Microwave-induced bismuth nitrate-catalyzed Michael reaction of 3-amino β-lactams with enones

Article abstract of DOI:10.14233/ajchem.2020.22168

Microwave-induced bismuth nitrate-catalyzed reaction of 3-amino β-lactams with unsaturated ketones is performed in order to obtain substituted amino β-lactams. Amino β-lactams were obtained through the strategy of [2+2] ketene-imine cycloaddition followed

Full text of DOI:10.14233/ajchem.2020.22168

Asian Journal of Chemistry; Vol. 32, No. 2 (2020), 233-236
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22168
Microwave-Induced Bismuth Nitrate-Catalyzed Michael
Reaction of 3-Amino β-Lactams with Enones
1,2
2
3,*
RAM NARESH YADAV , ASHOK KUMAR SRIVASTAVA and BIMAL KRISHNA BANIK
1Department of Chemistry, The University of Texas-Pan American, 1201 West University Drive, Edinburg 78539, U.S.A.
2Department of Chemistry, Faculty of Engineering & Technology, Veer Bahadur Singh Purvanchal University, Jaunpur-222003, India
3Department of Mathematics and Natural Sciences, College of Sciences and Human Studies, Deanship of Research, Prince Mohammad Bin
Fahd University, Alkhobar, Kingdom of Saudi Arabia
*Corresponding author: E-mail: bimalbanik10@gmail.com; bbanik@pmu.edu.sa
Received: 23 April 2019;
Accepted: 13 July 2019;
Published online: 30 December 2019;
AJC-19704
Microwave-induced bismuth nitrate-catalyzed reaction of 3-amino β-lactams with unsaturated ketones is performed in order to obtain
substituted amino β-lactams. Amino β-lactams were obtained through the strategy of [2+2] ketene-imine cycloaddition followed by
deprotection of phthalimido β-lactams with ethylene diamine.
Keywords: Microwave, Amino β-lactam, Bismuth nitrate, Catalysis, Michael reaction.
microwave irradiation (Scheme-I). Despite progress in β-lactam
research [10], no paper is published which describe functionali-
zation of 3-amino group present in β-lactam ring through a
catalytic Michael reaction [11,12]. In continuation of our efforts
to explore the catalytic properties of bismuth nitrate in the
synthesis of numerous organic molecules of biological interests,
we report here a simple and environmentally benign procedure
to obtain mono and bis-aza-substituted β-lactams under
microwave condition in excellent yield. In previous study, aza
Michael reaction of diverse aliphatic and aromatic amines to
unsaturated enones via bismuth nitrate-catalyzed reactions is
reported [13].
INTRODUCTION
Aza-Michael addition reaction is an important tool for the
formation of C-N bond between nitrogen atom of donor and
carbon atom of the acceptor molecules. This is a conjugate addi-
tion of nitrogen nucleophile to an α,β-unsaturated carbonyl
compound. This is an important reaction to accesses diverse
medicinally privileged molecules like antibiotics, anticancer and
biomimetic molecules of oligomer of β-amino acids and peptides
[1,2]. α-Amino β-lactams systems with cis-configuration are
present in numerous monocyclic and bicyclic antibiotics [3].
Similar structures with antibacterial trans-configuration are also
known [4]. trans α-Amino β-lactam is active against cancer cell
lines in vitro [5,6], whereas cis β-lactams with anticancer activities
are also reported in the literature [7]. β-Lactams are served as
the key molecules for the synthesis of numerous other compounds
including natural products, alkaloids, amino sugars and amino
acids [8,9]. Reactions at 3-amino center of β-lactam ring is nece-
ssary to functionalize them. In this paper, a simple microwave-
induced bismuth nitrate-catalyzed Michael reaction of 3-amino
β-lactams with α,β-unsaturated ketone is described.
NH2
H
EWG
EWG
GWE
N
N
MWI
EWG
Bi(NO3).5H2O
R2 +
O
R2
+
O
R2
N
O
N
N
R1
R1
R1
bis-adduct
Michael
acceptor
Michael
donor
mono-adduct
Scheme-I: Bismuth nitrate catalyzed aza-Michael mono and bi-addition
under microwave condition
3-Amino β-lactams as donor react with electron deficient
carbonyl compounds known as Michael acceptors lead to the
formation of corresponding mono aza and bis-aza-adducts under
We extended the scope of this reaction using amino β-
llactam. Our methodology of bismuth nitrate catalyzed aza-
Michael reaction of enone was very simple and highly efficient.
