molecules
Review
Synthetic Procedures Leading
towards Aminobisphosphonates
Ewa Chmielewska * and Paweł Kafarski
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology,
Wrocław 50-370, Poland; [email protected]
* Correspondence: [email protected]; Tel.: +48-71-320-29-77; Fax: +48-71-320-24-27
Academic Editor: György Keglevich
Received: 30 September 2016; Accepted: 2 November 2016; Published: 4 November 2016
Abstract: Growing interest in the biological activity of aminobisphosphonates has stimulated the
development of methods for their synthesis. Although several general procedures were previously
elaborated to reach this goal, aminobisphosphonate chemistry is still developing quite substantially.
Thus, innovative modifications of the existing commonly used reactions, as well as development of
new procedures, are presented in this review, concentrating on recent achievements. Additionally,
selected examples of aminobisphosphonate derivatization illustrate their usefulness for obtaining
new diagnostic and therapeutic agents.
Keywords: bisphosphonates; bisphosphonylation procedures; Vilsmayer-Haack-like reactions;
functionalization of aminoalkylbisphosphonates
1. Introduction
Bisphosphonates are a class of compounds that are currently receiving significant attention.
Over 50 new papers are seen each week when searching the literature with the keyword
“bisphosphonate” via Web of Science. More than 17,000 various bisphosphonate structures have been
synthesized and described in the literature [1]. Most papers concern their important subclass, namely
aminobisphosphonates. This strong interest results from these compounds acting as strong inhibitors
of bone resorption, with several representatives of this class already commercialized as drugs of choice
for the treatment of osteoporosis, skeletal complications of malignancy, Paget’s disease, multiple
myeloma, hypercalcemia and fibrous dysplasia [2–7] Consequently, most of the papers are devoted
to various clinical aspects of the anti-resorptive effects that bisphosphonates exert towards bone
tissues; however, there is also a growing interest in their applications as anticancer and antibacterial
agents [5–7]. Additionally, aminobisphosphonic acids have found important industrial applications,
largely as inhibitors of scale formation and as corrosion inhibitors, actions which result from their
ability to complex metal ions [8–10].
Thus, simple and effective procedures for their synthesis are becoming increasingly important.
However, only a few general reactions leading to these compounds have been described to date and are
only partially reviewed in the literature [11,12]. Novel reports are mostly concentrated on modifications
and improvement of these procedures, and there are only a few papers aiming at new reactions, which
results from the commonly applied procedures being simple, economical and effective.
In this paper, we comprehensively review the recent studies (supplemented by older papers
if necessary) on reactions applied to synthesize the most important class of bisphosphonates—
aminobisphosphonates—and discuss their scope and limitations.
Molecules 2016, 21, 1474; doi:10.3390/molecules21111474
www.mdpi.com/journal/molecules
Molecules 2016, 21, 1474
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2. Overview of Synthetic Procedures
There are contradictory reports of the origin of bisphosphonates [13]. Most likely, the first one
was obtained in the 19th century by Nikolay Menschutkin and/or Theodor Saltzer as an impurity in
Molecules 2016, 21, 1474
of 25
reactions
designed to obtain different compounds. It was further identified by Hans von2Baeyer
and
Wilhelm2.Heideprim
as
1-hydroxyethanebisphosphonic
acid.
Overview of Synthetic Procedures
There are only a few general methods for the synthesis of aminobisphosphonates. However, there
There are contradictory reports of the origin of bisphosphonates [13]. Most likely, the first one
are many individual procedures described for their preparation [11,12]. In this review, the following
was obtained in the 19th century by Nikolay Menschutkin and/or Theodor Saltzer as an impurity in
general reactions
reactions
are presented:
(i) starting
from carboxylic
acids
and (ii)bytheir
(iii)
reactions
designed
to obtain different
compounds.
It was further
identified
Hansamides;
von Baeyer
and
using nitriles
and
(iv)
isonitriles
as
substrates;
(v)
syntheses
based
on
addition
of
phosphites
to
Wilhelm Heideprim as 1-hydroxyethanebisphosphonic acid.
There are(vi)
onlythree-component
a few general methods
for the synthesis
aminobisphosphonates.
However, there
oxophosphonates;
condensation
of of
amines,
trialkyl orthoformates
and dialkyl
are many
described
for their preparation [11,12]. Inand
this (viii)
review,functionalization
the following
phosphites;
(vii)individual
additionprocedures
of amines
to vinylidenebisphosphonates;
of
general reactions are presented: (i) starting from carboxylic acids and (ii) their amides; (iii) reactions
simple bisphosphonates treated as building blocks for the preparation of more complex structures.
using nitriles and (iv) isonitriles as substrates; (v) syntheses based on addition of phosphites to
Additionally,
some specific and non-conventional procedures that have been elucidated will be
oxophosphonates; (vi) three-component condensation of amines, trialkyl orthoformates and dialkyl
presented
in
this
phosphites;review.
(vii) addition of amines to vinylidenebisphosphonates; and (viii) functionalization of
simple bisphosphonates treated as building blocks for the preparation of more complex structures.
2.1. Synthesis
from Carboxylic
Acids
Additionally,
some specific
and non-conventional procedures that have been elucidated will be
presented in this review.
1-Hydroxyethylidene-1,1-bisphosphonic acids are perhaps the oldest group of bisphosphonates.
They are2.1.
standardly
prepared
byAcids
a large-scale, one-step reaction of carboxylic acids with phosphorus
Synthesis from
Carboxylic
trichloride and phosphorous or phosphoric acids, followed by hydrolysis with water; the procedure
1-Hydroxyethylidene-1,1-bisphosphonic acids are perhaps the oldest group of bisphosphonates.
was optimized
by Kieczykowski
al. [14]. one-step
The reaction
carriedacids
out with
in selected
They are standardly
prepared by et
a large-scale,
reaction ofiscarboxylic
phosphorussolvents
(phenylsulphonic
acid,
various phenols,
chlorobenzene,
diphenyl
etherwith
or ionic
with sulfone
trichloride and
phosphorous
or phosphoric
acids, followed
by hydrolysis
water;liquids)
the procedure
was optimized by acid
Kieczykowski
et al. [14].
The reaction
is carried
out many
in selected
solvents
and methanesulphonic
being preferred
choices
[11,15–20].
Despite
theories
[19,21–23],
various phenols,
chlorobenzene,
diphenyl
ether or
ionic
liquids) with
sulfone
the exact(phenylsulphonic
mechanism of acid,
this reaction
is not fully
understood;
however,
the
formation
of acid
chloride as
and methanesulphonic acid being preferred choices [11,15–20]. Despite many theories [19,21–23], the
a first intermediate has been undoubtedly demonstrated (Scheme 1). This intermediate may react with
exact mechanism of this reaction is not fully understood; however, the formation of acid chloride as
methanesulphonic
acid (when used as a solvent), and the formed mixed anhydride is also considered
a first intermediate has been undoubtedly demonstrated (Scheme 1). This intermediate may react with
a potential
intermediate
for(when
the next
[24], which
is an
Arbuzov-like
reaction
phosphorus
acid
methanesulphonic acid
usedstep
as a solvent),
and the
formed
mixed anhydride
is alsoofconsidered
a
or one of
its several
derivatives
anhydrides
of variable structure
[17]) formed
during
the
potential
intermediate
for the(including
next step [24],
which is an Arbuzov-like
reaction of phosphorus
acid
or
of formed
its several
derivatives
anhydridesis of
variable structure
formed
during of
thetrivalent
reaction.one
The
derivative
of(including
ketophosphonate
a substrate
for the [17])
addition
reaction
reaction. The
derivative of ketophosphonate
is a substrate
the also
addition
reaction
of trivalentthat the
P-OH species,
andformed
bisphosphonate
is obtained (Scheme
1). Itforhas
been
documented
P-OH species, and bisphosphonate is obtained (Scheme 1). It has also been documented that the use of
use of phosphorous acid could be omitted if water was added to the reaction medium, and thus this
phosphorous acid could be omitted if water was added to the reaction medium, and thus this
compound
was formed
in situ.
compound
was formed
in situ.
O
R
1./ PCl3/H3PO3
R
2./ H2O
OH
1./ SOCl2
or CH3SO3H
PO3H2
OH
PO3H2
1
2./ H2O
PCl3
O
OH
R
CH3SO3H
SOCl2
O
R = H2N
n
n =1-5
R
O
Cl
R1
HO
P O
R2
R
Cl
R2 P
R1
O
O
S
O
OH
R1
R2
O
P
R1
HO
PH O O
R2
S
R
O O
R
O
PO3H2
OH
R
PO3H2
1
R
R2 P
R1
OH
R1 = Cl, OH
R2 = Cl, OPR1R2
Scheme 1. Presumable mechanism of the synthesis of 1-hydroxy-1,1-bisphosphonic acids.
Scheme 1. Presumable mechanism of the synthesis of 1-hydroxy-1,1-bisphosphonic acids.
This reaction was commonly used for the preparation of a wide variety of anti-osteoporotic
bisphosphonic
acidscommonly
containing free
amino
(so called dronic
1). In
this case,
This reaction was
used
for groups
the preparation
of aacids,
widecompound
variety of
anti-osteoporotic
free
unblocked
amino
acids
are
used
as
substrates,
and
the
final
neutralization
of
reaction
mixtures
to this
a
bisphosphonic acids containing free amino groups (so called dronic acids, compound 1). In
case,
pH of approximately 4 causes precipitation of the desired products, which are formed in satisfactory
free unblocked amino acids are used as substrates, and the final neutralization of reaction mixtures to
a pH of approximately 4 causes precipitation of the desired products, which are formed in satisfactory
Molecules 2016, 21, 1474
3 of 26
Molecules 2016, 21, 1474
3 of 25
Molecules
yields
and2016,
are21,of1474
good
3 of 25
reaction
purity [16,23–26]. Because of its technological importance, this
is
yields and are of good purity [16,23–26]. Because of its technological importance, this reaction is still
still quite intensively studied and optimized; however, most of the studies are done in industrial
quite intensively
and optimized;
the studies are
done in industrial
laboratories,
yields
and are ofstudied
good purity
[16,23–26].however,
Becausemost
of itsoftechnological
importance,
this reaction
is still
laboratories, and their results are mostly disseminated as patents. Consequently, it is difficult, if not
and
their
results
are
mostly
disseminated
as
patents.
Consequently,
it
is
difficult,
if
not
impossible,
to
quite intensively studied and optimized; however, most of the studies are done in industrial laboratories,
impossible,
to
determine
which
conditions
are
optimaloffor
the synthesis
ofisindividual
drugs. as
It is
determine
which
conditions
are
optimal
for
the
synthesis
individual
drugs.
It
important
because,
and their results are mostly disseminated as patents. Consequently, it is difficult, if not impossible, to
important
because,
as
in
the
case
of
any
multicomponent
reaction,
a
synthetic
course
is
strongly
in the casewhich
of any
multicomponent
reaction,
a synthetic
course is drugs.
strongly
applied
determine
conditions
are optimal
for the synthesis
of individual
It isdependent
important on
because,
as
dependent
on
applied
conditions
and
molar
ratios
of
reagents.
For
example,
one
of
the
patents
reports
conditions
molar
ratios of reagents.
For example,
one of
the patents
reports
that the omission
of
in
the caseand
of any
multicomponent
reaction,
a synthetic
course
is strongly
dependent
on applied
that
the omission
of phosphorus
chloride
in
the reactionofof
acid
as the substrate
phosphorus
chloride
in the of
reaction
of For
4-aminobutyric
as4-aminobutyric
the substrate
methanesulphonic
conditions
and
molar ratios
reagents.
example, oneacid
the
patents
reportsinthat
the omission of
in phosphorus
methanesulphonic
acid
provides
anhydrides
as
products
(compounds
and 3,
acid
provideschloride
mixtures
anhydrides
finalofproducts
(compounds
2 and 3,inScheme
2) [11].2 This
in of
the
reactionmixtures
ofas4-aminobutyric
acid
as final
the substrate
methanesulphonic
Scheme
2)
[11].
