, 170.3; IR (KBr) 1753, 1534, 1346, 1144, 869, 851, 705 cm-1.
Anal. Calcd for C18H17ClN4O3: C, 57.99; H, 4.60; N, 15.03. Found: C; 57.99, H; 4.73, N; 14.81.
(21j) Yield (0.21 g, 23%); mp 201-203 ºC; 1H NMR (400MHz, DMSO-d6): δ = 1.07 (3H, s, CH3), 1.34
(3H, s, CH3), 1.60 (3H, s, CH3), 7.32 (2H, d, ArH, J =8.4), 7.38 (2H, d, ArH, J =8.4), 7.89 (2H, d, ArH, J
13
= 9.2), 8.40 (2H, d, ArH, J = 9.2), 9.08 (1H, s, NH); C NMR (100MHz, DMSO-d6) 13.8, 17.9, 22.9,
48.5, 81.6, 123.2, 125.1, 128.8, 129.3, 132.3, 132.8, 148.7, 154.0, 165.3, 179.1. IR (KBr) 3300, 1742,
1661, 1532, 1492, 1344, 1102, 1085, 713.7, 687.2 cm-1.
Synthesis of N-acyl hydrazide derivative as rearrangement product (24)
(1g, 2.8 mmol) of the azoacetate derivative (15) was dissolved in hot EtOH (40 mL) to which (0.24 g, 3.7
mmol) of potassium cyanide was added. The solution was allowed to reflux overnight, before being
evaporated to dryness. Water (100 mL) was added to the reaction vessel and this was extracted with
EtOAc:EtO2 (15:85). The combined extracts were dried over magnesium sulfate and upon evaporation to
a reduced volume a pale brown solid precipitated. The precipitate was filtered off and washed with
petroleum ether and dried. Yield (0.31 g, 35%); mp 172-174 ºC; 1H NMR (400MHz, DMSO-d6): δ = 1.23
(3H, t, CH3, J = 6.8), 1.27 (3H, s, CH3), 1.36 (3H, s, CH3), 1.88 (3H, s, CH3), 4.16-4.06 (2H, m, CH2),
6.90 (1H, d, ArH , J = 7.6), 7.15 (1H, d, ArH, J = 7.6), 8.11 (1H, d, ArH, J = 8.0), 8.17 (1H, d, ArH, J =
7.6), 9.58 (1H, s, NH). Anal. Calcd for C13H19N3O5: C, 54.36; H, 6.14; N, 13.58. Found C, 54.53; H,
6.29; N, 13.51.
Synthesis of N-acyl hydrazide derivative (25) by decarboxylation
(0.5 g, 1.6 mmol) of N-acyl hydrazide derivative (24) was added to a 2.5 molar solution of sodium
hydroxide (3.99 g dissolved in 40 mL of water) the solution was allowed to reflux for 4 h. The pH was
adjusted to 7-8 with conc. HCl to give a yellow precipitate which was extracted into EtOAc (3 x 20 mL)
1
dried over magnesium sulfate and evaporated to dryness Yield (0.41 g, 90%); mp 215-216 ºC; H NMR
(400MHz, DMSO-d6): δ = 1.21 (3H, s, CH3), 1.32 (3H, s, CH3), 1.94 (3H, s, CH3), 6.90-6.85 (1H, m,
ArH), 7.15-7.10 (1H, m, ArH), 8.27-8.23 (2H, m, ArH) 9.50 (1H, s, NH); IR (KBr) 3347, 1710, 1619,
1599 cm-1. Anal. Calcd for C12H15N3O5: C, 51.24; H, 5.38; N, 14.94. Found C, 51.12; H, 5.50; N, 14.71.

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2699
Synthesis of diazetidinone derivative (26)
A 0.05 M solution of N-acyl hydrazide derivative (25) was made up in MeCN (0.85 g/60 mL). (3.7g, 18
mmol) of dicyclohexylcarbodiimide was added and the reaction refluxed overnight under a nitrogen
atmosphere. After removal of the bulk of the excess dicyclohexylcarbodiimide and dicyclohexylurea by
filtration, the remaining organic elements were evaporated to dryness and subjected to flash column
chromatography to separate any persistent dicyclohexylurea. The desired diazetidinone derivative (26)
was isolated and further purified by recrystallization from pet. ether EtOAc 20:80. Yield (0.35g, 45%);
mp 112-114 ºC; 1H NMR (400MHz, CDCl3): δ = 1.70 (6H, s, 2 x CH3), 2.20 (3H, s, CH3), 7.33-7.28 (2H,
m, ArH), 8.30-8.22 (2H, m, ArH); IR (KBr) 1796, 1696, 1627 cm-1. Anal. Calcd for C12H13N3O5: C,
54.75; H, 4.98; N, 15.96. Found C, 54.38; H, 4.93; N, 15.84.