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234 Yadav et al.
Asian J. Chem.
This method had solved the difficulties of using of stoichio-
metric amount of Lewis acid catalysts. Most of the Lewis acid
catalysts are moisture sensitive and corrosive in nature and not
benign to environment [14]. The use of strong acids for this
reaction also increased the chances of polymerization of acid-
sensitive vinyl ketone, nitrile and ester.
microwave reactor for 2-5 min at elevated temperature. The
rac-3-amino β-lactams (2a-d) was obtained in good to excellent
yield.
α-Phthalimido β-lactams (1a-d) were obtained by
Staudinger [2+2] ketene-imine cycloaddition reaction. The
ketene derived from either N-phthalimido acetyl chloride or
N-phthalimido acetic acid/triethylamine or Mukiyama reagent
as an acid activator. The stereochemical outcome of β-lactam
formation was greatly depending on the mode of addition of
base to acid chloride or acid chloride to base. In addition, de-
protection of α-phthalimido-β-lactams to α-amino β-lactams
was also investigated [18].
Numerous substituted β-lactams (α-acetoxy, α-hydroxy,
α-amido, α-unsubstituted, α-tosylate, α-sulfonamide, α-alkoxy,
α-ether, α-benzyl ether, α-halo, α-carboxylate, α-amino, α-
tosylate, α-mesylate) were prepared and tested against a variety
of cancer cell lines. A few of them were also evaluated in vitro
at the US National Cancer Institute against a panel of 60 cancer
cell lines in 2001-2002 Diverse pyrrole-substituted β-lactams
were prepared through 3-amino β-lactams [19].
Aza-Michael addition of 3-amino-β-lactams with enones
was performed. In this context, racemic trans-3-amino-α-lactam
(2) was reacted with methyl vinyl ketone (3) (Scheme-III) in
the presence of catalytic amounts of Bi(NO3)3·5H2O in THF
as the solvent under microwave condition. The reaction mixture
was allowed to irradiate for 2-6 min at ambient temperature in
an automated microwave reactor. The reactions proceed
smoothly and the products (4a-d) were obtained along with
substantial amount of bis-aza-adduct (5a-d) in good yield
(Table-1).
EXPERIMENTAL
General procedure for the synthesis of Michael
products: To amino β-lactam (1 mmol) was added ketone (2
mmol) in THF (0.2 mL) and bismuth nitrate pentahydrate (2.10
g, 10 mol%). The mixture was irradiated in an automated
microwave oven at 50 ºC for a short period of time (Table-1).
After the reaction, dichloromethane was added to the reaction
mixture, it was washed with Na2CO3 solution (10 %, 2 mL),
brine (2 mL), dried with sodium sulfate and the solvent was
evaporated. The crude product was purified over silica gel using
ethyl acetate and n-hexane (30: 70) as the solvents.
TABLE-1
AZA-MICHAEL REACTION OF rac-α-3-AMINO
β-LACTAMS (2a-d) WITH METHYL VINYL KETONE (3)
Amine (2)
R1
Yielda
4:5 (%)
Timeb
(min)
Entry
T (°C)
R
1
2
3
4
Ph
PMP
Ph
50:50
60:40
80:20
90:10
50
50
50
50
2
4
6
6
Ph (2a)
Ph (2b)
Cinnamyl (2c)
Cinnamyl (2d)
PMP
aYield of pure isolated mono-and bis-adducts 4 and 5; bHeating time
PMP = para-methoxy phenyl
RESULTS AND DISCUSSION
O
O
H
The starting compound for Michael reaction was rac-3-
amino β-lactams (1a-d). Synthesis of α-amino β-lactams (2a-
d) was achieved by a de-protection of an α-phthalimido group
in β-lactam (1a-d) by ethylene diamine and other reagents in
excellent yield under microwave irradiation [15-17] (Scheme-
II).
NH2
N
N
N
O
3
O
R2
O
R1
R1
O
O
+
N
R
2
N
R
4
Bi(NO3).5H2O
MWI
R
5
Scheme-III: Aza-Michael rection under microwave condition
H
H
N
H H
N
Z
R2
R1
H2N
R2
Regardless of reaction time, catalyst loading and molar
MWI
ratio of acceptor, mono-aza adduct 4 was not formed selec-
tively. The crude products formed were purified by column
chromatography (Table-1).
The method was then extended to optically active 3-amino
β-lactams 8. Enantiopure α-3-amino β-lactams 8 were obtained
by reported method [20]. The chiral induction was achieved
by the imine component 7 by a reaction with N-phthalimido
acetic acid 6 in presence of Mukiyama reagent as an acid acti-
vator under basic conditions (Scheme-IV).
