4,4-Bis(methylthio)azetidin-2-ones as synthons of 1,2- and 1,3-dicarbonyl systems

Article abstract of DOI:10.1016/j.tetlet.2011.02.046

The importance of β-lactams as synthetic building blocks has been widely recognized in organic synthesis due to possible ring cleavage at any of the four single bonds of the β-lactam ring. We now report reactions involving breaking of the N1-C4 bond in differently substituted at C3 4,4-bis(methylthio)azetidin-2-ones, leading to formation of 1,2- and 1,3-dicarbonyl systems.

Full text of DOI:10.1016/j.tetlet.2011.02.046

Tetrahedron Letters 52 (2011) 1909–1912
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
4,4-Bis(methylthio)azetidin-2-ones as synthons
of 1,2- and 1,3-dicarbonyl systems
Monika I. Konaklieva a, , Lita S. Suwandi a, Maya Kostova a, Jeffrey Deschamps b
⇑
a Department of Chemistry, American University, 4400 Massachusetts Ave., NW, Washington DC 20016, USA
b Naval Research Laboratory, Code 6030, 4555 Overlook Ave., Washington DC 20375, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2008
Revised 7 February 2011
Accepted 9 February 2011
Available online 13 February 2011
The importance of b-lactams as synthetic building blocks has been widely recognized in organic synthesis
due to possible ring cleavage at any of the four single bonds of the b-lactam ring. We now report reactions
involving breaking of the N1–C4 bond in differently substituted at C3 4,4-bis(methylthio)azetidin-2-ones,
leading to formation of 1,2- and 1,3-dicarbonyl systems.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactams
1,2-Dicarbonyl
1,3-Dicarbonyl systems
1,2,3-Vicinal tricarbonyl systems
C1–N4 bond breaking
CAN
a-Hydroxy-b-keto-acid derivatives
1. Introduction
of 4,4-bis(methylthio)azetidin-2-ones. Synthesis of several
4,4-bis(methylthio)azetidin-2-ones of type 3 (Fig. 1) having a phe-
In addition to their biological activity, predominantly as inhib-
itors of the serine enzymes of mammalian, bacterial, and viral
origin,1 the importance of b-lactams as synthetic building blocks
has been widely recognized in organic synthesis due to the ring
cleavage at any of the four single bonds of the lactam ring. How-
ever, the sequential or simultaneous fragmentation of two bonds
of the b-lactam ring has been rarely reported in the literature.2
The cleavage of the C4–N1 bond in 2-azetidinones having an aryl
substituent at C4 under palladium–catalyzed hydrogenolysis has
been described by the Ojima’s group2 and in systems having aryl
substituents at C3 and C4, and a benzoyl group at C4 under basic
conditions—by the Alcaide’s group.2 Cleavage of two bonds of the
2-azetidinone ring has also been observed by the Alcaide’s group
when N-arylidene- or N-arylidene-amino-b-lactams were treated
with ozone, followed by reduction with NaBH4.2 Recently, the
N1–C4 bond breaking with 2-azetidinones lacking an aryl moiety
at C4 has been shown to occur by the latter research group.3 We
now wish to report N1–C4 bond breaking in differently substituted
at C3 4,4-bis(methylthio)azetidin-2-ones, leading to the formation
of 1,2 and 1,3-dicarbonyl systems.
nyl ether at C3, which have been used to prepare C4-unsubstituted
b-lactams 3 (Fig. 1) by desulfurization with Raney-Nickel, has been
reported by Sharma et al.4 Under the desulfurization, as well as
under oxidation conditions of the starting b-lactams with mercury
and cadmium oxides, in addition to the C4-unsubstituted
b-lactams 3 (Fig. 1), small amounts (about 30% yield) of the open
chain amides of type 2b (Fig. 1) have been observed by the
authors.4
We have prepared b-lactams 3–10 (Fig. 2) utilizing the
Staudinger reaction between a ketene generated in situ from the
corresponding acyl chloride and the dithiocarbonimidates using
the procedure described by Sharma et al.4 Preparation of the corre-
sponding b-lactam sulfones 11–14 (Fig. 2) was done by oxidation
with meta-chloro-peroxybenzoic acid (mCPBA). Synthesis of
b-lactams 3, 6 (Fig. 2)3,9 and 75 have been described earlier, how-
ever, preparation of the rest of the b-lactams shown below
(Fig. 2) has not been previously reported.
2. Results and discussion
In continuation of our efforts on the design and the synthetic
applications of b-lactams, we set to explore the synthetic utility
2.1. Formation of 1,2-dicarbonyl systems
When compound 6 (Fig. 2) having an ester group at C3 was sub-
jected to column chromatography with silicagel, it underwent a
⇑
Corresponding author. Tel.: +1 202 885 1777; fax: +1 202 885 1752.
E-mail address: mkonak@american.edu (M.I. Konaklieva).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.046