This
corresponds
well
to
the
known
tendency
of
phosphonic
acids
to
cyclize.
corresponds
well
to
the
known
tendency
of
phosphonic
acids
to
cyclize.
acid provides mixtures of anhydrides as final products (compounds 2 and 3, Scheme 2) [11]. This
corresponds well to the known tendency of phosphonic acids to cyclize.
H2N
H2N
O OH
HO P O O
O OH P
OH
HO P
P O
O O
O
OHP OH
2
P O
O
OH
2of the reaction
OH
O
H2O3P POHO
NH2
H2N H O PO P
PO3H2 NH
O
O
P
2 3
2
O
3 OHO
H2N
P OPO3H2
HO
3
Scheme
Cyclic products
products of the reaction between
between carboxylic
in in
Scheme
2. 2.Cyclic
carboxylicacids
acidsand
andphosphorous
phosphorousacid
acid
methanesulphonic
acid.
Scheme 2. Cyclicacid.
products of the reaction between carboxylic acids and phosphorous acid in
methanesulphonic
methanesulphonic acid.
Among modifications of this procedure are (i) replacement of phosphorus trichloride with
Among modifications of this procedure are (i) replacement of phosphorus trichloride with thionyl
thionyl
chloride
to generate of
acid
chloride
in theare
first(i)reaction
step [11];
(ii) replacement
of acid by
its
Among
modifications
this
procedure
replacement
of phosphorus
trichloride
with
chloride
to
generate
acid
chloride
in
the
first
reaction
step
[11];
(ii)
replacement
of
acid
by
its
chloride
chloridechloride
or anhydride
[11] or
(iii)
t-butylinester
[27];reaction
(iv) blocking
the (ii)
amino
moiety inofthe
of
thionyl
to generate
acid
chloride
the first
step [11];
replacement
acidcase
by its
or α-amino
anhydride
[11]
or and
(iii) (v)
t-butyl ester [27];
(iv) blocking the procedures
amino moiety
the case of α-amino
acids
[28];
of microwave-assisted
[29].in
chloride or
anhydride
[11] application
or (iii) t-butyl
ester [27]; (iv) blocking
the amino
moiety in the case of
acids [28]; and (v) application of microwave-assisted procedures [29].
α-amino acids [28]; and (v) application of microwave-assisted procedures [29].
2.2. Synthesis from Amides
2.2. Synthesis from Amides
2.2. Synthesis
Amides
Althoughfrom
studies
on the biological activity of 1-amino-1,1-bisphosphonic acids are scarce, a
Although
studies
on the biological
activity
of have
1-amino-1,1-bisphosphonic
acids
are been
scarce,
significant
number
of procedures
for their activity
preparation
been described. Theyacids
have
recently
Although
studies
on the biological
of 1-amino-1,1-bisphosphonic
are
scarce,
a
a significant
number
of
procedures
for
their
preparation
have
been
described.
They
have
recently
reviewed
by
Romanenko
and
Kukhar
[12].
Amides,
being
highly
stable
and
easily
available
compounds,
significant number of procedures for their preparation have been described. They have recently been
been
by
andmost
Kukhar
[12]. being
Amides,
being
highly
stable
and
easily
available
arereviewed
substrates
of Romanenko
choice,and
andKukhar
the
applied
procedures
simple
modifications
of
reviewed
by Romanenko
[12].commonly
Amides,
highly
stable
andare
easily
available
compounds,
compounds,
are
substrates
of
choice,
and
the
most
commonly
applied
procedures
are
simple
those
elaborated
for
carboxylic
acids.
The
most
straightforward
are
reactions
of
N-acylamines
and
are substrates of choice, and the most commonly applied procedures are simple modifications of
modifications
of those
elaborated
for
carboxylic
acids.
The most
are tribromide
reactions
N-formylamines
with
phosphorus
trichloride
andstraightforward
phosphorous
acid
[30–32],
those
elaborated
for carboxylic
acids.
The most
arestraightforward
reactionsphosphorus
of N-acylamines
and of
N-acylamines
andwith
N-formylamines
with
phosphorus
trichloride
and phosphorous
[30–32],
[33], or triphosgene
[34],
which provide
a wide
structural
varietyacid
of 1-amino-1,1-bisphosphonic
acids
N-formylamines
phosphorus
trichloride
and
phosphorous
[30–32],
phosphorus acid
tribromide
(compound
4,
Scheme
3).
They
are
based
on
modification
of
the
first
procedure
elaborated
by
Plöger
phosphorus
tribromide
[33],
or
triphosgene
[34],
which
provide
a
wide
structural
variety
[33], or triphosgene [34], which provide a wide structural variety of 1-amino-1,1-bisphosphonic acids of
et al. with formamide
substrate
[35]. on modification
1-amino-1,1-bisphosphonic
acids
(compound
4, Scheme 3).ofThey
are based
on modification
the first
(compound
4, Scheme as
3).aThey
are
based
the first
procedure
elaborated byofPlöger
procedure
elaborated
byasPlöger
et al. [35].
with formamide as a substrate [35].
et al. with
formamide
a substrate
O
PO3H2
PCl3/H3PO4
H2O3P
R1
R1
R O N
N 3H2
PO
PCl
/H
PO
2 1
3
3
4
R
H
O
P
R R
2 3
R2 R1
R
N
N
4
R= CH3, phenyl
2
R
R
R2
R1= H, alkyl
4
R=
3, phenyl
alkyl,
aryl, heteroaryl, cycloalkyl
R12=CH
R = H, alkyl
2
alkyl, aryl, heteroaryl, cycloalkyl
Scheme R3. =Bisphosphonylation
of amides.
Scheme3.3. Bisphosphonylation
Bisphosphonylation of
Scheme
ofamides.
amides.
The exact reaction mechanism in this case is also not fully known; however, a VilsmayerHaack-like
routereaction
via iminium
ion is postulated
here
The exact
mechanism
in this case
is (Scheme
also not 4).
fully known; however, a VilsmayerThe
exact reaction
mechanism
in thisorcase
is also notphosphites
fully known;
however,
a VilsmayerAnother
possibility
is
using
trialkyl
trimethylsilyl
in reactions
prompted
by
Haack-like route via iminium ion is postulated here (Scheme 4).
Haack-like
route
via
iminium
ion
is
postulated
here
(Scheme
4).
phosphoryl
chloride
[36–39],
trifluoromethanesulphonic
anhydride
(Tf
2
O)
[40],
zinc
chloride
[41]
or
Another possibility is using trialkyl or trimethylsilyl phosphites in reactions prompted by
Another
possibility
is
using
trialkyl
or
trimethylsilyl
phosphites
in
reactions
prompted
trimethylsilyl
trifluoromethanesulfonate
[42,43]. Unfortunately,
primary
amides
not suitable
phosphoryl
chloride
[36–39], trifluoromethanesulphonic
anhydride
(Tf2O) [40],
zincare
chloride
[41] orby
phosphoryl
chloride
[36–39],
trifluoromethanesulphonic
anhydride
(Tf2 O)
[40], are
zinc
chloride
[41]
substrates for
this
reaction
[38].
The use of [42,43].
triethyl phosphite
and phosphoryl
chloride
appeared
to be
trimethylsilyl
trifluoromethanesulfonate
Unfortunately,
primary
amides
not
suitable
especially
useful
when
lactams
were
used
as
substrates,
resulting
in
high
yields
of
aminomethyleneor substrates
trimethylsilyl
trifluoromethanesulfonate
[42,43].
Unfortunately,
primary
amides
are
not
suitable
for this reaction [38]. The use of triethyl phosphite and phosphoryl chloride appeared to be
gem-bisphosphonates
5) [36–39].
They
were
readily
hydrolyzed,
yielding
corresponding
substrates
foruseful
this reaction
[38]. The
use
of triethyl
phosphite
and
phosphoryl
chloride
appeared to be
especially
when(Scheme
lactams
were
used
as
substrates,
resulting
in high yields
of aminomethylenebisphosphonic
acids
(representative
example
compound
5).
On
the
other
hand,
this
reaction
is not
especially
useful when lactams
used asThey
substrates,
resulting
in high yields
of aminomethylenegem-bisphosphonates
(Schemewere
5) [36–39].
were readily
hydrolyzed,
yielding
corresponding
suitable for the acids
conversion
of benzoannulated
lactams,
of thehand,
desired
bisphosphonates
gem-bisphosphonates
(Scheme
5) [36–39].
They
were and
readily
yielding
corresponding
bisphosphonic
(representative
example
compound
5).mixtures
Onhydrolyzed,
the other
this
reaction
is not
and monophosphonates
ofof
variable
structures
were obtained
6,
7, reaction
8 and
9,isScheme
5).
suitable
for the
conversion
benzoannulated
lactams,
the desired
bisphosphonates
bisphosphonic
acids
(representative
example
compound
5).and
Onmixtures
the(compounds
otherofhand,
this
not suitable
In
fact,
monophosphonates
are
usually
major
products,
and
the
reaction
course
is
dependent
on
the
of variable structures
6, 7,bisphosphonates
8 and 9, Scheme 5).
forand
themonophosphonates
conversion of benzoannulated
lactams,were
andobtained
mixtures(compounds
of the desired
and
In fact, monophosphonates are usually major products, and the reaction course is dependent on the
Molecules 2016, 21, 1474
4 of 26
monophosphonates of variable structures were obtained (compounds 6, 7, 8 and 9, Scheme 5). In fact,
Molecules 2016, 21, 1474
4 of 25
Molecules 2016, 21, 1474are usually major products, and the reaction course is dependent on the size
4 of
monophosphonates
of25the
substrate
ringaliphatic
[44]. Additionally,
these bisphosphonates
and monophosphonates
appeared to
size of aliphatic
the substrate
ring [44]. Additionally,
these bisphosphonates
and monophosphonates
of the substrate aliphatic ring [44]. Additionally, these bisphosphonates and monophosphonates
be size
unstable
upon
acid
hydrolysis
and
upon
storage,
and
undergo
degradation
with
cleavage
of the
appeared to be unstable upon acid hydrolysis and upon storage, and undergo degradation with cleavage
appeared to be unstable upon acid hydrolysis and upon storage, and undergo degradation with cleavage
carbon-to-phosphorus
bond
(for
example
compound
10,
Scheme
5).
Thus,
corresponding
acids
have
of the carbon-to-phosphorus bond (for example compound 10, Scheme 5). Thus, corresponding acids
of the carbon-to-phosphorus bond (for example compound 10, Scheme 5). Thus, corresponding acids
nothave
yet been
obtained.
not yet
been obtained.
have not yet been obtained.
O
O
R
R
PCl3
R1 PCl3
N R1
N
R22
R
Cl
Cl
R
R
O
H PO
H
P
HO OH
HO OH
R1
N R1
N2
R2
R
R
R
PO3H2
PO3H2 1
R
N R1
N
R22
R
R
R
PO3H2
PO3H2 1
R
N R1
N2
R2
R
O
H PO
H P OH
HO
HO OH
H2O3P
H2O3P
PO3H2
PO3R
H12
N R1
R N2
R R2
4 R
4
Scheme
Bisphosphonylationof
of amides and
and the
this
Scheme
4. 4.
Bisphosphonylation
the presumable
presumablemechanism
mechanismof
thisreaction.
reaction.
Scheme
4.
Bisphosphonylation ofamides
amides and the
presumable
mechanism
ofofthis
reaction.
