A telescopic one-pot synthesis of β-lactam rings using amines as a convenient source of imines

Article abstract of DOI:10.1039/c6ra02744j

A facile synthetic approach to substituted β-lactams was designed, using secondary benzylic amines and acid chlorides as starting materials. The reactions proceeded smoothly and all the products were obtained in good yields.

Full text of DOI:10.1039/c6ra02744j

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A telescopic one-pot synthesis of b-lactam rings
using amines as a convenient source of imines†
Cite this: RSC Adv., 2016, 6, 38553
a
a
a
b
*
Suvi H. M. Rajamaki, Lidia De Luca, Francesca Capitta and Andrea Porcheddu
¨
Received 29th January 2016
Accepted 12th April 2016
DOI: 10.1039/c6ra02744j
www.rsc.org/advances
A facile synthetic approach to substituted b-lactams was designed,
using secondary benzylic amines and acid chlorides as starting ramines,15 we designed
materials. The reactions proceeded smoothly and all the products synthesis using N-chloramines as a convenient source of imines
Following our previous work on both b-lactams14 and chlo-
modied Staudinger b-lactam
a
were obtained in good yields.
(Scheme 1). The in situ-generated imine may subsequently react
with a preformed ketene via a [2 + 2] cycloaddition to afford the
corresponding b-lactam.
Since the introduction of penicillin in the 1940s,1 antibiotics
have become a milestone of modern medicine.2 Penicillins,
cephalosporins and monobactams all belong to the family of b-
lactam antibiotics,3 in which the b-lactam ring is part of the core
structure.4 Antibiotics now face a critical and unprecedented
challenge resulting from the combination of two different
problems. First, antibiotic resistance to commonly used drugs
is increasing at an alarming rate.5 Second, the development of
new antibiotics has become so expensive and unattractive for
pharmaceutical companies that the antibiotic pipeline is
running dry.6 The need to overcome the problem caused by
drug-resistant bacteria7 has motivated chemists to modify the
structure of b-lactam antibiotics, aiming to render it insensitive
to the b-lactamase attack.8
Today, despite an enormous number of synthetic strategies to
prepare the b-lactam ring,9 the Staudinger approach10 using
ketenes and imines is regarded as the most effective and versatile
procedure for the synthesis of 2-azetidinone rings (Scheme 1).11
However, the preparation of labile imines12 requires an addi-
tional synthetic step, and several issues affect the yield due to the
existence of equilibrium conditions between the reactants and
the corresponding imines. Taking these factors into consider-
ation, we planned to generate imines by oxidation of the corre-
sponding amines in order to develop an effective procedure to
facilitate the access to substituted b-lactam rings.13
The rst step was the formation of a chloramine, followed by
subsequent elimination with base to form the corresponding
imine. N-Benzylamine 1 (1.0 mmol), chosen as a model
substrate, was dissolved in dry Et2O and treated with N-chlor-
osuccinimide (NCS, 1.1 mmol) at room temperature in an inert
atmosphere. Aer
1 h, TLC analysis showed complete
consumption of the starting amine, and the aqueous work-up of
the reaction mixture afforded chloramine 2 in an almost
quantitative yield (Scheme 2).16
In the following step, the resulting chloramine 2 (1 mmol)
dissolved in Et2O was treated overnight at room temperature
with an ethanolic solution of KOH (1.1 mmol), to afford the
corresponding imine 3 in good yield (71%, Scheme 2).
A set of bases in different solvents was then screened to
optimise the yield of imine 3 without isolating the intermediate
chloramine 2.17 The best results were obtained by performing
both the formation of chloramine and the elimination reaction
to give the imine in sequence in acetonitrile, using triethyl-
amine (1.5 mmol) as base (Table 1, entry 3). The imine forma-
tion was complete in just 3 hours at room temperature.
a
`
Universita degli Studi di Sassari, Dipartimento di Chimica e Farmacia, via Vienna 2,
Sassari, Italy
b
`
Universita degli Studi di Cagliari, Dipartimento di Scienze Chimiche e Geologiche,
Cittadella Universitaria, SS 554 bivio per Sestu, 09042 Monserrato, Ca, Italy.
E-mail: porcheddu@unica.it
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra02744j
Scheme
chloramines.
1
A
modified Staudinger b-lactam synthesis using
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Table 2 Screening of solvents and reagent quantities for the final
Staudinger b-lactam synthesisa
Scheme 2 Preparation of imines directly from secondary amines.
