A flexible route to 4-substituted β-lactams

Article abstract of DOI:10.3987/COM-10-S(E)39

A variety of 4-substituted β-lactams can be readily prepared by the radical addition-transfer of 4-S-xanthyl-azetidinones to unactivated olefins. For this radical chain process to operate efficiently it is necessary to place an acyl group on the nitrogen of the azetidinone ring. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)39

HETEROCYCLES, Vol. 82, No. 1, 2010
263
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 263 - 271. © The Japan Institute of Heterocyclic Chemistry
Received, 27th May, 2010, Accepted, 21st June, 2010, Published online, 22nd June, 2010
DOI: 10.3987/COM-10-S(E)39
A FLEXIBLE ROUTE TO 4-SUBSTITUTED !-LACTAMS
Béatrice Quiclet-Sire* and Samir Z. Zard*
Department of Chemistry, Ecole Polytechnique, CNRS UMR 7652, 91128
Palaiseau, France. zard@poly.polytechnique.fr
This paper is dedicated with respect and admiration to Prof. Albert Eschenmoser
on the occasion of his 85th birthday.
Abstract – A variety of 4-substituted !-lactams can be readily prepared by the
radical addition-transfer of 4-S-xanthyl-azetidinones to unactivated olefins. For
this radical chain process to operate efficiently it is necessary to place an acyl
group on the nitrogen of the azetidinone ring.
INTRODUCTION
The enormous importance of !-lactam antibiotics and the rich chemistry associated with the strained
lactam ring, especially in its capacity to act as an activated, latent !-aminoacid, have continued to
stimulate the interest of organic chemists.1,2 In addition to the development of methods for constructing
the !-lactam ring itself, much effort has been expanded for the modification of existing structures. The
introduction of a substituent at position 4 of !-lactams has often been realised by replacement of a
potential leaving group X in structure 1 by various nucleophilic reagents to give derivatives 2 (Scheme
1).3 Thus, carbanions, organometallics, enol silyl ethers, ketene silyl acetals and allylsilanes can be used
for the substitution reaction, the last three families of nucleophiles usually requiring the mediation of a
Lewis acid. In stark contrast, the introduction of substituents by reactions proceeding by way of radical 3
and leading to structures 4, has very seldom been exploited, despite its obvious potential. One rare
example reported a quarter of a century ago by Fliri and Mak and portrayed in Scheme 1 is the radical
allylation of azetidinone 5 with allyltributyltin to provide compound 6 in good yield.4 This approach is
however limited to very simple allylations and requires the use of organotin derivatives, which are not
acceptable in a pharmaceutical context because of the acute toxicity of organotin derivatives and the
extreme practical difficulty in completely removing tin residues from the products.

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HETEROCYCLES, Vol. 82, No. 1, 2010
R'
O
X
R
R'
O
Nu
R
R'
O
R'
O
R"
R
Nu
- X
N
N
N
N
R
2
3
4
1
OSiH(Ph)2t-Bu
OSi(Ph)2t-Bu
SCSOEt
SnBu3
(AIBN)
N
N
72%
OMe
O
H
O
H
5
7
6
OMe
S
CN
S
Cl
O
Cl
8
EtO
S
S
76%
OEt
CN
N
N
N
(lauroyl peroxide)
EtOAc, reflux
O
9
R
S
S
H
R
11
SCSOEt
OEt
N
lauroyl
peroxide
O
H
O
10
12 (very poor yield)
Scheme 1. Modification of !-lactams
RESULTS AND DISCUSSION
Over the past years, we have demonstrated the unique ability of xanthates for creating new carbon-carbon
bonds by intermolecular radical addition to unactivated alkenes.5 More generally, relatively slow and
otherwise difficult radical transformations can often be accomplished because the xanthate transfer
process imparts a comparatively long lifetime to the intermediate radicals, even under concentrated
conditions. We exploited this property to construct the !-lactam ring itself, but it seemed interesting to
expand the scope to the modification of existing !-lactam structures. However, while the addition of
S-cyanomethyl xanthate 8 to N-allyl !-lactam 7 could indeed be readily accomplished, the addition of
!-lactam xanthate 10 to simple unactivated alkenes 11 proceeded in very poor yield (Scheme 1).
The most likely reason underlying this disappointing failure may be traced to the relative stabilities of the
various radical intermediates involved in the xanthate addition-transfer, which can be readily understood
by a brief examination of the simplified mechanism displayed in Scheme 2. One of the key requirements
of the process is that, in the absence of special polar factors, the initial radical, in this case 14, must be
more stable than the adduct radical 15 in order for the equilibrium involving intermediate 16 to favour the
forward pathway and thus sustain the desired chain reaction. In other words, the fragmentation of
intermediate 16 has to preferentially lead to addition product 17 and starting radical 14, rather than back
to adduct radical 15. The failure of the desired addition indicated that this is probably not the case, and
that the stabilisation of radical 14 by the lone pair of the nitrogen is not sufficient, presumably for reasons
related to the strained geometry of the azetidinone structure.