NH2.CH2CH2.NH2
solventless
2a
O
O
R1
rac (+/-) - trans
rac (+/-) - trans
R1 = Ph R2 = Ph (90%)
2b R1 = PMP R2 = Ph (85%)
2c R1 = Ph R2 = cinnamyl (85%)
1a
R1 = Ph R2 = Ph
1b R1 = PMP R2 = Ph
1c R1 = Ph R2 = cinnamyl
2d
R1 = PMP R2 = cinnamyl (75%)
1d
R1 = PMP R2 = cinnamyl
O
z =
N
H
O
O
Et3N(2.5 equv.)
Mukaiyama reagent
(3.0 equv.)
H H
Z
Scheme-II: Mild and efficient ethylenediiamine mediated deprotection of
N-phthalimido group. A facile synthesis of ( ) rac-trans-3-
amino β-lactam
(S)
O
(R)
(R)
O
H
N
O
(S)
Z
+
N
R
O
COOH
CH2Cl2
0 0C-rt
R
80-90%
This de-protection reaction was performed in solvent or
without solvents. The reaction protocols were involved in treat-
ment of N-phthalimido-β-lactam (1a-d) with 1.0 M solution
of ethylene diamine in THF under the exposure of automated
7
6
8
Z= N-phthalimido (NtPh) R = Ph, PMP, 4-Me.C6H4-,4-X.C6H4- etc.
Scheme-IV: Asymetric staudinger [2+2] ketene-imine cyloaddition reaction

Vol. 32, No. 2 (2020)
Microwave-Induced Bismuth Nitrate-Catalyzed Michael Reaction of 3-Amino β-Lactams with Enones 235
TABLE-2
AZA-MICHAEL ADDITION REACTION OF ENANTIOPURE 3-AMINO-β-LACTAM (9a-e) WITH METHYL VINYL KETONE (3)
3-Amino
(cis)-β-lactam
Heating time
(min)
Yielda 8:9 (%)
Entry
Temp. (°C)
Catalyst (mmol)
Solvent
1
2
3
4
5
9a R = Ph
9b R = PMP
25
25
25
35
35
1.0
1.0
1.5
1.5
1.5
3
4
5
6
7
Tetrahydrofuran
Tetrahydrofuran
Dichloroethane
Dichloroethane
Dichloroethane
80:20
90:10
85:15
80:20
80:20
9c R = 4-Me.C6H4
9d R = 4-Cl.C6H4
9e R = 4-F.C6H4
aIsolated yield of 10 and 11.
The excellent stereochemical selectivity was observed and
the reaction yield compound 8 (3R,4R) as the major products
in all instances. The N-phthalimido group in compound 8 was
then de-protected by using reported protocol [20] to get free
chiral 3-amino β-lactams (9a-e) in excellent yields (Scheme-V).
β-lactams, next focus was to explore the scope of present
methodology with other Michael accepter (Scheme-VII, Table-
3). The electro-withdrawing group in aromatic ring took longer
time to complete the reaction. Tetrahydrofuran and dichloro-
ethane were the good choice of solvent system for this reaction.
The catalyst used 1.0-1.5 mmol and the reaction mixture
irradiated for 2-10 min in automated microwave reactor.
H
H
O
O
H
H
H
H
H2N
(R)
Z
(R)
(s)
(s)
MWI
(R)
NH2
H
(R)
O
EWG
O
EWG
EWG
R1
H
N
(R)
(R)
N
N
N
O
NH2.CH2CH2.NH2
solventless
R
O
(s)
O
14/15
R
(R)
O
(R)
N
R
O
O
+ O
R1
(R)
(R)
8(a-e)
N
R
Bi(NO3).5H2O
9(a-e)
N
R
MWI
THF
rt
Z = N-phthalimido(-NtPh)
9(a-e)
16(a-e)
17(a-e)
12(a-e)
13 (a-e)
H
Yielda
(%)
O
T
(0C)
Time
(min)
N-phthalimido
β-lactam(8)
(R)
(s)
O
R=
Scheme-VII: Aza-Michael reaction of nitrile and ester under microwave
8a R = Ph
80
90
90
75
75
25
25
25
40
40
5
6
6
8
8
condition
8b
R = 4-OMe.C6H4
8c R = 4-Me.C6H4
8d R = 4-Cl.C6H4
TABLE-3
8e
R = 4-F.C6H4
DIFFERENT MICHAEL ACCEPTER WITH β-LACTAM AMINE
Yielda (%)
(12/13:16/17)
a: isolated yield of 9(a-e)
Entry
Acceptor (14/15)
β-Lactam amine
Scheme-V: Deprotection of N-phthalimido group under microwave
1
14
9a
12a + 16a (85:15)
CN (
)
irradiation
2
3
4
5
14
14
14
14
9b
9c
9d
9e
12b + 16b (90:10)
12c + 16c (85:15)
12d + 16d (75:25)
12e + 16e (80:20)
3-Amino-β-lactams (9a-e) were subjected to react with
methyl vinyl ketone (3) under microwave condition with
catalytic amount of bismuth nitrate in moist THF for 3-5 min.