Table 1 Screening of bases and solvents for imine formation
Amine 1
(eq.)
PhOCH2COCl
(eq.)
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
7
2.0
1.0
1.5
1.0
1.0
1.0
1.5
1.0
1.5
1.0
2.0
2.0
2.0
2.0
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
CH2Cl2
THF
42
71
51
85
16
69
22
Entry
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
DBUb
DBU
NEt3
NEt3
NEt3
K2CO3
CH2Cl2
CH3CN
CH3CN
CH2Cl2
Et2O
CH3CN
CH3CN
CH3CN
CH3CN
49
54
99
85
81
8
—
—
61
c
a
b
Reactions were carried out at room temperature under Ar. Isolated
DABCOd
TMGe
yields.
NEt3/DMAPf
a
Yields were determined by NMR from crude reaction mixture. b DBU ¼
benzylic amines (Scheme 3, b-lactams 5–14). Benzylic amines
with either an electron-withdrawing (2-Br, 3-CF3) or an electron-
donating group (3-MeO or 3-MeO, 4-MeO) on the aryl ring
proved to be suitable substrates for this reaction, affording the
corresponding b-lactams 5–8 in high yields. The position and
activating or deactivating nature of substituents on the rings
did not signicantly affect the diastereoselectivity of the reac-
tion (cis/trans > 9/1) and they also had negligible inuence on
the yield of the isolated products (ranging from 72% to 79%).
Ethyl, isopropyl and benzyl groups on the benzylic nitrogen
were well tolerated, providing the corresponding b-lactams 9–11
in high overall isolated yields. Conversely, the reaction with N-
benzyl anilines (Scheme 3, b-lactam 12) was problematic and
only traces of product were detected.20
1,8-diazabicyclo[5.4.0]undec-7-ene. c Anhydrous K2CO3. d DABCO ¼ 1,4-
e
diazabicyclo[2.2.2]octane.
TMG
¼
1,1,3,3-tetramethylguanidine.
f
DMAP ¼ 4-dimethylaminopyridine.
Having established a reliable and easy procedure to convert
amines into imines, we then turned our attention to study the [2
+ 2] cycloaddition reaction of in situ-generated imines with
ketenes.
Initially, to the imine 3 was added a solution of phenox-
yacetyl chloride that had been previously treated with an equi-
molar amount of triethylamine to generate the corresponding
ketene. The pre-formed ketene reacted smoothly with the imine
3 giving a cis-b-lactam as the product (see Scheme in Table 2). In
order to nd the best route to prepare 2-azetidinone rings, we
carried out several experiments in parallel, reacting amine 1
with various amounts of phenoxyacetyl chloride and triethyl-
amine, as summarised in Table 2. The best results were ach-
ieved dissolving the phenoxyacetyl chloride in acetonitrile, and
using 2 equivalents of acid chloride and triethylamine for each
equivalent of N-methylbenzylamine (Table 2, entry 4). Once it
was established that in situ imine and ketene formation, as well
as the subsequent 2 + 2 rearrangement, proceeded smoothly in
acetonitrile, we then explored the possibility of developing the
synthesis of b-lactams 4 via a one-pot two-step protocol.
Therefore, N-methylbenzylamine 1 (1 mmol) dissolved in dry
acetonitrile (10 ml) was rst chlorinated with NCS (1.1 mmol),
treated with excess triethylamine (3.5 mmol) for 1 h under
argon at rt, and nally reacted overnight with phenoxyacetyl
chloride (2 mmol) in dry acetonitrile (10 ml).18 Under these
optimised reaction conditions, the cis-b-lactam 4 was isolated
(85%) as the major product.19
With these optimised reaction conditions, the scope and
Scheme 3 Synthesis of a-phenyloxy-b-lactams with aryloxyacetyl
limitations of this protocol were studied applying it to various chlorides and an array of benzyl amine derivatives.
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In the case of b-lactam 13, the product was formed in good
1
yield as judged by H NMR analysis of a sample of the crude
reaction mixture. Unfortunately the presence of many side
products rendered the reaction unviable and any attempt to
purify the product proved unsuccessful. It is worth noting that
aryloxyketenes possessing a substituent (Me, OMe, Cl, NO2) on
the aromatic ring (Scheme 3, b-lactams 14–17) were compatible
with the designed method. Moreover, in general, acid chlorides
containing electron-rich substituents on the phenyl ring
provided better yields than those bearing electron-withdrawing
groups (Scheme 3).