N
H
N
H
O
O
POCl3/(EtO)3P
POCl3/(EtO)3P
N
H
N
H
N
H
N
H
O
O
HCl/H2O
P(O)(OEt)2
HCl/H2O
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
1./ POCl3/(EtO)3P
1./ POCl3/(EtO)3P
PO3H2
PO3H2
N
PO3H2
H
N
H 5 PO3H2
5
N
H
N
H
6
6
P(O)(OEt)2
P(O)(OEt)2 +
P(O)(OEt)2 +
P(O)(OEt)2
N
N
N
H
N
H
1./ POCl3/(EtO)3P
1./ POCl3/(EtO)3P
O
O
N
N
7
7
HCl/H2O
HCl/H2O
P(O)(OEt)2
P(O)(OEt)2
PO3H2
PO3H2
+
N
H
N
H
8
8
P(O)(OEt)2 +
P(O)(OEt)
P(O)(OEt)2 2
P(O)(OEt)2
HCl/H2O
HCl/H2O
NH2
NH2
N
H
N
H
9
9
P(O)(OEt)2
P(O)(OEt)2
COOH
COOH
10
10
Scheme 5. Representative reactions of lactams with triethyl phosphite prompted by phosphoryl chloride.
Scheme
Representativereactions
reactionsof
of lactams
lactams with
byby
phosphoryl
chloride.
Scheme
5. 5.Representative
with triethyl
triethylphosphite
phosphiteprompted
prompted
phosphoryl
chloride.
The formation of a Vilsmayer-Haack-like intermediate is also proposed in this case with the
The formation of a Vilsmayer-Haack-like intermediate is also proposed in this case with the
further
addition ofof
a nucleophilic
phosphorus reagent.
This assumption
is additionally
The
a Vilsmayer-Haack-like
intermediate
is also proposed
in thissupported
case withby
further formation
addition of a nucleophilic
phosphorus reagent.
This assumption
is additionally
supported
bythe
studies
on
the
use
of
structurally
variable
imine
salts
as
substrates
for
synthesis
of
compounds
11
further
addition
of a of
nucleophilic
reagent.
assumption
is additionally
supported
studies
on the use
structurallyphosphorus
variable imine
salts asThis
substrates
for synthesis
of compounds
11
(Scheme
6)
[41–45].
by (Scheme
studies on
the use of structurally variable imine salts as substrates for synthesis of compounds 11
6) [41–45].
(Scheme 6) [41–45].
OTMS
F3CO2SO P(O)(OTMS)2
OTMS
OTMS
OEt of dibutoxyphosphine
F3COwith
P(O)(OTMS)2
+
The reaction
or bis(trimethylsiloxy)phosphine
dimethylformamides
2SO
CF3SO3TMS
OTMS
OEt
+ TMSO P
R
NH2
P OTMS
CF3SO3TMS
R
NH
TMSO
OTMS
NH
R
-CF3SO3
2
R
NH2 of trimethylsilyl
2
in the presence
trifluoromethanesulfonate
affords
the
corresponding
NH2 Cl
R
-CF3SO3
R
NH2 Cl
OTMS
Cl
Cl
OTMS
aminomethylenebisphosphonites 12 in high yields (Scheme 7) [41–43]. Similar
products were
P
TMSO P OTMS
TMS = Me3Sidiethyl pivaloylphosphonite with dialkylformamides in
obtained by reacting
the presence
of excess
TMSO
OTMS
TMS = Me3Si
-CF3SO3TMS decomposes in these
ethanol and catalytic Hamounts
of
zinc
chloride
(Scheme
7).
Pivaloylphosphonite
CH
OH
PO3H2
(TMSO) (O)P P(O)(OTMS)
3
-CF3SO3TMS
2O3P
CH3OH (TMSO)22(O)P P(O)(OTMS)22
H2O3P PO3H2
R
NH
R
NHis
reaction conditions, yielding
diethoxyphosphine,
which
2
2 the real substrate of the reaction [41].
R
NH2
R
NH2
N-Octylpyrrolidinone11
11treated with LDA, followed by the addition of diethyl phosphorochloridite
and oxidation ofRthe
reaction
mixture
, HOwith 30% hydrogen peroxide resulted in bisphosphonylated
= H, CH
3, phenyl,
R = H, CH3, phenyl, N , HO
lactam 13 with excellent yieldN (Scheme 8). This reaction was then applied for the synthesis
Scheme 6. Imine salts as substrates for preparation of bisphosphonic acids.
Scheme 6. Imine salts as substrates for preparation of bisphosphonic acids.
3 2
1./ POCl3/(EtO)3P
N
H
N
H
8
O
P(O)(OEt)2
+
N
H
9
P(O)(OEt)2
Molecules 2016, 21, 1474
P(O)(OEt)2
5 of 26
HCl/H2O
COOH
of N-geranylated lactams 14 and 15 and linear amides,
potential inhibitors of farnesyl:protein
NH
10
transferase [46]. In the case of cyclic imides, in which two equivalent positions for enolate formation
Scheme 5. Representative reactions of lactams with triethyl phosphite prompted by phosphoryl chloride.
areMolecules
present
on the imide rings, and thus two carbon atoms may be phosphonylated, the structure
2016, 21, 1474
5 of 25
of the product
was dependent
on the mode of reaction.
If phosphonylation
carried
out inthe
one
The formation
of a Vilsmayer-Haack-like
intermediate
is also proposed was
in this
case with
step,
two
carbon
atoms
were
phosphonylated
and
vicinal
bisphosphonate
was
obtained.
Step-by-step
Theaddition
reactionofofadibutoxyphosphine
or bis(trimethylsiloxy)phosphine
dimethylformamides
further
nucleophilic phosphorus
reagent. This assumption is with
additionally
supported by
in
theresulted
trimethylsilyl
affords
theof compounds
corresponding
reaction
in the
predomination
of trifluoromethanesulfonate
the
phosphonylation
of one
carbon
atom,
and the desired
studies
onpresence
the use
ofofstructurally
variable
imine
salts as substrates
for
synthesis
11
aminomethylenebisphosphonites
12
in
high
yields
(Scheme
7)
[41–43].
Similar
products
were
gem-bisphophonate
was
the
major
product.
(Scheme 6) [41–45].
obtained by reacting diethyl pivaloylphosphonite with dialkylformamides in the presence of excess
ethanol and catalytic amounts of zinc chloride
(SchemeOTMS
7). Pivaloylphosphonite
F3CO2SO decomposes
P(O)(OTMS)2 in these
OTMS
OEt
+
P
CF3SO3TMS
R
NHreaction
OTMS
reaction conditions, yielding diethoxyphosphine, TMSO
which is
the real substrate of the
[41].
2
2
R
NH2
R
-CF3SO3
Cl
NH2
Cl
OTMS
OMe
P
RO
OR
OR
1
TMSO
OTMS
P
+ MeO N R
TMS = Me3Si
P
1
RO
R
H
OR
-ROH
2
Molecules 2016, 21, 1474
5 of 25
P -CF
N 3SO3TMS
CH3OH (TMSO)2R
H2O3P PO3H2
(O)P P(O)(OTMS)2
OR R2
R
=
Et,
Bu,
SiMe
3
R
NH2
R
NH2
12
The reaction of dibutoxyphosphine
with dimethylformamides
R1=R2= CH3 or bis(trimethylsiloxy)phosphine
11
in the presence of trimethylsilyl trifluoromethanesulfonate affords the corresponding
,12
R = H,
HOin high yields (Scheme
aminomethylenebisphosphonites
7) [41–43]. EtO
Similar
O CH3, phenyl,
OEt products were
OEt
N
P
OEt
EtOH/ZnCl2
1
OEt
R
obtained by reactingP diethyl
pivaloylphosphonite
with
dialkylformamides
in
the
presence
of excess
+ EtO N
EtO
R1
P
P
N
- t-BuCOOEt
-EtOH
H
OEt
2
ethanol and catalyticOEt
amounts
of zinc chloride
(Scheme 7). Pivaloylphosphonite
decomposes
in these
R
OEt
R2
Scheme6.6.Imine
Iminesalts
saltsas
assubstrates
substrates for
for preparation
of
bisphosphonic
acids.
Scheme
preparation
of
bisphosphonic
acids.
reaction conditions, yielding diethoxyphosphine, which is the real substrate of the
12 reaction [41].
R1= R2 = CH3, n-propyl,
R1, R2 = -(CH2)5-, -CH2CH2OCH2CH2OMe
RO
OR
OR
1
P
+ MeO N R with the acetal of dimethylformamide.
Scheme 7. Reaction ofP diethoxyphosphine
RO
R1
H
OR
-ROH
P
N
R2
2
OR R
R = with
Et, Bu, LDA,
SiMe3 followed by the addition of diethyl phosphorochloridite
N-Octylpyrrolidinone treated
12
1
2
R =R = CH3
and oxidation of the reaction mixture with 30% hydrogen peroxide resulted in bisphosphonylated
lactam 13 with excellent yield (Scheme 8). This reaction was then applied for the synthesis of
O
EtO
OEt
OEtinhibitors of farnesyl:protein
N-geranylated lactams
14 and 15 and linear amides,
potential
transferase
P
OEt
EtOH/ZnCl2
1
OEt
R
+ EtOpositions
P
EtO formation
R1
P equivalent
N
[46]. In the case of cyclic
imides,
in
which
two
for
enolate
are
present
P
N
- t-BuCOOEt
-EtOH
H
OEt
OEt
R2
2 of the product
on the imide rings, and thus two carbon atoms may be phosphonylated,
the structure
OEt R
12 step, two carbon
was dependent on
of reaction. If phosphonylation was carried out in one
R1=the
R2 =mode
CH3, n-propyl,
1
2
R , R = -(CH2)5and
-, -CHvicinal
atoms were phosphonylated
was obtained. Step-by-step reaction resulted
2CH2OCHbisphosphonate
2CH2in the predomination of the phosphonylation of one carbon atom, and the desired gem-bisphophonate
Scheme
Reactionofofdiethoxyphosphine
diethoxyphosphine with
with the
Scheme
7. 7.Reaction
the acetal
acetalof
ofdimethylformamide.
dimethylformamide.
was the major
product.
N-Octylpyrrolidinone treated with LDA, followed by the addition of diethyl phosphorochloridite
LDA (2 equiv.)with 30% hydrogen peroxide
and oxidation of the reaction1./mixture
resulted
in bisphosphonylated
H2O2
N
N
2./ ClP(OEt)2 (2 equiv.)
N
lactam 13 with excellent yield (Scheme 8). This reaction
was then applied
O for the synthesis of
O
O
(EtO) (O)P
P(O)(OEt)2
(EtO)2P
P(OEt)2
N-geranylated lactams 14 and 15 and linear amides,
potential
inhibitors2 of farnesyl:protein
transferase
13
[46]. In the case of cyclic imides, in which two equivalent positions for enolate formation are present
on the imide rings, and thus two carbon
atoms may be phosphonylated, the structure of the product
O
was dependent on the mode of reaction.
If phosphonylation was carried out in one step, two carbon
N
atoms were phosphonylated and vicinal
bisphosphonate
was obtained. Step-by-step reaction resulted
O
1./ LDA (1 equiv.)
2./ ClP(OEt)
in the predomination1./of
the
phosphonylation
of
one
carbon
atom,
and
the desired gem-bisphophonate
2 (1 equiv.)
LDA (2 equiv.)
3./ H2O2
2./ ClP(OEt)2 (2 equiv.)
was the major product.
3./ H2O2
O
N
N
(EtO)2(O)P
O
O
(EtO)2(O)P
1./ LDA (2 equiv.)
2./ ClP(OEt)2 (2 equiv.)
14
N
(EtO)2P
(EtO)2(O)P
(EtO)2(O)P
O
O
P(OEt)2
O
1./ LDA (1 equiv.)
H2O22 (1 equiv.)
