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142 Chemistry and Biology of Beta-Lactams
Ph
AcO
1
=p-anisyl,
2
https://t.me/med1917
O
AcO
OAc
OAc
O
O
O
O
O
HH
N
HH
N
Ph
Bi(NO
Ac
ii)
i)
3)3
O,
2
.5H
Pyridine
or
2
H
O
THF,
O,
2
2
H
O
THF,
HCI,
R
Ph
i)
HCI,
THF,
H
O
2
R
or
THF,
H
O
2
.5H
3)3
2
O,
O,
2
Pyridine
Bi(NO
Ac
R
ii)
R
R
HH
R
O
2
O
R
=p-anisyl,
1
R
=p-anisyl,
1
HH
O
2
O
=p-anisyl,
1
N
R
1
=H
R
2
R
=Ac
2
Ph
N
R
1
=H
R
2
R
=Ac
SCHEME 4.14 Preparation of Chiral Hydroxy β-Lactams.
However, a reaction of β-lactam alcohol and glycal with these reagents failed to produce iodinated
compounds.
To understand the precise function of molecular iodine in this process, a few other catalysts were
examined. Nitrate of potassium, iron, copper, and zinc on reaction with the beta-lactam alcohol and
diverse glycal failed to yield the products. Sulfuric acid, hydrochloric acid, boron triuoride, and stannic chloride produced products in low yields. The neutral catalysts iodonium dicollidinium perchlorate,
N-iodosuccinimide, and N-bromosuccinimide were tested in this reaction. In some instances, the products were found to be O-glycosides with halogens in them.
The formation of the alpha-isomer as the exclusive product from this reaction was unprecedented. To
understand the mechanism of the process, a few more reactions were conducted. For instance, the reaction was conducted with catalytic amounts of hydroiodic acid. The desired product was obtained in poor
yields. Surprisingly, an aqueous solution of iodine failed to produce any glycosides. This suggested that
a complex was formed upon the reaction between iodine and the alkene of the glycal. The proton NMR
was taken by reacting glycal and iodine (10 mol%) in CDCl3. The olenic part of the glycal was changed.
However, no alteration of the proton NMR data was seen when glycal was reacted with iodine and potassium carbonate. These data were explained due to an allylic isomerization of glycal to a dehydro sugar,
and this was followed by a nucleophilic reaction.
These experiments were explained by an axial attack of the alcohol group to the anomeric carbon center of the allylic carbonium ion. A similar attack from the equatorial side may give the beta-glycosidic
143Polyaromatic Beta-Lactams
O
Ph
HO
R=p-anisyl, phenyl, and benzyl
O
HH
Ph
HO
HH
HH
HH
HH
O
Ac
Ph
Ac
R=p-anisyl, phenyl and benzyl
https://t.me/med1917
O
HH
Ph
O
THF
I
,
+
OAc
2
OAc
HH
O
N
R
HH
O
O
OAc
N
O
O
Ph
HCO
R
2NH4
EtOH
CH
CH
Pd-C
,
or
OH
2
OH
2
OAc
H
O
O
O
O
OAc
SCHEME 4.15 Glycosylation and Hydrogenation of Glycosylated β-Lactams.
HH
O
N
CH
O
3
Ph
AcO
+
N
O
R
CH
OAc
O
3
AcO
THF
I
,
2
OAc
Ph
N
+
R
O
Ph
H
N
Ph
R
+
R
CH
O
3
AcO
+
O
O
O
O
HH
H
N
O
O
N
R
Ph
R
N
R
SCHEME 4.16 Glycosylation of cis-Hydroxy β-Lactams.
O
CH
O
CH
O
3
O
O
3
HH
O
O
Ph
H
THF,
HCI,
N
R
Bi(NO
THF,
or
.5H
3)3
H
O
2
Ph
THF,
HCI,
N
Bi(NO
R
THF,
HO
O
2
O
2
O
HO
H
O
2
or
.5H
O
2
3)3
H
O
2
O
Ph
N
R
HH
N
Ac
CH
Ph
R
TEA
O,
2
2Cl2
Ac
CH
AcO
Ph
N
O
AcO
TEA
O,
2
2Cl2
O
R
HH
N
R
SCHEME 4.17 Synthesis of the Taxol and Taxotere Side Chains Through Deglycosylation.
isomer. However, the equatorial route was not favored. The nonbonding electronic repulsive forces
between the oxygen of the sugar ring and the lone pair of the electrons in the oxygen of the beta-glycoside
were high. This route was conclusive as no peaks for the beta-glycosides were observed by NMR. The
initially formed carbonium reacted with hydroxy compound from the axial site only. Therefore, only
alpha-glycosides were formed.