Aer these encouraging results from the initial experiments,
the general scope of this protocol was further explored by
reacting the in situ-generated imine 3 with a set of different acid
chlorides used as precursors of ketenes. The reaction worked
well also with methoxyacetyl chloride (Scheme 4, b-lactams 18–
22). The presence of a longer side chain on the ketene did not
signicantly affect the nal yield (Scheme 4, b-lactams 22).
Although the yields of these 2-azetidinones were somewhat
lower than with phenoxyacetyl chloride, they should be
considered satisfactory, since reactions are performed in a one-
pot, three-step fashion.
Scheme 5 Synthesis of b-lactams with substituted acetyl chlorides.
Next, we decided to explore the scope of this modied
Staudinger procedure combining the ketene derived from the
phenylacetyl chloride with a set of imines generated from
substituted benzylic amines. Generally, substituents on the aryl
group of N-methylbenzylamine do not seem to inuence the
outcome of the reaction (Scheme 5, b-lactams 29 and 30). When
N-methylfurfurylamine was employed, product 31 was identi-
ed in the crude NMR, but as for b-lactam 13, isolation and
purication proved very difficult and the product was not iso-
lated in acceptable purity.
The reaction failed to provide the desired b-lactam using
aliphatic amines with either of the protocols. The reaction was
tested with N-methylbutylamine and phenoxyacetyl chloride,
varying the base22 used in imine formation as well as solvent
and temperature of the reaction (Scheme 6).
While the synthesis of the chloramine proceeded smoothly,
both imine formation and the subsequent Staudinger reaction
with ketene to give a b-lactam resulted in a complex mixture of
products, unidentiable by NMR.
Despite some unsuccessful attempts, we were pleasantly
surprised by the high number of unknown compounds (>85%)23
prepared using this procedure, suggesting that our method-
ology may provide a direct and alternative route to b-lactam
structures.
Surprisingly, when the phenoxyacetyl chloride was replaced
with phenylacetyl chloride, no product was obtained when the
reaction was carried out at room temperature. We reoptimised
the reaction conditions and we were delighted to nd that
ꢀ
heating the reaction mixture overnight at 60 C in the ketene
formation step, the Staudinger reaction proceeded as smoothly
as before, affording the b-lactam 23 in reasonable yields
(Scheme 5).
The reaction yields decreased slightly for substituted phe-
nylacetyl chlorides bearing electron-withdrawing groups on the
aromatic ring (Scheme 5, compare compounds 23 and 24). In
contrast, electron-donating groups increased the yields signi-
cantly, giving an overall quantitative yield of cis and trans
isomers (Scheme 5, see b-lactams 25 and 26). We also attempted
to carry out the reaction with aliphatic acyl chlorides, but the
annulation reaction to give b-lactam 27 was unsuccessful
(Scheme 5).21
It is important to note that the reaction with (phenylthio)
acetyl chloride failed to give the desired b-lactam 28 at room
temperature, but with the procedure used for phenylacetyl
chlorides the reaction proceeded smoothly and in good yield,
giving the trans isomer as the only isolated product.
On the basis of above results and previously published
mechanisms,24 we postulate the most plausible reaction
pathway for the overall conversion of secondary benzyl amines
and acid chlorides into b-lactams (Scheme 7). In the rst step,
NCS promotes the chlorination of the N-alkylamine 32,
releasing an equivalent amount of succinimmide. In the second
step, NEt3 abstracts a proton from both chloramine 33 and acid
Scheme 6 Synthesis of b-lactams with butylamine and phenoxyacetyl
Scheme 4 Synthesis of b-lactams with methoxyacetyl chloride.
chloride.
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di
Sardegna
(Project:
Prot.
U875.2014/AI.758.MGB,
Prat.2014.0803).
Notes and references
1 American Chemical Society International Historic Chemical
Landmarks. Discovery and Development of Penicillin.
Retrieved from http://www.acs.org/content/acs/en/education/
whatischemistry/landmarks/emingpenicillin.html.
2 Antibiotics have not only saved millions of human lives, but
they have opened up signicant new vistas for research that
would have been unmanageable without them. L. Demain
and R. P. ElanderAntonie van Leeuwenhoek1999, 75 5–19;
¨
W. Durckheimer, J. Blumbach, R. Lattrell and
K. H. Scheunemann, Angew. Chem., Int. Ed. Engl., 1985, 24,
180–202; A. Cometta and M. P. Glauser, Schweiz. Med.