1910
M. I. Konaklieva et al. / Tetrahedron Letters 52 (2011) 1909–1912
SCH3
H
PhO
PhO
O
R2
R3
R1
PhOCH2COCl
SCH3
H
Ra-Ni, H2, acetone, reflux
Et3N, CH2Cl2, r.t.
R1 = PMP, Bn, i-
N
N
N
C4H9,CH2CO2C2H5
O
R1
R1
3
2
1
S
S
H
N
PhO
PhO
PhO
S
R2
R3
PhOCH2COCl
S
H
+
Ra-Ni, H2, acetone, reflux
H
Et3N, CH2Cl2, r.t.
N
N
N
O
O
O
R'
R1 = PMP
2a R'
R'
R1
3
2b
1
R1 = PMP, Bn, i-
C4H9,CH2CO2C2H5
Figure 1. Synthesis and chemical transformations of 4,4-bis(methylthio)azetidin-2-ones performed by Sharma et al.4
SCH3
SCH3
SCH3
SCH3
SO2CH3
SO2CH3
RO
O
O
O
RO
O
O
N
N
N
R
7
3. R = Ph
4. R = Bn
5. R = Me
6. R = Ac
. R = PMP
8. R = Bn
. R = i-C4H9
OCH3
OCH3
11 R = Ph
12. R = Bn
13. R = Me
14. R = Ac
9
10
. R = 4-F-Ph
Figure 2. Structures of 4,4-bis(methylthio)azetidin-2-ones prepared in our laboratories.
SCH3
SCH3
SCH3
4
H
SCH3
O
H
O
H
HO
O
acid or base
SCH3
3
SCH3
O
2
1
NH
N
N
R
O
R
O
R
6
15
16a R = PMP
16b R = 4-F-Ph
16c R = Bn
16d R = i-C4H9
Figure 3. Proposed course of the reaction for the formation of 1,2-dicarbonyl systems from 4,4-bis(methylthio)azetidin-2-ones having a hydrolysable group at C3.
rearrangement leading to 1,2-dicarbonyl system of type 16 (Fig. 3)
whose bis(methylthio)-group could be considered as masked car-
bonyl functionality.5 1,2,3-Vicinal tricarbonyl systems have been
shown to serve as potent electrophiles in organic synthesis. The
synthetic utility of this functional group has been demonstrated
by H. H. Wasserman et al.6–10 Currently, methods for the introduc-
tion of the 1,2,3-tricarbonyl group include ozonolysis or single
oxygen cleavage of 2-enamino-3-keto esters;11 2-phosphorus ylide
derivatives of 3-keto esters;12 or the ozonolysis of 2-iodoiumyl-
3-keto esters,13 and the hydrolysis of 2-oximino-3-keto esters,14
as well as the treatment of 2-(nosyloxy)-3-keto esters with
triethylamine.15 Several important classes of biologically active
compounds6–10,16–22 have been synthesized by routes employing
the 1,2,3-vicinal tricarbonyl moiety as part of the key intermedi-
ates, based on the multiple reactivity patterns of vicinal tricarbonyl
systems in the synthesis of a variety of heterocyclic systems.23
We obtained the 1,2-dicarbonyl systems of type 16 (Fig. 3) from
a novel rearrangement of 3-acetoxy-4,4-bis(methylthio)azetidin-
2-ones of type 3 (Fig. 2) having different substituents at the lactam
nitrogen. These substituents include para-substituted phenyl, with
(PMP) 16a and (4-F-Ph) 16b, a benzyl group 16c, and an aliphatic
group (i-C4H9) 16d (Fig. 3). The rearrangement occurs when the
bis(methylthio)-b-lactams are exposed to silicagel (flash chroma-
tography) for prolonged periods of time. The resultant dicarbonyl
compounds 16 (Fig. 3) are highly stable and can be stored for
months without observable decomposition. This is an attractive
feature of this dicarbonyl system, since 1,2,3-tricarbonyl com-
pounds are often difficult to isolate in a pure state.10,17,21,22 Our at-
tempts, however, to find an appropriate oxidizing reagent to
‘unmask’ the terminal carbonyl functionality from the bis(methyl-
thio)-moiety without destroying the 1,2-dicarbonyl system were
unsuccessful. Since the rearrangement from b-lactams to 1,2-dicar-
bonyl system occurs with quantitative yield, the overall yield of the
1,2-dicarbonyls depends on the yield of the [2+2] reaction. The
highest yields for the latter were observed when the substituent
at N1 is benzyl and aryl—70%, or the substituent is aliphatic—
60%. We were not able to prepare 4,4-bis(methylthio)azetidin-2-
ones, where the substituent of the phenyl group at N1 is at other
than p-position, even in the case of electron donating group. An
ester group, such as acetoxy group at the C-3 position, which could
be hydrolyzed to an alcohol, is absolutely necessary in order for the
rearrangement to occur.
Previously, it has been observed that 1-(40-methoxy-phenyl)-
3-acetoxy-4,4-bis(methylthio)azetidin-2-one
6
(Fig. 2) upon
hydrolysis with 1% NaOH in aqueous methanol gives a 3-hydroxy
derivative.23 This C3 hydroxy-C4-dimethylthio b-lactam has
been found to be unstable at room temperature slowly changing
into a new unidentified compound with higher Rf than the C3