2./ ClP(OEt)
3./ H2O2
(EtO)2(O)P
N
O
P(O)(OEt)2
13
N
15
O
N
Scheme8.8.Synthesis
Synthesis of
of bisphosphonate
Scheme
bisphosphonatelactams.
lactams.
O
1./ LDA (1 equiv.)
2./ ClP(OEt)2 (1 equiv.)
3./ H2O2
1./ LDA (2 equiv.)
2./ ClP(OEt)2 (2 equiv.)
3./ H2O2
2.3. Synthesis from Nitriles
1-Aminoalkylidene-1,1-bisphosphonic acids could also be prepared from nitriles by applying
1./ LDA (1 equiv.)
the same procedures as in
O syntheses starting from amides. Despite being readily available substrates,
2./ ClP(OEt) (1 equiv.)
(EtO)2(O)P
3./ H2O2
N
O
14
2
Molecules 2016, 21, 1474
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2.3. Synthesis from Nitriles
1-Aminoalkylidene-1,1-bisphosphonic
Molecules
2016, 21,
21, 1474
1474
Molecules
2016,
acids could also be prepared from nitriles by applying
ofthe
25
66 of
25
same procedures as in syntheses starting from amides. Despite being readily available substrates, there
is
limited
literature
on their
use use
for that
purpose.
The
most
popular
route
there
is limited
limited
literature
on their
their
use
for that
that
purpose.
The
most
popular
routeisis
isthe
thereaction
reactionof
ofnitriles
nitriles
there
is
literature
on
for
purpose.
The
most
popular
route
the
reaction
of
nitriles
with
phosphorous
acid,
in
some
cases
prompted
by
phosphorus
trichloride
and
phenylsulphonic
or
phosphorous
some
cases
prompted
by
phosphorus
trichloride
and
phenylsulphonic
with phosphorous acid, in some cases prompted by phosphorus trichloride and phenylsulphonic or
methylsulphonic
The
conditions
of
this
reaction
sufficiently
delicate
to
use
acids
[12,31,47,48].
The
conditions
of
this
reaction
are
methylsulphonic acids [12,31,47,48]. The conditions of this reaction are sufficiently delicate to use
demonstrated using
peptidyl
peptidyl nitriles
nitriles as
as substrates,
substrates, which
which was
was demonstrated
demonstrated
using cyanoethyl
cyanoethyl derivatives
derivatives of
of dipeptides
dipeptides
16,
Scheme
9)
[49].
(for
example,
peptide
16,
Scheme
9)
[49].
(for example, peptide 16, Scheme 9) [49].
NC
NC
N
N
H
H
H
H
N
N
COOH
COOH
O
O
PCl3/H
/H3PO3
PCl
3 3PO3
S
S
PO3H2
H2N
N PO3H2
H
2
N
H2O
O3P
N
H
H
2 3P
H
16
16
H
H
N
N
COOH
COOH
O
O
S
S
Scheme 9.
9. Representative
Representative example
example of
of the
the synthesis
from nitriles.
nitriles.
synthesis of
of peptidylbisphosphonates
peptidylbisphosphonates from
Scheme
from
nitriles.
Recently, elegant,
elegant, mild,
mild, and
and atom
atom economical
economical double
double phosphonylation
phosphonylation of
of nitriles
nitriles in
in the
the presence
presence
Recently,
of titanocene
titanocene has
has been
been described.
described. This
This
procedure
used induced
induced phosphorus-centered
phosphorus-centered radicals
radicals
This procedure
procedure used
of
has
been
described.
mediated
by
titanocene
dichloride
(Cp
2TiCl2) (Scheme 10) and provided a wide structural variety of
(Scheme 10)
10) and
and provided
provided a wide structural variety of
mediated by titanocene dichloride (Cp22TiCl22)) (Scheme
aminobisphosphonates 17
17
[50]. This
This
is
double radical
radical transfer
transfer reaction
reaction initiated
initiated
by the
the reaction
reaction of
of
aminobisphosphonates
17 [50].
This is
is aa double
initiated by
aminobisphosphonates
titanocene
with
zinc
dust
and
the
transfer
of
the
obtained
radical
to
epoxypropane
by
cleavage
of
its
titanocene with zinc dust and the transfer of the obtained radical to epoxypropane by cleavage of its
titanocene
oxirane ring,
ring, followed
followed by
by transfer
transfer of
of this
this radical
radical to
to diethyl
diethyl phosphite,
phosphite, which
which in
in turn
turn reacts
reacts with
with nitrile
nitrile
oxirane
(Scheme 10).
10). The
The reaction
reaction carried
carried out
out without
without epoxide,
epoxide, under
under microwave
microwave stimulation,
stimulation, also
also results
results in
in
(Scheme
the
desired
bisphosphonates,
although
it
is
accompanied
by
formation
of
many
side
products.
the desired bisphosphonates, although it is accompanied by
by formation
formation of
of many
many side
side products.
products.
Cp TiCl
Cp22TiCl22
Cp TiCl =
Cp22TiCl22 =
Ti
Ti
Zn
Zn
Cp TiCl
Cp22TiCl22
O
O
O(Cl)TiCp
O(Cl)TiCp22
H
H
Cl
Cl
Cl
Cl
HP(O)(OEt)
HP(O)(OEt)22
O(Cl)TiCp
O(Cl)TiCp22
(EtO) (O)P
P(O)(OEt)
(EtO)22(O)P
P(O)(OEt)22
R NH
R NH22
17
17
RCN
RCN
O
O
P OEt
P OEt
OEt
OEt
Ph
R = alkyl, cycloalkyl, halogenoalkyl, aryl, HOOC-CH -,CH -CH CH -, Ph N
R = alkyl, cycloalkyl, halogenoalkyl, aryl, HOOC-CH22-,CH33-CH22CH22-, Ph N
Ph
Scheme 10.
10. Radical procedure
procedure for the
the synthesis of
of bisphosphonates from
from nitriles.
nitriles.
Scheme
Scheme 10. Radical
Radical procedure for
for the synthesis
synthesis of bisphosphonates
bisphosphonates from nitriles.
2.4. Synthesis from
from Isonitriles
2.4.
2.4. Synthesis
Synthesis from Isonitriles
Isonitriles
Isonitriles,
which
are quite common
common substrates,
substrates, especially
especially in multicomponent
multicomponent reactions
reactions [51],
[51], have
Isonitriles,
Isonitriles, which
which are
are quite
quite common substrates,
especially in
in multicomponent reactions
[51], have
have
been
seldom
used
for
the
preparation
of
aminobisphosphonates
18.
Their
reactions
with
H-phosphine
been
seldom
used
for
the
preparation
of
aminobisphosphonates
18.
Their
reactions
with
H-phosphine
been seldom used for the preparation of aminobisphosphonates 18. Their reactions with H-phosphine
oxides carried out
out in the
the presence of
of typical palladium
palladium catalysts (Pd
(Pd22dba
dba33)) afforded
afforded the
the product
product 19
19
oxides
oxides carried
carried out in
in thepresence
presence oftypical
typical palladiumcatalysts
catalysts (Pd
2 dba3 ) afforded the product
of monophosphonylation,
monophosphonylation, whereas
whereas the
the use
use of
of various rhodium
rhodium catalysts afforded
afforded products of
of
of
19
of monophosphonylation,
whereas the
use ofvarious
various rhodiumcatalysts
catalysts afforded products
products of
diphosphonylation
(Scheme
11)
[52].
diphosphonylation
(Scheme 11)
11) [52].
[52].
diphosphonylation (Scheme
Far simpler is the addition of diethyl phosphite to isonitriles. This reaction
is carried out with
O
H
1 O
O
O
R
H
1
O
O chloridePd
N
P nitrile
an excess of hydrogen
incat.
aprotic solvents. Under
conditions,
is converted to
R P
Rh cat.
cat.
R11 these
N
R11 P
Rh
R
+
H P
P R
Pd cat.
R NC
NC +
N
R22
R
R
H
R
N
R
2P
2
R
an onium salt, andR2after
addition
of
the
first
phosphite
molecule,
iminium
salt
is
formed,
a substrate
R2
R
P 1
R
R
O P2 R
R1
19
O
for the addition of a second
phosphite
molecule
(Scheme
12)
[53].
Using
this
procedure,
two
distinct
R2
19
R
18
libraries of bisphosphonates 20 and 21 have
been prepared [54–56].
18
Et
Et N
,, N
Et
Et
1
R
1 = CH3, t-butyl, cyclohexyl, aryl
R 2 = CH3, t-butyl, cyclohexyl, aryl
= CH
CH3,, t-butyl,
t-butyl, cyclohexyl,
cyclohexyl, aryl
aryl
R2 =
R
,,
R=
=
R
,,
3
Scheme 11.
11. Addition
Addition of
of H-phosphine
H-phosphine oxides
oxides to
to isonitriles
isonitriles catalyzed
catalyzed by
by metallocatalysts.
metallocatalysts.
Scheme
Isonitriles, which are quite common substrates, especially in multicomponent reactions [51], have
been seldom used for the preparation of aminobisphosphonates 18. Their reactions with H-phosphine
oxides carried out in the presence of typical palladium catalysts (Pd2dba3) afforded the product 19
of monophosphonylation,
whereas the use of various rhodium catalysts afforded products
Molecules
2016, 21, 1474
7 of of
26
diphosphonylation (Scheme 11) [52].
O
R P
N
R
R2
Molecules 2016, 21, 1474
19
Pd cat.
1
O
1
H P R
2
R
R NC +
Rh cat.
O
R1 P
R2
H
N
R
P
O 2 R1
R
18
Et
7 of 25
, to isonitriles. This reaction is carried out with an
, N
Far simpler is the
phosphite
R = addition, of diethyl
Et
excess of hydrogen chloride
in
aprotic
solvents.
Under
these conditions, nitrile is converted to an
R1 = CH3, t-butyl, cyclohexyl, aryl
2addition of the first phosphite molecule, iminium salt is formed, a substrate for
onium salt, and after
R = CH3, t-butyl, cyclohexyl, aryl
the addition of a second phosphite molecule (Scheme 12) [53]. Using this procedure, two distinct
11.
H-phosphine
oxides
to
catalyzed
by metallocatalysts.
metallocatalysts.
Scheme
11. Addition
Addition
ofand
H-phosphine
oxides
to isonitriles
isonitriles
catalyzed by
libraries ofScheme
bisphosphonates
20of
21 have been
prepared
[54–56].
R N C
R
R
HCl
R N C H
N
P(OEt)3
OEt
H
Cl
Cl
R = alkyl, Ph(CH2)nn = 0-3
H
P
OEt
OEt
N
OEt
P
OEt
O
HCl
R
(EtO)2(O)P
NH
20
P(OEt)3
P(O)(OEt)2
R
H
N
H
Cl
OEt
P
OEt
O
R
C=N
HCl/P(OEt)3
N=C
(EtO)2(O)P HN
NH
(EtO)2(O)P
P(O)(OEt)2
21
=
X
n
n
,
,
,
R1
,
R1
,
n
n
, -(CH2)m-
n =0, 1
m=6
X= -CH2-, -CH2CH2-, O, S, SO2
R1= H, OCH3
Scheme
Scheme 12.
12. Addition
Addition of
of phosphites
phosphites to
to isonitriles.
isonitriles.