HETEROCYCLES, Vol. 82, No. 1, 2010
265
S
R
R
11
R"
O
S
R"
O
R"
O
peroxide
OEt
N
N
N
R'
R'
R'
13
15
13
14
R
R
R"
R"
R"
O
R'
O
S
OEt
S
S
+
N
N
N
N
O
R'
O
R'
R'
S
EtO
R"
17
14
16
R"
O
R"
O
R"
N
N
N
O
O
O
O
Me
Me
Me
18a
18b
18c
Scheme 2. Simplified mechanistic rationale
With the aim of enhancing the stability of radical 14 sufficiently to tilt the equilibrium along the forward
direction, we contemplated starting with the N-acyl derivatives 13 (R’ = MeCO-), where we hoped the
radical would acquire a certain degree of allylic character through canonical structures 18a-c of the imide,
as pictured in the lower part of Scheme 2. A similar spin delocalization appears to operate in the case of
phthalimidomethyl radicals, which we exploited to accomplish a very efficient and broadly applicable
radical aminomethylation of alkenes.6 Because of the strain involved, the extra stabilisation provided by
canonical structures 18b and 18c would be expected to be less effective than in the case of the much less
strained phthalimido analogues, but even a small stabilisation could prove decisive in ensuring success.
EtOCSSK
or
neoPnOCSSNa
(CH2)8CO2Me
SCSOEt
S
OAc
H
S
R
(CH2)8CO2Me
11a
OR'
N
N
N
(lauroyl peroxide)
EtOAc, reflux
acetone
Ac2O
22a 65%
(from 21a)
O
O
O
Ac
19
10, R = H; R' = Et
20, R = H; R' = neoPn 97%
(Me3Si)3SiH
(AIBN)
21a, R = Ac; R' = Et 93%
21b, R = Ac; R' = neoPn 90%
(CH2)8CO2Me
Ph
O
N
X
O
N
23a 96%
O
Ac
p-MeOC6H4
11b
N Ph
21b
N
(lauroyl peroxide)
EtOAc, reflux
O
Ac
22b, X = -SCSOneoPn 51%
23b, X = H 81%
(Me3Si)3SiH
(AIBN)
OMe
Scheme 3. Radical additions of S-azetidinyl xanthates