Wochenschr., 1988, 118, 1817–1822; R. Bud, Penicillin:
Triumph and Tragedy, Oxford University Press, Oxford,
2009; E. Torok, E. Moran and F. Cooke, Oxford Handbook of
Infectious Diseases and Microbiology, Oxford University
Press, Oxford, 2009.
Scheme 7 A plausible reaction pathway for the overall conversion of
secondary benzyl amines and acid chlorides into b-lactams.
3 “List of b-lactam antibiotics”, retrieved from https://
en.wikipedia.org/wiki/b-lactam_antibiotic.
4 P. G. Sammes, Chem. Rev., 1976, 76, 113–155; R. B. Morin and
M. Gorman, Chemistry and Biology of b-Lactam Antibiotics,
chloride 34 generating the imine 35 and ketene 36 respectively.
In the following step, the imine nitrogen attacks the ketene
giving a zwitterionic intermediate, 37. The subsequent intra-
molecular ring closure of the zwitterionic intermediate delivers
b-lactam 38. The cis or trans conguration of the nal b-lactam
is always the result of a complex dynamic balance between two
competitive reactions involving the conrotatory ring closure on
one hand and the imine isomerization (39) of the zwitterionic
intermediate 37 on the other.
In general, electron-donating (EDG) ketene substituents
accelerate direct ring closure, promoting the formation of cis-b-
lactam 38. On the contrary, weak electron-donating and
electron-withdrawing (EWG) ketene substituents slow down
direct ring closure, strongly favouring trans-b-lactam isomer.
¨
Academic Press, New York, 1982, vol. 1–3; W. Durkheimer,
J. Blumbach, R. Lattrell and K. H. Scheunemann, Angew.
¨
Chem., 1985, 97, 183–205; W. Durkheimer, J. Blumbach,
R. Lattrell and K. H. Scheunemann, Angew. Chem., Int. Ed.
Engl., 1985, 24, 180–202; Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products, ed. R.
Southgate, C. Branch, S. Coulton, E. Hunt and G. Lukacs,
Springer-Verlag, Berlin, 1993, vol. 2, p. 621; R. Southgate,
M. Jayaraman, A. R. A. S. Deshmukh and B. M. Bhawal,
Contemp. Org. Synth., 1994, 1, 417–432; E. L. Setti, D. Davis,
T. Chung and J. McCarter, Bioorg. Med. Chem. Lett., 2003,
13, 2051–2053; B. K. Banik, b-Lactams: Unique Structures of
Distinction for Novel Molecules, Springer, 2013.
Conclusions
5 D. M. Shlaes, Antibiotics: The Perfect Storm, Springer,
Dordrecht: Heidelberg, London, NY, USA, 2010;
J. N. Pendleton, S. P. Gorman and B. F. Gilmore, Expert
Rev. Anti-Infect. Ther., 2013, 11, 297–308; W. Qin,
M. Panunzio and S. Biondi, Antibiotics, 2014, 3, 193–215.
6 This has led to an alarming situation where some bacterial
infections are difficult, if not impossible, to cure. Over
time this problem looks set to get worse. D. I. Andersson
and D. Hughes, Nat. Rev. Microbiol., 2010, 8, 260–271;
D. Jabes, Curr. Opin. Microbiol., 2011, 14, 564–569;
T. R. Frieden, Antibiotic resistance threats in the United
States, Cdc, 2013, pp. 22–50; T. R. Frieden, N. Engl. J. Med.,
2015, 373, 1748–1754.
A facile synthetic approach to substituted b-lactams was
designed, starting from secondary benzyl amines and acid
chlorides. Instead of classical imines, which are labile mole-
cules, secondary amines are used expanding the molecular
diversity of the traditional Staudinger methodology. Generally,
the reactions proceeded smoothly and all synthesised products
were isolated in good to high yields. This modication of the
traditional Staudinger synthesis, where both imine and ketene
are formed in situ from cheap starting materials and no addi-
tives apart from a base are used, reduces both the costs and the
purication steps of the procedure to a minimum.