All the reaction are smooth with excellent yields (Scheme-
VI, Table-2).Aza-Michael addition reaction with chiral β-lactam
amines (9a-e) produced better selective to mono aza-adduct
10a-e over the bis-adduct 11a-e. The better selectivity was
obtained with β-lactam that has p-methoxyphenyl group at
N-1 position (entry 2, Table-2). It seemed electron withdrawing
groups at nitrogen lowers the selectivity of product formation
(entry 4 and 5, Table-2).
6
9a
13a + 17a (85:15)
15
CO2Me (
)
7
8
9
10
15
15
15
15
9b
9c
9d
9e
13b + 17b (90:10)
13c + 17c (85:15)
13d + 17d (75:25)
13e + 17e (80:20)
aIsolaled yield
Other bismuth salts were not effective in pursuing Michael
reaction of 3-amino β-lactams. For example, bismuth chloride,
bismuth iodide and bismuth chloride was partially successful
(about 20 % yield of the products). Because of the sensitivity
of β-lactam ring, the use of stronger acids in catalytic amounts
or higher amounts caused considerable difficulties in perfor-
ming Michael reaction as described herein. Indeed, HCl, SnCl4,
BF3·Et2O,AlCl3, Et2AlCl2 were not as effective as bismuth nitrate
pentahydrate. It is important to mention that the reactions
tolerated moisture and did not require inert atmosphere. The
coordination of vacant d-orbital of bismuth with lone pair of
oxygen of ketone and ester facilitated a nucleophilic attack by
amino group of β-lactam ring.
O
O
O
H
NH2
N
N
3
MWI
H
H
(R)
(R)
O
H
O
(R)
O
O
(s)
O
O
(s)
O
+
O
(s)
O
(R)
N
R
(R)
N
R
Bi(NO3).5H2O
(R)
N
R
THF
rt
10(a-e)
9(a-e)
11(a-e)
Scheme-VI: Bismuth nitrate catalysedAza-Michael reaction of methy vinyl
ketone with β-lactam amine under microwave condition
After the realization of successful aza-Michael reaction
of methyl vinyl ketone with various racemic and enantiopure

236 Yadav et al.
Asian J. Chem.
8. I. Ojima, Acc. Chem. Res., 28, 383 (1995);
The reaction required approximately 10 mol % of bismuth
https://doi.org/10.1021/ar00057a004.
nitrate. It was not necessary to use much solvent in this reaction.
For 1 mmol of β-lactam, 0.2 mL of solvent was proved to be
fine. Present protocol is very efficient high yielding reaction
with diverse Michael acceptors.
9. I. Ojima, E.S. Zuniga and J.D. Seitz, ed.: B.K. Banik, Advances in the
Use of Enantiopure β-Lactams for the Synthesis of Biologically Active
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10. B.K. Banik, Heterocycl. Lett., 4, 441 (2014).
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12. D. Almasi, D.A. Alonso, E. Gómez-Bengoa, Y. Nagel and C. Nájera,
Eur. J. Org. Chem., 2328 (2007);
ACKNOWLEDGEMENTS
One of the authors, BKB gratefully acknowledges the
funding support from NIH, NCI and Kleberg Foundation of
USA.
https://doi.org/10.1002/ejoc.200700031.
13. N. Srivastava and B.K. Banik, J. Org. Chem., 68, 2109 (2003);
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14. J.H. Clark, Green Chem., 1, 1 (1999);
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
https://doi.org/10.1039/a807961g.
15. A. Loupy, Microwaves in Organic Synthesis, Wiley-VCHVerlag GmbH
& Co. KGaA, edn 2 (2008).
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Induced Synthesis of Heterocycles of Medicinal Interests, In: Green
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