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HETEROCYCLES, Vol. 82, No. 1, 2010
We therefore prepared N-acetyl derivative 21a from known xanthate 10,7 itself readily obtained from
commercial 4-acetoxyazetidinone 19 (Scheme 3). In the same manner, we prepared the neopentyl
analogue 21b (neoPn = neopentyl). We have observed over the years that S-neopentyl xanthates tended to
be more crystalline than their ethyl analogues, and this can be advantageous when there is a need to purify
delicate structures.8 Neopentyl derivatives were also much less susceptible to undesired ionic
transformations. When a concentrated solution of xanthate 21a and methyl 10-undecenoate 11a was
heated at reflux in ethyl acetate in the presence of a small amount of lauroyl peroxide, we were gratified
to find that a relatively smooth reaction took place to give the desired product 22a in 65% yield. To
simplify the characterization of the product, the xanthate group was removed to give 23a in near
quantitative yield by reduction with tris-(trimethylsilyl)silane and a small amount of AIBN in refluxing
1:1 toluene:cyclohexane (Scheme 3).9
OSi(Me)2t-Bu
OTBS
OTBS
(CH2)8CO2Me
S
OAc
S
R
(CH2)8CO2Me
EtOCSSK
acetone
SCSOEt
11a
OEt
N
N
N
(lauroyl peroxide)
EtOAc, reflux
27a 73%
O
H
O
O
Ac
24
25, R = H 98%
Ac2O
(Me3Si)3SiH
(AIBN)
26, R = Ac 87%
CO2Me
OTBS
N
OTBS
(CH2)8CO2Me
CO2Me
11c
CO2Me
SCSOEt
MeO2C
26
N
(lauroyl peroxide)
EtOAc, reflux
28 71%
O
Ac
O
Ac
27b 50%
Scheme 4. Radical additions of functionalized S-azetidinyl xanthates
The success of this preliminary reaction opens up numerous possibilities for rapidly constructing highly
functional and indeed quite complex azetidinones. One such example, also pictured in Scheme 3, is the
synthesis of di-!-lactam 23b by the addition of S-azetidinyl xanthate 21b to 3-allyl azetidinone 11b and
reductive removal of the xanthate group from the intermediate adduct 22b. One of the main features of
the present radical process is its tolerance for numerous functional groups because of the extreme
mildness of the experimental conditions. This is illustrated by the addition reactions of 3-substituted
xanthate 26, derived from commercially available 4-acetoxyazetidinone derivative 24 (Scheme 4). Thus,
the addition reaction of 26 with methyl 10-undecenoate 11a proceeded as effectively as with the simpler
xanthate 21a leading finally to compound 28 following the removal of the xanthate group. Only one
isomer is obtained since the bulky protected hydroxyethyl substituent on C-3 of the azetidinone forces the
new carbon-carbon bond to form from the opposite side of the ring. The addition of 26 to the dimethyl
ester 11c of Feist’s acid is another example of the degree of complexity that can be swiftly attained.

HETEROCYCLES, Vol. 82, No. 1, 2010
267
Me
O
Me
F
N
N
O
O
MeO
Me
Me
EtSO2
Cl
Cl
OTBS
N
OTBS
N
Cl
Cl
Me
O
29
31
26
lauroyl peroxide
EtOAc, reflux
(lauroyl peroxide)
EtOAc, reflux
O
Ac
O
Ac
CN
30 84%
32 49% E/Z : 5/1
lauroyl peroxide
EtOAc, reflux
N
33
H
OTBS
NC
O
N
34 44%
N
Ac
H
Scheme 5. Radical vinylation, allylation and heteroarylation of functionalised S-azetidinyl xanthates
We had previously reported the use of allyl and vinyl ethylsulfones as tin-free allylating and vinylating
reagent for both aliphatic iodides and xanthates.10 An example of the latter transformation is shown in
Scheme 5, whereby S-azetidinyl xanthate 26 is converted in high yield into nicely crystalline (mp:
85-86 °C) dichlorovinyl derivative 30 upon reaction with sulfone 29. Very recently, we discovered that
allylic alcohols become highly versatile radical allylating agents when they are converted into their
6-allyloxy-2-fluoropyridinyl derivatives.11 This process has an enormous potential for synthesis in view of
the central position played by alkenes in organic chemistry. An illustration in the present case is the
formation of protected enal 32, as a 5:1 mixture of geometrical isomers by addition-fragmentation of
xanthate 26 to derivative 31. It is worth noting that in this case, the lauroyl peroxide must be used in
stoichiometric amounts since the departing fluoropyridinyloxy radical is unable to propagate the chain.
Another process, which also requires the use of stoichiometric peroxide, is the intermolecular addition of
xanthates to certain heteroaromatic derivatives, as illustrated by the formation in moderate yield of
compound 34 by reaction of xanthate 26 with 3-cyanoindole 33. While this approach is somewhat limited
in scope as far as the heteroaromatic component is concerned, it can nevertheless furnish in one step some
very interesting structures.12
In all the preceding examples, the N-acetyl group serves to stabilize the radical and, even if this
stabilization is presumably relatively small in absolute terms, it has proved essential for implementing the
chain process, which does not operate in its absence. The drawback is that it is very difficult to remove
this acetyl group without destroying the azetidinone ring, and this obliterates to a large extent the utility
of this approach. In order to circumvent this rather serious problem, we examined the replacement of the
acetyl by an oxalyl group. It was known by researchers in the !-lactam field that an N-oxalyl group could