M. I. Konaklieva et al. / Tetrahedron Letters 52 (2011) 1909–1912
1911
hydroxy-C4-dimethylthio b-lactam.23 Initially, we felt that this
unidentified product could be identical to the 1,2-dicarbonyl sys-
tem we obtained. In order to determine the mechanism of the rear-
rangement of the 3-acetoxy-4,4-bis(methylthio)azetidin-2-ones,
studies involving titration of two of the b-lactam systems with acid
and base solutions, respectively, were performed. The changes in
the b-lactam ring were followed by NMR and showed that adding
base solution leads to both the ‘classical’ opening of the b-lactam
ring, along the C1–N1 bond, and the aforementioned rearrange-
ment, while the rearrangement to the 1,2-dicarbonyl systems takes
place cleanly under acidic conditions. This leads us to suggest that
only under acidic or mild basic conditions, which would allow for
the ester hydrolysis, but not for the amide hydrolysis, the forma-
tion of systems of type 16 (Fig. 3) is possible.
The mechanism we propose for the rearrangement of the dim-
ethylthio-b-lactams having an acetate group at C3 to the corre-
sponding 1,2-dicarbonyl systems of type 16 (Fig. 3)5 involves the
following: hydrolysis of the acetate group to the alcohol group at
C3, followed by the formation of a carbonyl group at C3 leading
to a hydride shift of the H-atom from C3 to C4, which in turn leads
to breaking of the C4–N1 bond and protonation of the lactam
nitrogen.
This mechanism is based on the observed progress of the acid
hydrolysis of two of the 3-acetoxy-4-dimethylthio b-lactams, 16a
and 16b (Fig. 3) by NMR, that is, (a) appearance of a proton signal
at C4 whose chemical shift is with about 0.5 ppm upfield (in the
1,2-dicarbonyl system) as compared to the proton at C3 of the cor-
responding b-lactam; and (b) loss of the methyl group of the ace-
tate in conjunction with the appearance of the broad signal for
the proton on the amide N-atom after opening of the ring.
Figure 5. Structure of compound 20 as determined by X-ray diffraction. Displace-
ment ellipsoids are at the 50% level.
SO2CH3
RO
O
SO2CH3
SO2CH3
RO
O
SO2CH3
CAN
N
N
CH3CN, water
reflux
NO2
OCH3
11
. R = Ph
. R = Bn
. R = Me
. R = Ac
OCH3
12
13
14
21
Figure 6. Introduction of a nitro-group in the o-position of the PMP substituent at
N1 using 4,4-bis(methylthio sulfonyl)azetidin-2-ones using CAN.
2.2. Formation of 1,3 dicarbonyl systems
N-Deprotection of 1-(4-methoxyphenyl)azetidin-2-ones by
chemical oxidation by Cerium Ammonium Nitrate (CAN) is an
established method in b-lactam chemistry.24
When b-lactams 3–6 (Fig. 2) were treated with 6 molar equiva-
lents (twice the amount usually used) for the b-lactam N1 depro-
tection with CAN under the standard reaction conditions,24 we
The rest of the b-lactams we have examined, with methoxy,
benzyloxy, and acetoxy groups at C3 and PMP group at N1 upon
the treatment with CAN do not appear to undergo the deprotection
of the lactam nitrogen, thus leading only to formation of the
1,3-dicarbonyl systems of type 19 (Fig. 4). Similar behavior of 4,4-
bis(methylthio)azetidin-2-ones has been observed by Sharma et. al
upon the treatment of phenoxy substituted lactams at C3 with mer-
cury oxides or cadmium carbonate and mercury salts.4 We have
found that in order for the 1,3-dicarbonyl systems to be formed, it
is absolutely necessary for the methylthio groups to be in their re-
duced state. Oxidation of the methylthio groups to the correspond-
ing sulfones (11–14, Fig. 2) prior to the treatment with CAN does
not lead to ring opening. When other than PMP group is present on
the lactam nitrogen such as benzyl (17, Fig. 4), as well as 4-F-phenyl
obtained a-alkoxy-b-keto-acid derivatives of type 19 (Fig. 4).
When the substituent at C3 is phenoxy, and the group at N1 is
p-methoxyphenyl (PMP), deprotection of the lactam nitrogen, (com-
pound 20, Fig. 4) occurs in 50% yield. The structure of the latter was
confirmed by X-ray analysis (Fig. 5). To the best of our knowledge,
deprotection of the lactam nitrogen of the 1-(40-methoxy-phenyl)-
3-phenoxy-4,4-bis(methylthio)azetidin-2-one leading to the
formation of 1,3-dicarbonyl system 20 (Fig. 4) has not been reported
previously.
SCH3
H
S(O)2CH3
H
O
O
Ph
Ph
CAN
SCH3
S(O)2CH3
3
2
4
1
N
N
O
O
17
18
O
O
SCH3
H
O
O
O
R
R
R
SCH3
SCH3
SCH3
3
4
CAN
+
2
1
NH
NH2
N
O
O
O
1
20
when R = Ph
19
OCH3
OCH3
Figure 4. Synthesis of 1,3-dicarbonyl systems from 4,4-bis(methylthio)azetidin-2-ones using CAN.