2.5. Synthesis via Ketophosphonates
2.5. Synthesis via Ketophosphonates
Presumably, the addition of phosphites to ketophosphonates was the first procedure for
Presumably, the addition of phosphites to ketophosphonates was the first procedure for
preparation of dialkyl 1-hydroxy-1,1-bisphosphonates [16,19,57]. Starting ketophosphonates are
preparation of dialkyl 1-hydroxy-1,1-bisphosphonates [16,19,57]. Starting ketophosphonates are
obtained by the Arbuzov reaction of acyl chlorides with trialkyl phosphites and used as substrates in the
obtained by the Arbuzov reaction of acyl chlorides with trialkyl phosphites and used as substrates in the
next step, namely, the addition of dialkyl phosphite to carbonyl double bonds (a representative example
next step, namely, the addition of dialkyl phosphite to carbonyl double bonds (a representative example
for preparation of tetramethyl pamidronate 22 is shown in Scheme 13). Since ketophosphonates are
for preparation of tetramethyl pamidronate 22 is shown in Scheme 13). Since ketophosphonates
unstable species [58], the desired bisphosphonates are usually obtained via one-pot procedures
are unstable species [58], the desired bisphosphonates are usually obtained via one-pot procedures
applying mixtures of trialkyl- and dialkylphosphonates at elevated temperature [59]. Additionally, in
applying mixtures of trialkyl- and dialkylphosphonates at elevated temperature [59]. Additionally, in
situ generation of dialkyl- from trialkyl phosphites is possible by the addition of a protic solvent to the
situ generation of dialkyl- from trialkyl phosphites is possible by the addition of a protic solvent to
reaction mixture. A useful modification of this procedure is the application of tris(trimethylsilyl)
the reaction mixture. A useful modification of this procedure is the application of tris(trimethylsilyl)
phosphite, followed by the easy removal of ester groups by methanolysis [23,60,61]. This was used to
phosphite, followed by the easy removal of ester groups by methanolysis [23,60,61]. This was used
prepare a wide variety of 1-hydroxy-1,1-bisphosphonates containing amino groups [19,23,61–63].
to prepare a wide variety of 1-hydroxy-1,1-bisphosphonates containing amino groups [19,23,61–63].
Additionally, the use of bis((trimethylsilyl)oxy)phosphine generated from ammonium hypophosphite
Additionally, the use of bis((trimethylsilyl)oxy)phosphine generated from ammonium hypophosphite
was applied to prepare hydroxybisphosphinic acids (also presented in Scheme 13) [64]. Another
was applied to prepare hydroxybisphosphinic acids (also presented in Scheme 13) [64]. Another
modification was the use of acyl phosphonamidates readily prepared from phosphoramidite type
modification was the use of acyl phosphonamidates readily prepared from phosphoramidite type
reagents and a range of acid chlorides, followed by reaction with trimethyl phosphite in the presence
of pyridinium perchlorate [65].
Molecules 2016, 21, 1474
8 of 26
reagents and a range of acid chlorides, followed by reaction with trimethyl phosphite in the presence
of
pyridinium
[65].
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2016, 21,perchlorate
1474
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Molecules 2016, 21, 1474
8 of 25
O
O
H2N
H2N
O
O
P(OMe)3
P(OMe)3
Cl
Cl
H2N
H2N
P(O)(OMe)2
P(O)(OMe)2
HP(O)(OMe)2
HP(O)(OMe)2 H2N
H2N
O
O
N
N
H
H
N
N
H
H
HO
HO P(O)(OMe)2
P(O)(OMe)2
P(O)(OMe)2
P(O)(OMe)2
22
22
Cl
Cl
or
or
O
O
B
O B
O
1./ P(OSiMe3)3
1./ P(OSiMe3)3
2./ MeOH
2./ MeOH
N
N
H
H
HO
HO P(O)(OH)2
P(O)(OH)2
P(O)(OH)2
P(O)(OH)2
23
23
Scheme
13. Representative
syntheses via
via ketophosphonates.
ketophosphonates.
Scheme 13.
13.
Representative syntheses
syntheses
Scheme
Representative
via ketophosphonates.
Recently, a one-pot synthesis was described reacting carboxylic acids with catecholborane, followed
Recently,
synthesis
waswas
described
reacting
carboxylic
acids with
catecholborane,
followed
Recently, aaone-pot
one-pot
synthesis
described
reacting
carboxylic
acids
with catecholborane,
by the treatment of the formed acyloxy-benzodioxaborolane with tris(trimethylsilyl)phosphite
by
the
treatment
of
the
formed
acyloxy-benzodioxaborolane
with
tris(trimethylsilyl)phosphite
followed by the treatment of the formed acyloxy-benzodioxaborolane with tris(trimethylsilyl)phosphite
(Scheme 13) [66]. The efficiency of that simple methodology was proved by the syntheses of alendronate
(Scheme 13) [66]. The efficiency of that simple methodology was proved by the syntheses of alendronate
and N-methyl pamidronate (compound 23) without additional steps for the protection/deprotection
and N-methyl pamidronate (compound 23) without
without additional
additional steps
steps for
for the
the protection/deprotection
protection/deprotection
of their amine functions.
of their amine functions.
2.6. Three-Component Condensation of Amines with Triethyl Orthoformate and Diethylphosphite
2.6. Three-Component Condensation of Amines with Triethyl
Triethyl Orthoformate
Orthoformate and
and Diethylphosphite
Diethylphosphite
Simple three-component condensation of stoichiometric ratios of amines, diethyl phosphite
condensation of stoichiometric
Simple three-component condensation
stoichiometric ratios of amines, diethyl phosphite
and triethyl orthoformate, first reported in patent literature by Suzuki [67] and further extended by
triethyl orthoformate,
orthoformate,first
firstreported
reportedininpatent
patentliterature
literature
Suzuki
[67]
and
further
extended
and triethyl
byby
Suzuki
[67]
and
further
extended
by
Maier [68], is perhaps the most common procedure for the preparation of a wide variety of
by Maier
is perhaps
most
commonprocedure
procedurefor
forthe
thepreparation
preparationofof aa wide
wide variety
variety of
Maier
[68],[68],
is perhaps
thethe
most
common
aminomethylenebisphosphonic acids (Scheme 14). Since this reaction usually gives a complex mixture
aminomethylenebisphosphonic acids (Scheme 14). Since this reaction usually gives a complex mixture
of products [56] that are difficult to separate, the resulting esters are not isolated but rather, the crude
of products [56] that are difficult to separate, the resulting esters are not isolated but rather, the crude
reaction mixtures are hydrolyzed, yielding bisphosphonic acids that are isolated after the hydrolytic
reaction mixtures are hydrolyzed, yielding bisphosphonic acids that are isolated after the hydrolytic
step. Some modifications of this classic procedure have also been reported. They include the use of a
step. Some modifications of this classic procedure have also been reported. They include the use of a
solvent-free, microwave-assisted reaction [69–71] and reactions catalyzed by titanium dioxide [72] and
solvent-free, microwave-assisted reaction [69–71] and reactions catalyzed by titanium dioxide [72] and
by crown ethers (increasing the selectivity of the process by 10%–20%) [73]. Additionally, a reaction
by crown ethers (increasing the selectivity
selectivity of the process by 10%–20%) [73]. Additionally, a reaction
carried out in a micellar environment was described [74].
carried out in a micellar environment was described [74].
R NH + H-C(OEt) + HP(O)(OEt)
R NH22 + H-C(OEt)33 + HP(O)(OEt)22
1./
1./
2./ HCl/H O
2./ HCl/H22O
R = over 300 structurally variable substituents
R = over 300 structurally variable substituents
PO H
PO33H22
R
R N
PO H
N
PO33H22
H
H
Scheme 14. Condensation of amines with triethyl orthoformate and diethyl phosphite.
Scheme
phosphite.
Scheme 14.
14. Condensation
Condensation of
of amines
amines with
with triethyl
triethyl orthoformate
orthoformate and
and diethyl
diethyl phosphite.
The three-component reaction was applied to synthesize a large series of physiologically active
The three-component reaction was applied to synthesize a large series of physiologically active
The three-component
was applied
to synthesize
a large
seriesbone
of physiologically
compounds,
in some cases reaction
of very complex
chemical
structures,
including
antiresorptiveactive
drug
compounds, in some cases of very complex chemical structures, including bone antiresorptive drug
compounds,
in some
cases
of very[83,84],
complex
chemical structures,
including bone
antiresorptive
candidates [75–82];
bone
imaging
antiprotozoal
[85–88], antibacterial
[72,89–92],
anti-HIVdrug
[93]
candidates [75–82]; bone imaging [83,84], antiprotozoal [85–88], antibacterial [72,89–92], anti-HIV [93]
candidates
[75–82];
bone
imaging
[83,84],
antiprotozoal
[85–88],
antibacterial
[72,89–92],
anti-HIV
[93]
and anti-inflammatory [94] agents; herbicides [95–97]; and complex ones for various metals [10,98].
and anti-inflammatory [94] agents; herbicides [95–97]; and complex ones for various metals [10,98].
and anti-inflammatory
agents;
herbicides
and complex
ones forunexpected
various metals
[10,98].
In some cases, this[94]
reaction
appears
to be [95–97];
quite capricious
and affords
side-products
In some cases, this reaction appears to be quite capricious and affords unexpected side-products
some
this reaction
appears to be quite capricious
and affords unexpected
side-products
alongInwith
thecases,
expected
aminomethylenebisphosphonates
(see representative
examples in
Scheme 15),
along with the expected aminomethylenebisphosphonates (see representative examples in Scheme 15),
along
with the expected
aminomethylenebisphosphonates
(seeconditions
representative
examples
15),
the compositions
of which
are dependent on the applied
(molar
ratio in
of Scheme
substrates,
the compositions of which are dependent on the applied conditions (molar ratio of substrates,
the
compositions
of whichtime).
are dependent
the applied
(molar ratio 24
of and
substrates,
temperature
and reaction
Most often,onalkylation
(forconditions
example, compounds
25) or
temperature and reaction time). Most often, alkylation (for example, compounds 24 and 25) or
temperature
and reaction
Most
often,is alkylation
(for example,
compounds
25) or
formylation (compound
26)time).
of amine
moieties
observed [71,99],
while in selected
cases24
theand
formation
formylation (compound 26) of amine moieties is observed [71,99], while in selected cases the formation
formylation
(compound 26) of amineacid
moieties
is observed
while in
selectedthis
cases
the formation
of aminomethylenebisphosphonic
(compound
27) [71,99],
is observed.
Because
compound
was
of aminomethylenebisphosphonic acid (compound 27) is observed. Because this compound was
of
aminomethylenebisphosphonic
acidof(compound
27) is observed. Because this compound
was
previously
prepared by acid hydrolysis
N-benzhydrylaminomethylenebisphosphonic
acid [83,100],
previously prepared by acid hydrolysis of N-benzhydrylaminomethylenebisphosphonic acid [83,100],
previously
prepared
by acid
hydrolysis
of N-benzhydrylaminomethylenebisphosphonic
acid [83,100],
it may be that
it is formed
upon
hydrolysis
of N-aryl derivatives.
it may be that it is formed upon hydrolysis of N-aryl derivatives.
it may be that it is formed upon hydrolysis of N-aryl derivatives.
Molecules 2016, 21, 1474
Molecules 2016, 21, 1474
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9 of 25
Molecules 2016, 21, 1474
NH2
N
N
H
N
HC(OEt)3
H PO H
3 2H
N
PO
3
N
NH2 HP(O)(OEt)2
HC(OEt)3
N
HP(O)(OEt)2
H
N
PO3H
H
N
N
PO
PO33HH2
N
24
PO3H2
9 of 25
PO3H
PO3H2
24
P(O)(OEt)2
HC(OEt)3
NH2 HP(O)(OEt)
HC(OEt)32
NH2 HP(O)(OEt)
2
N P(O)(OEt)
P(O)(OEt)
2 2
+
H
N
P(O)(OEt)2
H
N P(O)(OEt)
P(O)(OEt)
2
2
N
PO3H2
NH2
P(O)(OEt)2
25
H
HC(OEt)3 2
NH2 HP(O)(OEt)
HP(O)(OEt)2
N
H
+
PO3H2
ON
26
PO3H2
+
+
P(O)(OEt)
N
P(O)(OEt)
2
2
+
25
H2 H
N PO3PO
3 2
HC(OEt)3
P(O)(OEt)2
P(O)(OEt)2
+
O
26
P(O)(OEt)2
H
H
2 H
H2NPO3H
PO
3 2
H2N
27
PO3H2
27
Scheme 15.