7 M. G. P. Page, Drug Resist. Updates, 2000, 3, 109–125;
S. Driussi, Antibiotic Resistant Bacteria, Hayle Medical, 2015.
8 S. M. Drawz and R. A. Bonomo, Clin. Microbiol. Rev., 2010, 23,
160–201; D. M. Shlaes, Ann. N. Y. Acad. Sci., 2013, 1277, 105–
114; R. R. Watkins, K. M. Papp-Wallace, S. M. Drawz and
R. A. Bonomo, Front. Microbiol., 2013, 4, 1–8; S. M. Drawz,
Acknowledgements
`
Financial support from the Universita degli Studi di Cagliari
(PRID 2015) and the Regione Autonoma della Sardegna (Project
`
L.R. 7/2007, annualita 2012, CUP F71J120001090002) is grate-
fully acknowledged. We are also grateful to Fondazione Banco
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K. M. Papp-Wallace and R. A. Bonomo, Antimicrob. Agents 13 We took inspiration from nature, where aldehydes and
Chemother., 2014, 58, 1835–1846; I. Olsen, Eur. J. Clin.
Microbiol. Infect. Dis., 2015, 34, 1303–1308.
ketones are generated in situ (via imines) by oxidation of
corresponding amino groups.
9 G. S. Singh, Tetrahedron, 2003, 59, 7631–7649; Heterocyclic 14 D. Donati, C. Morelli, A. Porcheddu and M. Taddei, J. Org.
Scaffolds I: b-Lactams, ed. B. K.Banik, Springer, Heidelberg, Chem., 2004, 69, 9316–9318.
2009, vol. 1; G. S. Singh and S. Sudheesh, ARKIVOC, 2014, 15 L. De Luca and G. Giacomelli, Synlett, 2004, 2180–2184; L. De
337–385.
Luca, G. Giacomelli and G. Nieddu, Synlett, 2005, 223–226;
R. Cadoni, A. Porcheddu, G. Giacomelli and L. De Luca,
Org. Lett., 2012, 14, 5014–5017; A. Porcheddu and L. De
Luca, Adv. Synth. Catal., 2012, 354, 2949–2953; S. Gaspa,
A. Porcheddu and L. De Luca, Org. Biomol. Chem., 2013, 11,
3803–3807.
10 H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51–123;
W.-B. Wang and E. J. Roskamp, J. Am. Chem. Soc., 1993,
115, 9417–9420; G. Martelli, G. Spunta and M. Pannunzio,
Tetrahedron Lett., 1998, 39, 6257–6260; M. Pannunzio,
S. Bacchi, E. Campana, L. Fiume and P. Vicennati,
Tetrahedron Lett., 1999, 40, 8495–8498; C. M. L. Delpiccolo, 16 In order to avoid possible decomposition of N-chloramine 2,
M. A. Fraga and E. G. Mata, J. Comb. Chem., 2003, 5, 208–
210; A. Weatherwax, C. J. Abraham and T. Lectka, Org.
Lett., 2005, 7, 3461–3463; F. L. Lin, H. M. Hoyt, H. Van
Halbeek, R. G. Bergman and C. R. Bertozzi, J. Am. Chem.
it was recovered by removing the extraction solvent at room
temperature and reduced pressure; M. R. Monaco, P. Renzi,
D. M. Scarpino Schietroma and M. Bella, Org. Lett., 2011, 13,
4546–4549 and references cited therein.
Soc., 2005, 127, 2686–2695; Y. Wang, Y. Liang, L. Jiao, 17 The previously optimised protocol for preparing imine 3 is
D. M. Du and J. Xu, J. Org. Chem., 2006, 71, 6983–6990;
L. Jiao, Y. Liang and J. Xu, J. Am. Chem. Soc., 2006, 128,
6060–6069; B. Li, Y. Wang, D.-M. Du and J. Xu, J. Org.
Chem., 2007, 72, 990–997; Y. Liang, L. Jiao, S. Zhang,
Z.-X. Yu and J. Xu, J. Am. Chem. Soc., 2009, 131, 1542–1549.
11 C. Palomo and J. M. Aizpurua, Chem. Heterocycl. Compd.,
not suitable for a one-pot procedure. Unfortunately, the
formation of N-chloramine with NCS in polar protic
solvents is accompanied by the formation of several by-
products that signicantly lower the yields and
considerably complicate the nal purication of N-
chloramines.
1999, 34, 1222–1236; C. Palomo, J. M. Aizpurua, I. Ganboa 18 Strict anhydrous conditions are generally required to
and M. Oiarbide, Eur. J. Org. Chem., 1999, 3223–3235; prevent the hydrolysis of acid chlorides, ketenes and imines.