144 Chemistry and Biology of Beta-Lactams
OBn
No reaction
HO
2
Ph
CH
HO
R=p-anisyl, phenyl and benzyl
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3
HH
Ph
Cl
SO
2
N
HO
O
O
R
HH
N
HH
N
O
SCHEME 4.18 Preparation of Optically Active trans-β-Lactam.
TEA, NaOAc, DMSO
Ph
+
R
Ph
+
R
OBn
BnO
AcO
O
OAc
O
OAc
AcO
HH
N
O
I
THF
,
2
THF
I
,
2
No reaction
R
SCHEME 4.19 Attempted Fer rier Rearrangement with Diverse Sugars.
4.6.2 Asymmetric Synthesis by Reaction of Imines and
Optically Active Acid Chlorides
The Ferrier rearrangement with carbohydrates was conducted with preformed monocyclic β-lactams
that have a single aromatic group or an aliphatic group at the N1 of the ring. But an identical reaction
of hydroxy β-lactams that have a polyaromatic group (chrysene and pyrene) at the N1 of the ring with
substituted glycals failed. The cause of the failure is not identied. The bulky polyaromatic group is
located far away than the hydroxyl group. So, a steric hindrance by the polyaromatic group on the possible cause of failure is not justied. Considering the above mechanism of glycosylation, it appears that
the nucleophilic attack of the hydroxy functionality to the alkene group of the sugar is crucial. Therefore,
it seems reasonable to consider that this failure is due to the weak nucleophilic character of the hydroxyl
group in these substrates with multicyclic aromatic rings. The electron-withdrawing power of many aromatic groups in the molecules has made the hydroxy a weak nucleophilic. To prepare chiral anticancer
β-lactams with polyaromatic substrates, alternative methods were developed.
A facile preparation of several β-lactams was achieved by indium-induced reactions. Reaction of ethyl
bromoacetate with diaryl imines (derived from monocyclic aromatic compounds) in the presence of
Bn=CH
Ph
145Polyaromatic Beta-Lactams
OH
Ph
Ar=PMP
https://t.me/med1917
AcO
O
AcO
H H
OAc
Ph
O
+
N
Ar
o
0
C-RT
Bi(OTf)
5-10
AcO
Ph
N
Ar
OAc
O
THF,
20hr,
O
HH
O
70%
mol%
AcO
+
AcO
AcO
3
OAc
O
O
HH
N
O
Ar
SCHEME 4.20 Glycosylation of the Hydroxyethyl Side Chain in β-Lactam.
indium powder afforded 3-unsubstituted β-lactams. This is a Reformatsky reaction. A few substituted
bromoacetates gave 3,4-disubstituted β-lactams with various proportions of the cis- and the trans-isomers. In some examples, β-amino esters were isolated as intermediates. The formation of the β-amino
esters depended on the nature of the amino component in the imines. It became predominant with imines
derived from primary aromatic amines. Imines obtained from benzyl amines and primary aliphatic
amines produced β-lactams instead of the intermediate β-amino esters. These reactions did not proceed
with polyaromatic imines. Instead, secondary amines were the products due to the reduction of the C=N
bond. Indium metal was able to reduce the C=N bond by electron transfer mechanism. A single electron
transfer by the indium metal to the C=N bond produced an ion radical which on further electron transfer generated dianion species of the imines. These dianions on protonation gave the secondary amino
compounds.