15. Representative
three-component procedure
for the
the synthesis
synthesis of
of
Scheme
Representative side
side products
products of
of the
the three-component
procedure for
Scheme 15. Representative side
products of the three-component procedure for the synthesis of
aminomethylenebisphosphonic
acids.
aminomethylenebisphosphonic acids.
aminomethylenebisphosphonic acids.
31P-NMR and by
The mechanism of this useful reaction had been thoroughly studied by using 31
The
mechanism
studiedby
byusing
using31P-NMR
P-NMR
and
The
mechanismofofthis
thisuseful
usefulreaction
reaction had
had been
been thoroughly
thoroughly studied
and
byby
isolation of all intermediates [71,72,99] and identifying interrelations between them (Scheme 16) [99].
isolation
of
all
intermediates
[71,72,99]
and
identifying
interrelations
between
them
(Scheme
16)
[99].
isolation of all intermediates [71,72,99] and identifying interrelations between them (Scheme 16) [99].
The mechanism appeared to be quite complex because the intermediates exist in thermodynamic
The
mechanism
the intermediates
intermediatesexist
existininthermodynamic
thermodynamic
The
mechanismappeared
appearedtotobe
bequite
quitecomplex
complex because
because the
equilibrium. Thus, its course is strongly dependent on the properties of the used amine and applied
equilibrium.
Thus,
on the
the properties
propertiesofofthe
theused
usedamine
amine
and
applied
equilibrium.
Thus,itsitscourse
courseisisstrongly
strongly dependent
dependent on
and
applied
reaction conditions.
reaction
conditions.
reaction
conditions.
OEt
HC OEt
HC OEt
OEt
EtO
EtO
NH2
R NH2
R
H
HN
RN
-- EtOH
EtOH
R-NH
R-NH22
R
OEt
OEt
EtOH
--EtOH
-- 22 EtOH
EtOH
HH
NN
RR
NN
RR
HH
H
P OEt
EtO
OEt
O
O
H
HN
P(O)(OEt)
P(O)(OEt)22
RN
R
HN
HN R
EtO
EtO
H
NH
R N
R-NH
R-NH22
R
P(O)(OEt)2
P(O)(OEt)2
OEt
- EtOH
- R-NH2
- R-NH2
- EtOH
R
R
R=
NN
RR
OEt
R
R=
OEt
OEt
N
N
NO2
P(O)(OEt)2
P(O)(OEt)2
H
H OEt
EtO P
O
P
EtO
OEt
O
NO2
H
N
R H
R
P(O)(OEt)2
N P(O)(OEt)
P(O)(OEt)
2 2
P(O)(OEt)
2
Scheme 16. Mechanism of the three-component reaction of
amines with orthoformates and phosphites.
Scheme 16. Mechanism of the three-component reaction of amines with orthoformates and phosphites.
Scheme 16. Mechanism of the three-component reaction of amines with orthoformates and phosphites.
Molecules 2016, 21, 1474
10 of 26
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10 of 25
Modification
of this procedure and the use of ethyl diethoxymethyl-H-phosphinate10 instead
Molecules
2016, 21, 1474
of 25
Modification of this procedure and the use of ethyl diethoxymethyl-H-phosphinate instead of
of diethyl phosphite allowed obtaining structurally variable bisphosphinates 28 (Scheme 17) [101].
diethyl
phosphite allowed
obtaining structurally
variable
bisphosphinates 28 (Scheme 17) [101].
Better
Modification
of this procedure
and the
of ethyl
instead
ofand
Better results
were obtained
if the reaction
wasuse
carried
outdiethoxymethyl-H-phosphinate
under nitrogen (air oxidizes substrates
results
were
obtained
if
the
reaction
was
carried
out
under
nitrogen
(air
oxidizes
substrates
and
diethyl
phosphite
allowed
obtaining
structurally
variable
bisphosphinates
28
(Scheme
17)
[101].
Better
products). Notably, aromatic amines provided the desired bisphosphinates in high yields (78%–92%),
products).
Notably,
aromatic
amines
provided
the desired
bisphosphinates
inoxidizes
high yields
(78%–92%),
resultsthe
were
obtained
if the
reaction
was
carried
out under
nitrogen (air
substrates
and of
whereas
reaction
yields
when
using
cyclic
and
aliphatic
derivatives
were
lower.
Interestingly,
whereas
the
reaction
yields
when
using
cyclic
and
aliphatic
derivatives
were
lower.
Interestingly,
of
products). Notably, aromatic amines provided the desired bisphosphinates in high yields (78%–92%),
many
methods
forfor
thethe
synthesis
ofofcorresponding
acids
29,acidolysis
acidolysisofofthe
theobtained
obtained
esters
28 appeared
many
methods
synthesis
corresponding
acids
29,
esters
28
appeared
whereas the reaction yields when using cyclic and aliphatic derivatives were lower. Interestingly, of
to be
optimal.
The
use
ofofother
conditions, including
mild transesterification
transesterification with
trimethylsilyl
to
be methods
optimal.
The
use
other
including
trimethylsilyl
many
for
the
synthesis
of conditions,
corresponding
acids 29,mild
acidolysis of the obtainedwith
esters
28 appeared
bromide
followed
byby
methanolysis,
ofside
sideproducts
products3030
and
bromide
followed
methanolysis,resulted
resultedin
in the
the formation
formation of
and
31.31.
to be optimal. The use of other conditions, including mild transesterification with trimethylsilyl
bromide followed by methanolysis, resulted in the formation of side products
30 and 31.
1
2
H
N 2
R1
R
H
1 N
R
R2
OEt
H
+ HC(OEt)3 +
EtO OEtP
OEt
O H
+ HC(OEt)3 +
EtO
P
OEt
O
1./ Me3SiBr/CH2Cl2/N2
2./ aq. NH3
1./ Me3SiBr/CH2Cl2/N2
2./ aq. NH3
H
R1
H
N
1
H H
H R
P N P
HO
O
O
OH
H
H
P
P
29O OH
HO O
29
R1
NH
O
R R
OEt N
OEt
R1 R2
EtO OEtP N P OEtOEt
EtO O O OEt
EtO
P
P
OEt
28
EtO O O OEt
28 HBr/CH COOH/rt
3
HBr/CH3COOH/rt
R1
+ H R1
+ H2N P H
H
O
P N P
O OH
+ HO
+ H2N P H
H O O OH
H
N
R2
1
2
H R R H
P N P
HO
P
P
H O O OH
H
31O OH
30
P 29 P
HO O O OH
HO O O OH
31 R1 = aryl, cycloalyk, alkyl
30
29
R2 = H, i-Pr
1
R = aryl, cycloalyk, alkyl
R2 = H, i-Prof aminobisphosphonates.
Scheme 17. Three-component synthesis
Scheme 17. Three-component synthesis of aminobisphosphonates.
Scheme 17. Three-component synthesis of aminobisphosphonates.
2.7. Addition of Amines to Vinylidenebisphosphonates
2.7. Addition of Amines to Vinylidenebisphosphonates
2.7. Addition
of Amines
to Vinylidenebisphosphonates
Tetraethyl
vinylidenebisphosphonate
32 is a versatile synthon useful for preparation of a wide
Tetraethyl
vinylidenebisphosphonate
is a versatile
synthon
useful for preparation
of aan
wide
variety
of bisphosphonates.
Its usefulness 32
is
of recent
comprehensive
review [102].
Tetraethyl
vinylidenebisphosphonate
32aissubject
a versatile
synthon
useful for preparation
of aAs
wide
variety
of
bisphosphonates.
Its
usefulness
is
a
subject
of
recent
comprehensive
review
[102].
As
an
electron-deficient
alkene, it can
undergo conjugate
addition
of strong
and mildreview
nucleophiles,
with
variety of bisphosphonates.
Its usefulness
is a subject
of recent
comprehensive
[102]. As
an
electron-deficient
alkene,
canclass.
undergo
conjugate
addition
of strong
and mild
nucleophiles,
with
amines
belonging
to the it
latter
Primary
amines addition
undergo of
smooth
addition
(Schemewith
18),
electron-deficient
alkene,
it can
undergo
conjugate
strongMichael
and mild
nucleophiles,
amines
belonging
to
the
latter
class.
Primary
amines
undergo
smooth
Michael
addition
(Scheme
18),
however,
the
obtained
compounds
33
must
be
quickly
purified
and
hydrolyzed
since
they
tend
to
amines belonging to the latter class. Primary amines undergo smooth Michael addition (Scheme 18),
however,
the
obtained
compounds
33
be
purified
and
hydrolyzed
since
they
tend
undergo
athe
retro-Michael
reaction [103,104].
free
acidsand
34 are
substantially
more
stable.
however,
obtained
compounds
33must
mustFortunately,
be quickly
quickly purified
hydrolyzed
since
they
tend
to to
undergo
a
retro-Michael
reaction
[103,104].
Fortunately,
free
acids
34
are
substantially
more
stable.
undergo a retro-Michael reaction [103,104]. Fortunately, free acids 34 are substantially more stable.
(EtO)2(O)P
(EtO)2(O)P
32
P(O)(OEt)2
RNH2/CH2Cl2
P(O)(OEt)2
r.t.
RNH2/CH2Cl2
r.t.
32
R = alkyl, cyckloalkyl, heterocycloalkyl, benzyl
(EtO)2(O)P
(EtO)2(O)P
P(O)(OEt)2
R
P(O)(OEt)
2
N
H
R
33
N
H
33
1./ Me3SiBr
H2O3P
PO3H2
2./ Me
MeOH
1./
3SiBr
H2O3P
PORH
N 3 2
H
R
N
34
H
34
2./ MeOH
R = alkyl, cyckloalkyl,
heterocycloalkyl,
benzyl of amines to vinylidenebisphosphonate.
Scheme
18. Michael addition
Scheme 18. Michael addition of amines to vinylidenebisphosphonate.
Scheme
18. Michael addition of amines
to vinylidenebisphosphonate.
The reactivity
of vinylidenebisphosphonates
has been
used for the synthesis of derivatives of
various
analogues
of
fluoroquinolone
antibacterial
agents
[105,106],
potential
The reactivity of vinylidenebisphosphonates has been used for heteroaromatics
the synthesis of with
derivatives
of
pharmaceutical
applications
[107,108],
simple
antiplasmodial
agents
[103,104],
HIV
reverse
transcriptase
The
reactivity
of
vinylidenebisphosphonates
has
been
used
for
the
synthesis
of
derivatives
various analogues of fluoroquinolone antibacterial agents [105,106], heteroaromatics with potential
inhibitors
[59,93],
potential
anti-osteoporotic
agents [109,110],
and[103,104],
N-alkylated
antitumor
pyridines
of various
analogues
of fluoroquinolone
antibacterial
agents
[105,106],
with
pharmaceutical
applications
[107,108],
simple antiplasmodial
agents
HIV heteroaromatics
reverse
transcriptase
[111].
Some
representatives
of
these
compounds
(35–39)
are
shown
in
Scheme
19.
potential
pharmaceutical
applications
[107,108],
simple
antiplasmodial
agents [103,104],
reverse
inhibitors
[59,93], potential
anti-osteoporotic
agents
[109,110],
and N-alkylated
antitumor HIV
pyridines
example,
albeit
far compounds
lessanti-osteoporotic
developed,
addition
of organometallic
amines
to
transcriptase
[59,93],
potential
agents
[109,110],
and N-alkylated
antitumor
[111].Another
Someinhibitors
representatives
of these
(35–39)isarethe
shown
in
Scheme
19.
vinylidenebisphosphonate
22
(Scheme
20)
[112].