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HETEROCYCLES, Vol. 82, No. 1, 2010
be removed under extremely mild conditions that did not affect the fragile azetidinone ring.13 We
therefore prepared xanthate 35 from !-lactam xanthate 10 and, indeed, found that the addition and
removal of the oxalyl group could be readily accomplished, as demonstrated by the synthesis of
compounds 39a,b possessing a free N-H group on the !-lactam ring (Scheme 6).
S
S
S
S
OneoPn
O
OR
O
N
N
O
O
O
O
O
OMe
35, R = Et ~100% (from 10)
37, R = neoPn 88% (from 20)
36 63% (from 20)
(CH2)8CO2Me
SCSOR
(CH2)8CO2Me
SCSOR
(CH2)8CO2Me
Et3N
MeOH, rt
11a
35 or 36
N
N
(lauroyl peroxide)
EtOAc, reflux
O
O
O
H
O
39a, R = Et; 65% from 35
39b, R = neoPn; 59% from 36
OR'
38a, R = Et; R' = Me
38b, R = neoPn; R' = 9-fluorenyl
R
Me
Me
Me
R
OAc
11d-h
X
O
OMe
11f
37
N
a,b
or
a,b,c
11e
11d
O
H
O
40-44
Me
Me
O
O
X = -SCSOneoPn or H
MeO
Me
O
Me
O
Me
a: (lauroyl peroxide), EtOAc, reflux
b: Et3N, MeOH, rt
c: (Me3Si)3SiH, (AIBN)
11h
11g
Me
Me
Me
Me
SCSOneoPn
SCSOneoPn
OAc
Me
Me
SCSOneoPn
O
N
O
O
N
N
N
O
H
O
H
O
H
O
H
41 33%
(over 3 steps
from 37 and 11e)
Me
Me
40 64%
(over 2 steps
from 37 and 11d)
OMe
42 54%
(over 2 steps
from 37 and 11f)
43 42%
(over 2 steps
from 37 and 11g)
H
N
O
O
MeO
44 47%
(over 3 steps
O
Me
O
from 37 and 11h)
Me
Scheme 6. Synthesis of N-unsubstituted !-lactams
The intermediate adduct 38a was not purified in this sequence but immediately converted into 39a by
exposure to triethylamine in methanol. In fact, the purification of N-oxalyl azetidinones proved rather

HETEROCYCLES, Vol. 82, No. 1, 2010
269
tricky and some decomposition was observed upon chromatographic separation. We attempted to
overcome this hurdle by replacing the O-ethyl xanthate group in 35 with an O-neopentyl xanthate and the
methyl oxalate with the much bulkier 9-fluorenyl ester.14 However, the resulting derivative 36 did not
prove superior in relation to the synthetic effort need to prepare it, as shown by the formation of
analogous product 39b in similar overall yield (59% vs 65%). The remainder of the study was therefore
performed using azetidinyl xanthate 37, which was readily obtained and proved easy to purify by
crystallisation.
Xanthate 37 was reacted with a selection of five olefins, 11d-h, to give the corresponding adducts 40-44
in useful overall yield. In two instances (41 and 44), the xanthate group was reductively removed. In the
case of 41, the volatility of the olefin caused a significant lowering of the yield. The attachment of a
!-lactam motif to a glucose residue as in 44 is noteworthy and further demonstrates the synthetic potential
of this novel chemistry
In summary, we have developed a flexible approach to highly substituted azetidinones. While the radical
additions of the !-lactam xanthates are slightly less efficient than the phthalimido substituted xanthates
we described previously, many of the compounds reported in this preliminary work would be exceedingly
tedious, if not impossible, to make by more traditional routes. Indeed, the xanthate transfer technology
represents a quite general solution to a longstanding problem in organic synthesis, namely the creation of
a carbon-carbon bond in an intermolecular fashion starting with non-activated alkenes.
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