Synthesis of succinimide derivative (27f)
(200 mg, 0.54 mmol) of the 2-iminopyrrolidine-5-one derivative 21f was dissolved in 10 mL of aqueous
acetic acid. The solution was heated to 50 oC for 24 h, 100 oC for a further 24 h and finally refluxed for 4
h after which TLC showed total consumption of the starting material. The solution was allowed to cool
and added to ice-water (100 mL) which induced precipitation of a pale yellow solid that was filtered from
1
solution. Yield (153 mg, 78%); product decomposed in air over 24 h; H NMR (400MHz, CDCl3): δ =
1.19 (3H, s, CH3), 1.42 (3H, s, CH3), 1.61 (3H, s, CH3), 7.30-7.25 (2H, m, ArH), 7.35-7.32 (1H, m, ArH),
7.43-7.37 (2H, m, ArH), 7.76 (2H, d, ArH, J = 8.8), 8.26 (2H, d, ArH, J = 9.2); 13C NMR (100MHz,
CDCl3) 13.3, 17.9, 24.4, 49.3, 83.1, 123.4, 124.8, 126.3, 128.7, 129.2, 131.9, 149.3, 153.9, 174.3, 180.5;
IR (KBr) 1719, 1529, 1396, 1374, 1346, 1146, 1126 cm-1.
Synthesis of azetidinone derivative (28h)
(100 mg, 0.28 mmol) of the azetidinone derivative (18h) was dissolved in glacial acetic acid (25 mL) and
o
heated to 80 C, to this was added 0.5 mL of hydrogen peroxide solution (35% by weight) at 15 min
intervals over 3 h. After 5 h the reaction mixture was treated with 2 mL of the hydrogen peroxide solution
o
and allowed to stir at 80 C overnight. A further 2 mL of hydrogen peroxide solution was added to the
reaction mixture and the reaction allowed to stir for a further 3 h after which no starting material could be
detected by TLC The reaction was cooled to room temperature and poured into 150 mL of ice-water
which induced precipitation of a pale yellow solid that was filtered from solution. Yield (66 mg, 63.9%);
mp 132-134 ºC; 1H NMR (400MHz, CDCl3): δ = 1.29 (3H, s, CH3), 1.51(3H, s, CH3), 1.69 (3H, s, CH3),
2.37 (3H, s, CH3), 7.24-7.17 (3H, m, ArH,), 7.38 (1H, d, ArH, J = 8.8), 8.26 (2H, d, ArH, J = 9.6), 8.29
(2H, d, ArH, J = 10.0); 13C NMR (100MHz, CDCl3) 14.5, 17.7, 18.7, 19.0, 60.3, 86.3, 123.4, 124.6, 126.6,
127.2, 128.6, 131.3, 132.5, 136.7, 149.9, 150.4, 171.0; IR (KBr) 1752, 1535, 1485, 1465, 1385, 1346,
1310, 868, 850, 760, 703 cm-1.

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HETEROCYCLES, Vol. 75, No. 11, 2008
Synthesis of pyrazole derivatives (29 and 30f)
Synthesis of pyrazole derivative (29)
(1 g, 3.1 mmol) of the azoacetate derivative (13) was dissolved in hot n-PrOH (40 mL) to which (0.3 g,
4.6 mmol) of potassium cyanide was added. The solution was allowed to reflux for 4 h, before being
evaporated to dryness. Water (100 mL) was added to the reaction vessel and this was extracted with
CH2Cl2 (15:85). The combined extracts were dried over magnesium sulfate and upon evaporation to a
reduced volume a pale brown solid precipitated. The precipitate was filtered off and washed with
petroleum ether and the product isolated after flash chromatography. Yield (0.13 g, 15%) mp 210-212 ºC;
1H NMR (400MHz, DMSO-d6): δ = 1.27 (3H, t, CH3, J = 7.2), 2.26 (3H, s, CH3), 4.20 (2H, q, CH2, J =
13
7.2), 6.64 (2H, s br, CH2), 7.81 (2H, d, ArH , J = 7.2), 8.32 (2H, d, ArH, J = 7.2); C NMR (100MHz,
DMSO-d6) 14.3, 14.4, 59.1, 93.9, 123.0, 124.9, 143.1, 144.9, 150.6, 151.2, 164.0. IR (KBr) 3349, 1676,
1548, 1344, 1286, 1131, 1112, 857, 789 cm-1.
Synthesis of pyrazole derivative (30f)
Yield (0.12 g, 15%); mp 181-183 ºC; 1H NMR (400MHz, DMSO-d6): δ = 2.94 (3H, s, CH3), 6.60 (2H, s
br, CH2), 7.06 (1H, t, ArH , J = 7.6), 7.32 (2H, t, ArH, J = 7.6), 7.63 (2H, d, ArH , J = 7.6), 7.88 (2H, d,
ArH , J = 9.2), 8.35 (2H, d, ArH, J = 9.2), 8.85 (1H, s, NH,); 13C NMR (100MHz, DMSO-d6) 14.2, 98.4,
120.4, 122.6, 123.3, 124.9, 128.5, 138.8, 143.3, 144.7, 148.2, 150.7, 163.3; IR (KBr) 3455, 3429, 3313,
1650, 1599, 1543, 1495, 1343, 864, 745, 684 cm-1.
ACKNOWLEDGEMENTS
This work was supported by the National Institute for Cellular Biotechnology (NICB) and the Irish
Research Council for Science Engineering and Technology (IRCSET). The authors would also like to
thank Mr. Damien McGuirk for assistance with NMR spectroscopy and Dr. Helge Müller-Bunz for X-ray
crystallography.
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