Chiral β-lactams with polyaromatic systems were prepared by cycloaddition of imines with acid chlo-
ride in the presence of tertiary base. As an example, indium-induced reaction was used. Indium-induced
reaction of acetobromoglucose with benzyl glycolate afforded an ester. On hydrogenolysis, the benzyl
group was cleaved to afford the β-glycoside in good yield (Scheme 4.22). Cycloaddition of the acid with
imine was performed in the presence of N-methyl-2-chloro pyridinium iodide and triethylamine. NMR
analyses of the crude reaction mixture indicated the presence of two diastereomeric trans-β-lactams in
55:45 ratios. These were separated using column chromatography over silica gel. The diastereomeric
O-glycosidic bond was cleaved with mild aqueous acid to the hydroxy compounds. These were then
converted to acetates. The cell growth inhibition data indicated that one of these optically active acetates
146 Chemistry and Biology of Beta-Lactams
R
Chrysenyl
Chrysenyl
R
OAc
O
AcO
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OAc
AcO
AcO
AcO
O
OAc
O
O
O
I
THF
,
2
H H
AcO
O
AcO
HO
O
H H
O
H
N
O
R
OAc
O
H
O
N
Ar
and
AcO
AcO
O
H H
O
O
H
O
N
Ar
SCHEME 4.21 Mechanistic Route for the Glycosylation.
6
R
5
O
R
4
N
R
6
R
5
O
4
R
3
R
2
O
=
R
1
=R
R
=H;
4
1=R2
R
CO
C
N
+
1
Chrysenyl
R
=R4=R5=R
R
;
=H;
2
H
2
3
O
=
R
2
CO
;
H
2
Cl
I
CH
3
NEt
/CH2Cl
2
3
70%
=OAc
6
R
=R
=OAc
5
6
R
R
4
H
H
R
3
5
R
H
O
N
O
Chrysenyl
R
6
O
H
3
HH
O
N
O
HCl/THF/CH
i)
Ac
O/TEA/CH2Cl
ii)
2
HCl/THF/CH
i)
Ac
O/TEA/CH2Cl
ii)
2
2Cl2
2Cl2
H
H
RO
RO
N
O
Ac
R=H,
H
H
N
O
Chrysenyl
Ac
R=H,
2
2
SCHEME 4.22 Cycloaddition with Optically Active Acids Toward Anticancer β-Lactams.
was about three times more potent than the racemic compounds in all cell lines tested. The absolute stereochemistry of the optically active trans-acetoxy-β -lactam was conrmed by a direct comparison with
known trans-β-lactam described earlier with respect to optical rotation and NMR data in the presence
of a chiral shift reagent.
In another method, axially substituted sugar derivative was used for the cycloaddition reaction with
imine derived from polyaromatic systems in the presence of triethylamine.24 This reaction produced a
147Polyaromatic Beta-Lactams
OA
O
OAc
Chrysenyl
O
H
2
O
https://t.me/med1917
OAc
OAc
O
O
N
Chrysenyl
OAc
Ph
O
c
+
O
O
N
Cl
TEA
CH
Chrysenyl
2I2
SCHEME 4.23 Cycloaddition Toward the Preparation of Chiral β-Lactams.
OH
NBS
O
Br
Jones
ethylene glycol
H
=
Ar
1
=
Ar
1
O
H
H
6-chrysenyl,
6-chrysenyl,
O
OH
Br
=
Ar
phenyl
2
=
Ar
p-methoxyphenyl
2
Ar
2
+
N
Ar
1
H
H
H
N
Cl
I
CH
3
NEt
/CH2Cl
3
H
2
Br
H
H
O
N
O
+
Ph
oxidation
Ar
2
Zn/AcOH/MeOH
Ar
1
OAc
O
O
O
Ph
N
OH
O
Br
H
H
H
H
HO
Ar
2
N
Ar
O
1
SCHEME 4.24 Asymmetric Synthesis of Anticancer β-Lactams.
mixture of two optically active trans-isomers in equal proportion (Scheme 4.23). Therefore, the synthesis
of chiral β-lactams with polyaromatic system was possible with two types of glycosides by cycloaddition
method. However, no stereochemical preferences were seen in this cycloaddition. It appeared that the
sugar group in the ketene component had an identical stereochemical preference although axially and
equatorially substituted glycosides were employed in these reactions.
In another method, natural optically active 3-(+)-carene was used. In the rst step, it was converted
to an acid.24 On cycloaddition with imines derived from chrysene, optically pure trans-isomer was
obtained. This reaction was very fascinating because the cycloaddition reaction is found to be highly
diastereoselective producing only trans-azetidin-2-one. It was then reduced to alcohol, and it was then
converted to acetate (Scheme 4.24). Unfortunately, this reaction produced the inactive isomer: the product had a weak anticancer prole.