Huisgen
copper-catalyzed
1,3-dipolar
cycloaddition
of
Another
example,
albeit far less
developed,
is the (35–39)
addition
organometallic
to
pyridines
[111]. Some
representatives
of these
compounds
areofshown
in Schemeamines
19.
this
bisphosphonate
to
azides
was
used
to
obtain
substrate
40
for
a
“click
reaction”.
This
reaction
vinylidenebisphosphonate
22 (Scheme
[112]. Huisgen
cycloaddition
of to
Another example, albeit
far less20)developed,
is copper-catalyzed
the addition of1,3-dipolar
organometallic
amines
yielded
compounds to
that
may was
be considered
aza-analogues
41for
of azoledronate
(Scheme
20)
[113].
this bisphosphonate
azides
used
obtain
substrate
40
“click reaction”.
This
reaction
vinylidenebisphosphonate
22 (Scheme
20) to
[112].
Huisgen
copper-catalyzed
1,3-dipolar
cycloaddition
Similar
substrates
could
also
obtained by aza-analogues
addition of propargylamine
to the
double20)
bond of
yielded
compounds
that
may be
be
(Scheme
of this
bisphosphonate
to azides
wasconsidered
used to obtain substrate41
40of
forzoledronate
a “click reaction”.
This [113].
reaction
vinylidenebisphosphonate
[114].
Similar substrates could also be obtained by addition of propargylamine to the double bond of
yielded compounds that may be considered aza-analogues 41 of zoledronate (Scheme 20) [113].
vinylidenebisphosphonate [114].
Similar substrates could also be obtained by addition of propargylamine to the double bond of
vinylidenebisphosphonate [114].
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Molecules 2016, 21, 1474
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Molecules 2016,
2016, 21,
21, 1474
1474
Molecules
11 of
of 25
25
11
O
HOOC
F
O
O
N
HOOC
HOOC
F
N
F
PO3H2
H
N
POPO
H 3H2
PO33H22
H
H
N
N agent
PO H
36, antiprotozoal
PO33H22
PO3H2
N
POPO
H 3H2
PO33H22
N
N
PO H
35, analog of CiprofloxacinPO33H22
N
N
N
N
35, analog of Ciprofloxacin
35, analog of Ciprofloxacin
H2N
H N
H22N
PO3H
N
F
F
F
N
N
36, antiprotozoal agent
36, antiprotozoal agent
PO3H2
H
N
N
N POPO
H 3H2
H
H
H PO33H22
H
N
N
N
N
PO
H
37, potential antiosteoporotic
N
N
PO33H22
H
H agent
H
H
37, potential antiosteoporotic agent
37, potential antiosteoporotic agent
HN
POPO
H 3H2
PO33H
PO H
PO33H22
38, anticancer agent
PO3H2
POPO
3H2 H
PO33H22
HN N
HN
PO3H2
S
N N PO3H2
N
N
39, inhibitor
S
N reverse transcriptase
Nof HIV
S
N
N
39, inhibitor of HIV reverse transcriptase
39, inhibitor
of HIVvia
reverse
transcriptase
bisphosphonates
obtained
addition
of
38, anticancer agent
38, anticancer
Scheme 19.
19. Representatives
ofofagent
useful
Scheme
Representatives
useful bisphosphonates obtained via addition of
vinylidenebisphosphonate.
Scheme
19.
Representatives
of
useful
bisphosphonates obtained
obtained via
via addition
addition of
of
vinylidenebisphosphonate.
Scheme 19. Representatives of useful bisphosphonates
vinylidenebisphosphonate.
vinylidenebisphosphonate.
(EtO)2(O)P
(EtO)2(O)P
P(O)(OEt)2 + H2N
amines
amines
amines
amines
to
to
to
to
P(O)(OEt)2
(EtO) (O)PHN P(O)(OEt)2
(EtO)22(O)P
P(O)(OEt)2
40
HN
HN
40
40
N3
(EtO) (O)P
P(O)(OEt) + H2N
(EtO)22(O)P 22 P(O)(OEt)22 +
H2N
22
22
N
N33
(EtO)2(O)P
P(O)(OEt)2
(EtO) (O)PHN P(O)(OEt)2
(EtO)22(O)P
P(O)(OEt)2
Scheme 20. An example of the synthesis of novel
HN
N
HN
N N
N
N
N41N
N N
41
bisphosphonates41
via
“click chemistry”.
Scheme 20.
20. An
An example
example of
of the
the synthesis
synthesis of
of novel
novel bisphosphonates
bisphosphonates via
via “click
“click chemistry”.
chemistry”.
Scheme
2.8. Miscellaneous Procedures
2.8. Miscellaneous
Miscellaneous
Procedures
2.8.
The desire toProcedures
obtain new aminobisphosphonate scaffolds for biological studies has stimulated
numerous
studies
on general
methods
of their synthesis.
The for
methods
discussed
are
mostly
The
desire
to
obtain
new aminobisphosphonate
aminobisphosphonate
scaffolds
for
biological
studieshere
has stimulated
stimulated
scaffolds
biological
studies
has
The desire to obtain new
new
aminobisphosphonate
designed
to
prepare
specific
scaffolds
or
are
applicable
only
to
specific,
if
not
unusual,
substrates.
numerous studies
studies on
on general
general methods
methods of
of their
their synthesis.
synthesis. The
The
methods
discussed
here are
are mostly
mostly
The methods
methods discussed
discussed here
numerous
synthesis.
Only sometoofprepare
them may
be considered
as novel,
general procedures.
designed
specific
scaffolds
or
are
applicable
only
to
specific,
if
not
unusual,
substrates.
unusual, substrates.
substrates.
designed to prepare specific scaffolds or are applicable only to specific, if not unusual,
of sodium
hypophosphite
terminal
alkynes in the presence of triethylborane,
OnlyRadical
some of
ofaddition
them may
may
be considered
considered
as novel,
novel,to
general
procedures.
some
them
be
as
general
procedures.
Only
general
procedures.
which
produced
1-alkyl-1,1-bis-H-phosphinates
yields, in
gives
to of
a wide
structural
Radical
addition
of sodium
sodium hypophosphite
hypophosphite in
to moderate
terminal alkynes
alkynes
the access
presence
triethylborane,
alkynes in
triethylborane,
Radical
addition
of
to
terminal
the
presence
of triethylborane,
varietyproduced
of bisphosphonates
[115]. When using propargylamino
acids, the
corresponding
bisphosphinates
which
1-alkyl-1,1-bis-H-phosphinates
in moderate
moderate
yields,
gives
access
toaccess
widetostructural
structural
which
produced1-alkyl-1,1-bis-H-phosphinates
1-alkyl-1,1-bis-H-phosphinates
in moderate
yields,
gives to
a wide
produced
in
yields,
gives
access
aa wide
were
obtained
in
satisfactory
yields
(a
representative
example
is
given
in
Scheme
21
for
analogue
42
variety
of
bisphosphonates
[115].
When
using
propargylamino
acids,
the
corresponding
bisphosphinates
structural
variety
of
bisphosphonates
[115].
When
using
propargylamino
acids,
the
corresponding
variety of bisphosphonates [115]. When using propargylamino acids, the corresponding bisphosphinates
of pamidronate).
Bisphosphinates
are
convertedexample
to bisphosphonates
by ozonolysis.
were
obtained in
inwere
satisfactory
yields
(a easily
representative
is given
given
in Scheme
Scheme
21 in
forScheme
analogue
42
bisphosphinates
obtainedyields
in satisfactory
yields (a representative
example
is given
21 for
were
obtained
satisfactory
(a
representative
example is
in
21
for
analogue
42
of
pamidronate).
Bisphosphinates
are
easily
converted
to
bisphosphonates
by
ozonolysis.
analogue
42 of pamidronate).
Bisphosphinates
are easilytoconverted
to bisphosphonates
by ozonolysis.
of
pamidronate).
Bisphosphinates
are easily converted
bisphosphonates
by ozonolysis.
P(O)(OH)(ONa)
H2N
H N
H22N
NaH2PO2
Et3BPO
NaH
NaH22PO22
Et B
Et33B
H2N
H N
H22N
Scheme 21. Procedure for the synthesis of bisphosphinates
P(O)(OH)(ONa)
P(O)(OH)(ONa)
P(O)(OH)(ONa)
42 P(O)(OH)(ONa)
P(O)(OH)(ONa)
42
42their conversion
and
into bisphosphonates.
Scheme 21.
21. Procedure for
for the synthesis
synthesis of bisphosphinates
bisphosphinates and
and their
their conversion
conversion into
into bisphosphonates.
bisphosphonates.
Scheme
Scheme 21.Procedure
Procedure forthe
the synthesis of
of bisphosphinates and
their conversion
into bisphosphonates.
1-(N-acylamino)alkylphosphonates, easily accessible from N-acyl-α-amino acids using a
two-step
transformation, underwent electrophilic
activation
at the
α-carbon by electrochemical
1-(N-acylamino)alkylphosphonates,
easily accessible
accessible
from
N-acyl-α-amino
acids using
using aa
1-(N-acylamino)alkylphosphonates,
easily
from
N-acyl-α-amino
acids
1-(N-acylamino)alkylphosphonates,
easily
accessible
from
N-acyl-α-amino
acids
using
a
two-step
α-methoxylation
in
methanol
in
a
process
mediated
by
NaCl.
Attempts
to
carry
out
a
Michaelistwo-step transformation,
transformation, underwent
underwent electrophilic
electrophilic activation
activation at
at the
the α-carbon
α-carbon by
by electrochemical
electrochemical
two-step
transformation,
underwent
electrophilic
activation
at theby
α-carbon
by electrochemical
α-methoxylation
Arbuzov-like reaction
of the
obtained
diethyl
1-(N-acetylamino)-1-methoxy-alkylphosphonates
with
α-methoxylation
in
methanol
in
a
process
mediated
NaCl.
Attempts
to
carry
out
Michaelisα-methoxylation in methanol in a process mediated by NaCl. Attempts to carry out aa Michaelistriethyl phosphite
failed;
however,
they
readily
reacted with triphenylphosphine (Scheme 22) [116].
Arbuzov-like
reaction
of
the
obtained
diethyl
1-(N-acetylamino)-1-methoxy-alkylphosphonates
with
Arbuzov-like reaction of the obtained diethyl 1-(N-acetylamino)-1-methoxy-alkylphosphonates with
The resulting
diethyl
1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate
tetrafluoroborates
triethyl
phosphite
failed;
however, they
they readily
readily reacted
reacted with
with triphenylphosphine
triphenylphosphine (Scheme
(Scheme
22) [116].
[116].
triethyl
phosphite
failed;
however,
22)
The
resulting
diethyl
1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate
tetrafluoroborates
The resulting diethyl 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates
Molecules 2016, 21, 1474
12 of 26
in methanol in a process mediated by NaCl. Attempts to carry out a Michaelis-Arbuzov-like reaction
of the obtained diethyl 1-(N-acetylamino)-1-methoxy-alkylphosphonates with triethyl phosphite
failed; however, they readily reacted with triphenylphosphine (Scheme 22) [116]. The resulting
Molecules 2016, 21, 1474
12 of 25
Molecules 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate
2016, 21, 1474
12 of 25
diethyl
tetrafluoroborates 43 reacted
smoothly
with trialkyl
dialkyl dialkyl
phosphonites
or alkyl
phosphinites
in the
presence
of
43
reacted smoothly
withphosphites,
trialkyl phosphites,
phosphonites
or alkyl
phosphinites
in the
presence
43
reacted
smoothly
with
trialkyl
phosphites,
dialkyl
phosphonites
or
alkyl
phosphinites
in
the
presence
Hünig’s
base
and
methyltriphenylphosphonium
44,
of
Hünig’s
base
and
methyltriphenylphosphoniumiodide
iodideas
ascatalysts.
catalysts. This
This gave
gave bisphosphonates
bisphosphonates 44,
of Hünig’s base and methyltriphenylphosphonium
iodide as catalysts.inThis
gave
bisphosphonates
44,
1-phosphinylalkylphosphonates
or
1-phosphinoylalkylphosphonates
good
yields.