A. Arrieta, F. P. Cossio and B. Lecea, J. Org. Chem., 2000, 19 As expected, the 1H-NMR spectrum of the crude reaction
65, 8458–8464; A. E. Taggi, A. M. Hafez, H. Wack,
B. Young, D. Ferraris and T. Lectka, J. Am. Chem. Soc.,
product showed the presence of a mixture of cis and trans
isomers in a 92 : 8 ratio. These data t those described in
literature for the classic Staudinger reaction, where a cis
selectivity is typically observed using acid chlorides
activated with heteroatoms at the alpha position.
¨
2002, 124, 6626–6635; M. Kohn and R. Breinbauer, Angew.
Chem., Int. Ed., 2004, 43, 3106–3116; S. Eguchi, ARKIVOC,
2005, 98–119; F. L. Lin, H. M. Hoyt, H. Van Halbeek,
R. G. Bergman and C. R. Bertozzi, J. Am. Chem. Soc., 2005, 20 These results were not entirely unexpected, as the
127, 2686–2695; L. Jiao, Y. Liang and J. Xu, J. Am. Chem.
Soc., 2006, 128, 6060–6069; N. Fu and T. T. Tidwell,
preparation of N-chloroanilines is extremely complex and
N-chloroanilines are highly unstable compounds.
´
Tetrahedron, 2008, 64, 10465–10496; F. P. Cossıo, A. Arrieta 21 To our knowledge, there are relatively few literature
and M. A. Sierra, Acc. Chem. Res., 2008, 41, 925–936;
precedents concerning the use of non-activated aliphatic
acid chlorides in the synthesis of b-lactamsM. Browne,
D. A. Burnett, M. A. Caplen, L.-Y. Chen, J. W. Clader,
M. Domalski, S. Dugar, P. Pushpavanam, R. Sher,
W. Vaccaro, M. Viziano and H. Zhao, Tetrahedron Lett.,
1995, 36, 2555–2558; C. M. L. Delpiccolo and E. G. Mata,
Tetrahedron Lett., 2004, 45, 4085–4088.
´
´
´
J. Bures, M. Martın, F. Urpı and J. Vilarrasa, J. Org. Chem.,
2009, 74, 2203–2206; Name reactions for carbocyclic ring
formations, ed. J. J.Li, Wiley, Hoboken, N. J., 2010, p. 47;
M. Zarei and A. Jarrahpour, Synlett, 2011, 2572–2576;
Z. Yang and J. Xu, Tetrahedron Lett., 2012, 53, 786–789;
I. Kim, S. W. Roh, D. G. Lee and C. Lee, Org. Lett., 2014,
16, 2482–2485; C. R. Pitts and T. Lectka, Chem. Rev., 2014, 22 Several unsuccessful attempts were conducted using NEt3,
114, 7930–7953; Z. Yang, N. Chen and J. Xu, J. Org. Chem.,
2015, 80, 2–11.
tBuOK, DBA–DBU, pyridine and KO2 as base.
23 SciFinder database.
12 A. T. Williamson, J. Am. Chem. Soc., 1934, 56, 2216–2218; 24 G. I. Georg, Organic Chemistry of b-Lactams, Wiley VCH, New
G. Friedrichs and H. G. Wagner, Z. Phys. Chem., 2001, 215,
1601–1623; T. T. Tidwell, Eur. J. Org. Chem., 2006, 563–576;
A. D. Allen and T. T. Tidwell, Eur. J. Org. Chem., 2012,
1081–1096; W. Qin, S. Long, M. Panunzio and S. Biondi,
Molecules, 2013, 18, 12264–12289.
York, 1992; F. P. Cossio, A. Arrieta and M. A. Sierra, Acc.
Chem. Res., 2008, 41, 925–936; Y. Liang, L. Jiao, S. Zhang,
Z.-X. Yu and J. Xu, J. Am. Chem. Soc., 2009, 131, 1542–1549;
H. Qi, X. Lia and J. Xu, Org. Biomol. Chem., 2011, 9, 2702–
2714; J. Xu, ARKIVOC, 2009, 21–44; S.-L. Hou, X.-Y. Li and
J. X. Xu, Sci. China: Chem., 2013, 56, 370–379; X. Z. Yang,
N. Chen and J. Xu, J. Org. Chem., 2015, 80, 3611–3620.
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