Ac
O/TEA/CH2Cl
2
2
H
H
AcO
Ar
N
Ar
1
148 Chemistry and Biology of Beta-Lactams
TsO
Ph
AcO
Ph
Ph
a: Ar=p-anisyl
b: Ar=p-bromophenyl
RO
Ph
RO
Ph
a: Ar=p-anisy
b:
O
Ar
Ph
https://t.me/med1917
4.6.3 Asymmetric Synthesis of β-Lactams: Enzymatic Approach
We showed baker’s yeast-mediated reduction of 3-keto β-lactam to produce optically active cis- and
trans-3-hydroxy β-lactams (Scheme 4.25).
25
Microwave-induced reduction using baker’s yeast was also performed, and the desired products were
obtained efciently. The absolute stereochemistry of the products was determined by a direct comparison with our previous compounds with respect to optical rotation and NMR data in the presence of chiral
shift reagent. Baker’s yeast-mediated enantioselective bio-reduction proceeded from the same or opposite face of the keto group, and therefore, enantiospecic face preference occurred.26 The corresponding
keto β-lactam with polyaromatic groups at the N1 of the ring was prepared through an oxidation of the
hydroxy group. However, baker’s yeast reduction of the 3-keto β-lactams that have a chrysenyl group at
N1 did not proceed. On the other hand, a reduction of the keto functionality of this β-lactam by sodium
borohydride afforded the desired product without any problem. On the basis of these observations by
baker’s yeast-mediated reduction, an exploration on the mechanism of this process is necessary.
The optically active cis-hydroxy β-lactams were used to prepare the corresponding trans-isomer
through an inversion reaction (Scheme 4.26). The alcohol was converted to the tosylate. Trans-acetoxy
was obtained by an inversion of conguration. Hydrolysis of trans-acetate afforded the hydroxy
derivative.
We also discovered that B. subtilis can be utilized for the enzymatic hydrolysis of the acetoxy group
in cis-acetoxy β-lactam. The hydrolysis of the acetate group in trans-acetoxy β-lactam and cis-acetoxy β-lactam (kinetic resolution) with different types of lipases was also performed (Scheme 4.27). It
was remarkable to note that such hydrolysis is substrate selective. The 3R, 4S-congured product was
obtained as the hydroxy derivative and the 3S, 4R-congured product as the acetoxy compound.
Ph
O
O
N
Glycerol,
Ar
Baker's
yeast
MW
N
Ar
O
N
Ar
O
SCHEME 4.25 Baker’s Yeast-Induced Reduction of the 3-Keto Group in β-Lactams.
SCHEME 4.26 Inversion of cis-Conguration to trans-Structure in β-Lactams.
l
Ar=p-bromophenyl
HO
Ph
N
Ar
O
TsCl
Py
O
AcO
Ac
Pyr
N
Ar
2
O/
Ph
N
NaOAc
DMSO
Ac
Pyr
AcO
O
O/
2
O
HO
O
N
Ar
N
Ar
NaOH/
MeOH
N
Ar
149Polyaromatic Beta-Lactams
AcO
H
H
1
H
H
2
https://t.me/med1917
R
1
Bacillus subtilis
N
R
O
R1= Phenyl, 4-Methoxypenyl
=Phenyl and p-Anisyl
R
SCHEME 4.27 Enzymatic Hydrolysis of the Acetate Group in β-Lactam.
2
AcO
O
R
1
N
R
2
HO
+
O
R
N
R
2
4.7 In Vitro Cytotoxicity of the Optically Active Acetoxy β-Lactams
These optically active β-lactams with positive and negative optical rotation were tested using seven
human cancer cell lines with cisplatin and racemic isomer as controls. A number of cancer cell lines were
used for this study. For example, BRO (melanoma), MDA-232 (breast), SKOV (ovary), PC-3 (prostate),
Hl-60 (leukemia), K-562 (leukemia), and HT-29 (colon) were employed for this investigation under identical conditions (time of incubation in the same solvent system).27 It was highly interesting to note that the
(+)-isomer of trans 3-ace toxy- 4-phe nyl-N -chry senyl -2-az etidi none is more active than the compound (-)
isomer and the corresponding racemic compound in all cancer cell lines tested. The cell growth inhibition data (IC50) of the (+)-isomer varied from 0.70 to 6 µM; (-)-isomer varied from 6 to 15 µM, and the
racemic isomer varied from 3.64 to 15.70 µM. The clinically active cisplatin under the same condition
inhibited these cancer cells at a concentration of 1.66–12.33 µM.