1912
M. I. Konaklieva et al. / Tetrahedron Letters 52 (2011) 1909–1912
or aliphatic groups (8–10, Fig. 2), only oxidation of the methylthio
groups (18, Fig. 4) takes place upon the treatment of these lactams
with CAN. It is conceivable that the oxidation of the methylthio
group to carbonyl by CAN with consecutive breaking of N1–C4 bond
leads to the 1,3-dicarbonyl systems 19 (Fig. 4), and simultaneous
oxidationof methylthio group to carbonyl and dearylation of the lac-
tam nitrogen lead to 1,3-dicarbonyl systems 20 (Fig. 4).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.046.
References and notes
When the disulfones having a PMP group at the lactam nitro-
gen, (compounds 11–14, Fig. 2)25 are refluxed in acetonitrile–water
for 10–12 h, nitronization of the PMP ortho to the methoxy group
takes place leading to the formation of compounds of type 21
(Fig. 6). Similar nitronization of the PMP group at N1 has been
reported earlier by Banik et al.26 of b-lactams having aromatic
substituents at C3 and C4.
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We have developed a two-step synthetic procedure for the
preparation of 1,2-dicarbonyl systems having terminal bis(methyl-
thio)-moiety as masked carbonyl functionality under very mild
conditions from 3-acetoxy-4-dimethylthio b-lactams having
different substituents at N1. 1,3-Dicarbonyl systems can also be
obtained from 4,4-bis(methylthio)azetidin-2-ones. All of these
b-lactam derivatives stem from the N1–C4 bond breaking under
different conditions. Studies on the reactivity of these systems
are under way in our laboratories.
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Acknowledgments
M.I.K. is thankful to the American University for the financial
support via the University Research Grant Program. Crystallo-
graphic studies were supported by the Naval Research Laboratory
(NRL) and the Office of Naval Research (ONR).
26. Banik, B. K.; Samajdar, S.; Ng, S. S.; Becker, F. F. Abstracts of Papers, 223rd ACS
National Meeting, Orlando, FL, United States, April 7–11, 2002.