In contrast, the activity of the corresponding cis-3-ace toxy- 4-phe nyl-N -chry senyl -2-az etidi none was
less compared to the trans-isomer in all of these cancer cell lines. The chiral cis-compounds (hydroxyl
and acetoxy) were prepared by the oxidation of the trans-hydroxy compound to a keto derivative, reduction by sodium borohydride to the alcohol, and subsequent acetylation.
4.8 In Vivo Assay Against SKOV-3, an Ovarian and
HT-29, a Colon Cancer Cell Line
In general, 1X106 HT-29 cancer cells in 100 µL were inoculated subcutaneously over the right shoulder
of male athymic (nu/nu) mice. The HT-29 tumor in racemic trans-3-acetoxy β-lactam with N-chrysenyltreated groups was delayed in achieving the tumor growth end point of 1 cm3 volume by an average of
9 days. The effect of this compound against the ovarian tumor SKOV-3 was very fascinating with some
of the treated mice showing no tumor at 7 weeks. The trans-3-acetoxy-phenanthrene β-lactam showed
results like chrysene trans-3-acetoxy β-lactam derivative.
4.9 Mechanism of Action of the Potent β-Lactams: Cell Cycle Blockade
The trans-acetoxy β-lactams containing phenanthrene and chrysene at the N1 induced a striking G2/M
cell cycle block.28 In order to determine whether alteration of the cell cycle occurred in a cell line that
had repeatedly demonstrated resistance to the in vitro effect, human breast cancer cell line MDA-231
was examined. While HL-60 cells treated with this compound (5 µg) demonstrated a striking increase
in the G2 phase at 24 h (34.1%), no increase was detected in MDA-231, which was in effect identical to
that in untreated MDA-231. These compounds also produced apoptotic damage as evidenced by a greatly
increased subG0/G1 fraction. However, acetoxy chrysene β-lactam was much more effective when calculated on a concentration basis. On a dose basis, this compound was 18 times more effective than the
phenanthrene derivative. The high degree of caspase-3 activation, PARP cleavage, and DNA damage
150 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
exerted by these two compounds demonstrated by the TUNEL assay clearly suggested that apoptotic
pathway was involved in resulting cell death.
4.10 Permeability and LogP Test
The optimal logP and Caco-2 for cell penetration and oral absorption (logP is 4.75 and Caco-2 is 234x10-6
cm/s) were calculated. Clearly, acetoxy β-lactam with chrysene demonstrated excellent cell permeability
and an excellent chance for absorption across the gut wall.
4.11 Mutagenicity of the Acetoxy β-Lactams
Neither of these two acetoxy β-lactams demonstrated a positive response with tester strains at any concentration in either the presence or the absence of aroclor-induced rat liver S9, indicating that neither of
these compounds demonstrate any mutagenicity.
4.12 Synthesis of Pyrrole-Substituted Polyaromatic β-Lactams
The investigations on anticancer β -lactams suggested that the basic character of the molecules is that
they have a role in their anticancer effects. On this basis, synthesis of pyrrole-substituted β-lactams
was initiated.
synthesis of 3-pyrrole-functionalized β-lactams was not investigated intensely. Tidwell et al. explored
3-pyrrole-substituted β-lactams following Staudinger reaction. A simple procedure for the synthesis of
pyrrole-substituted β-lactams was reported by our group. This method used bismuth nitrate-induced
and iodine-catalyzed reactions29 on 3-amino β-lactams and 2,5-dimethoxytetrahydrofuran. The 3-amino
β-lactams were synthesized from 3-phtalimido β-lactams by a deprotection reaction.
Cycloaddition of Schiff base derived from monocyclic aromatic amines and monoaromatic carbonyl
compounds with activated phthalimidoacetic acid in the presence of triethylamine was performed
(Scheme 4.28). This reaction produced a mixture of cis- and trans-β-lactams. However, a similar reaction with polyaromatic Schiff base gave only trans-β-lactams. A high-temperature process also yielded
identical products with the same conguration. The isomer formation indicated a limitation of earlier
studies. These studies also showed the formation of a mixture of two cis- and trans-compounds in some
examples. Electron-withdrawing functionalities at the C- and N-site of the imine gave the trans-isomer.
23c
Pyrrole rings are abundant in natural and medicinally active compounds. However,
4.12.1 Preparation of 3-Amino β-Lactams
The 3-amino β-lactams were obtained by a deprotection of the phthalimido group with hydrazine hydrate.
A reaction of phthalimido β-lactams with ethylene diamine also produced 3-amino β-lactams in good
yield. The stereochemistry of the amino β-lactams remained identical with the starting phthalimido
compound. No cleavage of the β-lactam ring structure was noted during this reaction (Scheme 4.29).
4.12.2 Synthesis of 3-Pyrrole-Substituted β-Lactams
A procedure for the preparation of pyrrole-fused β-lactams was developed by reacting 3-amino β-lactams
with 2,5-dimethoxytetrahydrofuran using bismuth nitrate as the catalyst (Scheme 4.30). This reaction
produced products within a few minutes in a microwave oven. About 5 mol % of bismuth nitrate was
required for this reaction. Bismuth chloride, bismuth triate, bismuth subnitrate, bismuth nitrate, bismuth bromide, and bismuth iodide were employed using 1 mmol of 3-amino-chrysene β-lactams with
1.1 mmol of 2,5-dimethoxytetrahydrofuran in a microwave oven (300 Watts, 50°C, 20–45 psi, 4 min).
The results are shown in Table 4.1.
151Polyaromatic Beta-Lactams
Ar
O
1
2
https://t.me/med1917
Ar
HC
1
Ar1= phenyl, p-methoxyphenyl, 6-chrysenyl, 9-phenanthrenyl, dibenzofluorenyl
= phenyl, p-methoxyphenyl, 2-thiophenyl, pyridine isomers
Ar
SCHEME 4.28 Synthesis of cis- and trans-β-Lactams with Phthalimido Acetic Acid.
2
+
N
O
N
O
O
N
O
HH
Ar
N
Ar
O
OH
TEA
CH
2Cl2
2
+
1
I
N
Me
O
HH
Ar
N
O
O
2
N
Ar
Bismuth nitrate was chosen as the superior catalyst based upon the performances (Entry 6, Ta ble
4.2). Microwave-induced reaction without any catalyst gave 20% product in 5 min (Entry 7, Table 4.3).
The same reaction was investigated to identify the exact amount of the catalyst needed for this reaction.
The experimental results indicated that 5 mol % bismuth nitrate was sufcient to complete the reaction.
The procedure was then examined in a variety of solvents using bismuth nitrate following microwaveinduced method.
The above method was able to prove that bismuth nitrate pentahydrate is the best catalyst for this reaction. On this basis, a few reactions using 3-amino β-lactams (1 mmol) with 2,5-dimethoxytetrahydrofuran (1.2 mmol) using bismuth nitrate (5 mol %) under microwave irradiation method were performed.
The results showed that pyrroles are obtained with amino β-lactams more rapidly (about 65% yield)
when monocyclic aromatic rings are present at the nitrogen of the β-lactam ring. In contrast, the pyrrole
formation reactions with polyaromatic β-lactams were slow. The decrease in reactivity was due to the
less basic character of the amino groups present in the system.
A mechanistic route for the synthesis of pyrrole-substituted β -lactams was postulated (Scheme 4.31).
The methoxy groups in dimethoxytetrahydrofuran were cleaved to a dialdehyde in the presence of an
acidic catalyst. The dialdehyde on reaction with 3-amino β-lactams produced 3-pyrrole-fused compounds
through nucleophilic and dehydration-aromatization routes. This mechanistic pathway indicated the role
of bismuth nitrate as a Lewis acid promoter. A solution of 2,5-dimethoxytetrahydrofuran in CDCl3 upon
treatment with microwave irradiation was used for an NMR investigation. This study identied a very
downeld peak for the CHO group. The signal for the -CHO group became predominant if NMR was
taken after irradiating 2,5-dimethoxytetrahydrofuran in CDCl3 in the presence of bismuth nitrate. This
indicated the generation of a 1,4-dialehyde in the presence of bismuth nitrate upon microwave treatment.
Clearly, a demethylation of 2,5-dimethoxytetrahydrofuran took place due to an electrophilic reaction by
bismuth nitrate. Nitric acid also was able to catalyze this process. However, reaction of a few substrates
with catalytic amounts of nitric acid produced products in low amounts.
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