This
reaction
has
1-phosphinylalkylphosphonates or 1-phosphinoylalkylphosphonates in good yields. This reaction
1-phosphinylalkylphosphonates
or 1-phosphinoylalkylphosphonates in good yields. This reaction
potential
to become
a general
procedure.
has potential
to become
a general
procedure.
has potential to become a general procedure.
O
O
H3C
H3C
R
R
N
H
N
H
1./ MeOH
MeOH
COOH 1./
-2e/-CO
2
COOH -2e/-CO2
O
O
R
R
H3C
H3C
N
H
N
H
OCH3
OCH3
O
O
PPh3/HBF4
PPh3/HBF4
H3C
H3C
R
R
N
PPh3
H
N
PPh3
BF4
H
BF4
43
43
P(OEt)3
P(OEt)3
O R PPh3 BF4
O R OMe
O
R
PPh3/HBF4
O R PPh3 BF4
O R OMe
MeOH/NaCl
O
R
PPh
/HBF
3
4
H3C
N
P(O)(OEt)2
H3C
N
P(O)(OEt)2 MeOH/NaClH3C
N
P(O)(OEt)2
H
H3C
N
P(O)(OEt)2
H
H3C
N
P(O)(OEt)2
H
H3C
N
P(O)(OEt)2
H
H
H
1 2 3
P(O)R1R2R3
P(O)R R R
O R P(O)R1R2
O R P(O)R1R2
H3C
N
P(O)(OEt)2
H
H3C
N
P(O)(OEt)2
H
44
44
R = H, CH3
R1==H,
CHPh
3
R
OEt,
R21 =
= OEt,
OEt, CH
Ph , Ph
R
3
2
= CH
OEt,, CH
R3 =
3, Ph
R
3 Et
R3 = CH3, Et
+ Ph3PR3BF4
+ Ph3PR3BF4
Scheme
22. Transformation
Transformationofof
diethyl
1-(N-acetylamino)-1-alkylphosphonates
bisphosphoric
Scheme 22.
diethyl
1-(N-acetylamino)-1-alkylphosphonates
intointo
bisphosphoric
acid
Scheme 22. Transformation of diethyl 1-(N-acetylamino)-1-alkylphosphonates into bisphosphoric
acid
viacorresponding
the corresponding
phosphonium
estersesters
via the
phosphonium
salts.salts.
acid esters via the corresponding phosphonium salts.
Alkylation of tetraalkyl methylenebisphosphonate 45, a classical method for synthesizing variable
Alkylation of tetraalkyl methylenebisphosphonate 45, a classical method for synthesizing variable
bisphosphonic acids, has been rarely used for the synthesis of amino derivatives. Thus, its direct
bisphosphonic acids, has been rarely used for the
the synthesis
synthesis of
of amino
amino derivatives.
derivatives. Thus, its direct
amination with the hydroxylamine ester of diphenylphosphinic acid, followed by its bromoacetylation
amination with the hydroxylamine ester of diphenylphosphinic acid, followed by its bromoacetylation
(Scheme 23), provided substrate 46 for functionalization into glycopeptide antibiotics, in the hope
(Scheme
functionalization
into
glycopeptide
antibiotics,
in the
that
(Scheme 23),
23),provided
providedsubstrate
substrate4646forfor
functionalization
into
glycopeptide
antibiotics,
in hope
the hope
that they will find an application as medication for osteomyelitis [117]. Another classical example is
they
will find
an application
as medication
for osteomyelitis
[117].
Another
classical
example
is the
that they
will find
an application
as medication
for osteomyelitis
[117].
Another
classical
example
is
the monoalkylation of tetraisopropyl methylenebisphosphonate with 1,6-dibromohexane, followed by
monoalkylation
of tetraisopropyl
methylenebisphosphonate
the monoalkylation
of tetraisopropyl
methylenebisphosphonatewith
with1,6-dibromohexane,
1,6-dibromohexane, followed
followed by
fluorination with Selectofluor and conversion of the remaining bromide into amine, which resulted in
fluorination with Selectofluor
Selectofluor and conversion
conversion of the remaining bromide into amine, which resulted in
compound 47 (Scheme 23) [118].
compound 47 (Scheme 23) [118].
(EtO)2(O)P
(EtO)2(O)P
P(O)(OEt)2 1./ NaH/DMF
1./Ph
NaH/DMF
P(O)(OEt)2 2./
2P(O)ONH2
45
2./ Ph2P(O)ONH2
45
Br
Br
Br
Br
H2N
H2N
(EtO)2(O)P
(EtO)2(O)P
P(O)(OEt)2 Br
P(O)(OEt)2 Br
NH2
NH2
Br
Br
P(O)(Oi-Pr)2
Selectofluor
P(O)(Oi-Pr)2
P(O)(Oi-Pr)2 Selectofluor
P(O)(Oi-Pr)2
47
47
P(O)(OH)2
P(O)(OH)
2
F
F
P(O)(OH)
2
P(O)(OH)2
Br
Br
(EtO)2(O)P
P(O)(OEt)2
(EtO)2(O)P
P(O)(OEt)2
HN
Br
HN
Br
O
O
46
46
P(O)(Oi-Pr)2
P(O)(Oi-Pr)
F
+2
F
+2
P(O)(Oi-Pr)
P(O)(Oi-Pr)2
Br
Br
H2NNH2
H2NNH2
O
O
O
O
N
N
O
O
O
O
NK
NK
O
O
P(O)(Oi-Pr)2
P(O)(Oi-Pr)
2
F
F
P(O)(Oi-Pr)
2
P(O)(Oi-Pr)2
Scheme 23. Synthesis of aminobisphosphonates via alkylation of tetraalkyl methylenebisphosphonates.
Scheme
of tetraalkyl
tetraalkylmethylenebisphosphonates.
methylenebisphosphonates.
Scheme23.
23.Synthesis
Synthesisofofaminobisphosphonates
aminobisphosphonates via
via alkylation
alkylation of
An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl
An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl
diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49
diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49
(Scheme 24) [119]. Among the tested catalysts, Rh2(NHCOCF3)4 was found to be the best.
(Scheme 24) [119]. Among the tested catalysts, Rh2(NHCOCF3)4 was found to be the best.
Molecules 2016, 21, 1474
13 of 26
An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl
diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49
(Scheme
24) 21,
[119].
Molecules 2016,
1474Among the tested catalysts, Rh2 (NHCOCF3 )4 was found to be the best.
13 of 25
Molecules 2016, 21, 1474
Molecules 2016, 21, 1474
(EtO)2(O)P
P(O)(OEt)2
(EtO)2(O)P
P(O)(OEt)2
(EtO)2(O)P N2 P(O)(OEt)2
N
2
48
N
482
48
R = H, CH3
1
R ==H,Ph,
CH3
OCH3 ,
R1==H,
CH3
R
Ph,
OCH3 ,
1
R = Ph,
OCH3 ,
1
R
R
R1 N
H R
1N
R
R
H
N
H
+
+
+
P(O)(OEt)2
Rh2(NHCOCF3)4 (EtO)2(O)P
(EtO)2(O)P
P(O)(OEt)2
Rh
2(NHCOCF3)4
toluene/
Rh2(NHCOCF3)4 (EtO)2(O)P1 N P(O)(OEt)2
R N R
toluene/
toluene/
R1 49
N R
R149 R
49
13 of 25
13 of 25
NO2 ,
NO2 ,
NO2 ,
Scheme 24.
24. N-H
the reaction
reaction of
of aromatic
aromatic amines.
amines.
Scheme
N-H insertion
insertion of
of the
Scheme 24. N-H insertion of the reaction of aromatic amines.
Scheme 24. N-H insertion of the reaction of aromatic amines.
A specific and unexpected reaction was the addition of silylated dialkyl phosphites to
A specific and unexpected reaction was the addition of silylated dialkyl phosphites to
4-phosphono-1-aza-1,3-dienes
50, reaction
which resulted
inaddition
γ-phosphono-α–aminobisphosphonates
A specific and unexpected
was thein
of silylated dialkyl phosphites 51
to
4-phosphono-1-aza-1,3-dienes
50, which
which resulted
γ-phosphono-α–aminobisphosphonates
4-phosphono-1-aza-1,3-dienes
50,
γ-phosphono-α–aminobisphosphonates
51
(Scheme
25)
[120].
This
reaction
is
interesting
in
that,
depending
on
the
steric
demand
of
the
substituent
4-phosphono-1-aza-1,3-dienes
which resulted in γ-phosphono-α–aminobisphosphonates
51
(Scheme
25) [120]. This reaction is50,
interesting
steric demand of the substituent
interesting
in that, 1,4-1,2-addition
depending on the
present
on
nitrogen,
double
1,2-addition
or tandem
with
formation
ofofbisphosphonate
(Scheme
25)
[120].
This
reaction
is
interesting
in
that,
depending
on
the
steric
demand
the
substituent
present on nitrogen, double 1,2-addition or tandem 1,4-1,2-addition with formation of bisphosphonate
52occurred
(Scheme double
25).
present
on nitrogen,
52
occurred
(Scheme 25).
25). 1,2-addition or tandem 1,4-1,2-addition with formation of bisphosphonate
52occurred
(Scheme
52occurred (Scheme 25).
N
N
(EtO)2(O)P
N H
(EtO)2(O)P
H
50
(EtO)2(O)P
H
50
50
(EtO)2P(O)SiMe3
(EtO)2P(O)SiMe3
(EtO)2P(O)SiMe3
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
HN
HN
HN P(O)(OEt)2
P(O)(OEt)
P(O)(OEt)
2 2
P(O)(OEt)
51 P(O)(OEt)
2 2
51 P(O)(OEt)2
51
N
(EtO)2(O)P
N
(EtO)2(O)P
(EtO)
N P(O)(OEt)2
(EtO)
2(O)P
2(O)P
(EtO)2(O)P
P(O)(OEt)2
52
(EtO)2(O)P
P(O)(OEt)2
52
52
4-phosphono-1-aza-1,3-dienes.
N
N
(EtO)2(O)P
N H
(EtO)2(O)P
50 H
(EtO)2(O)P
50 H
50
Scheme 25. Addition
(EtO)2P(O)SiMe3
(EtO)2P(O)SiMe3
(EtO)2P(O)SiMe3
of phosphites to
Scheme
Scheme 25.
25. Addition
Addition of
of phosphites
phosphites to
to 4-phosphono-1-aza-1,3-dienes.
4-phosphono-1-aza-1,3-dienes.
Scheme 25. Addition of phosphites to 4-phosphono-1-aza-1,3-dienes.
Additionally, the addition of phosphites to iminophosphonate esters has been studied. This
Additionally,
thespecific
addition
of phosphites
to iminophosphonate
esters has been
studied.
This
reaction
is limited to
substrates,
and usually
the obtained bisphosphonates
are unstable,
Additionally,
the addition
addition
phosphites
iminophosphonate
esters
has53been
studied.
the
ofofphosphites
to to
iminophosphonate
esters
has been
studied.
This
reaction
is
limited
to
specific
substrates,
and
usually
the
obtained
bisphosphonates
53
are
unstable,
and
phosphoryl
C-N
transfer
to substrates,
compounds
54usually
is observed
(Scheme
26), which may53
be
considered
This
reaction
is limited
to specific
and
obtained
bisphosphonates
53
are
unstable,
reaction
is limited
to specific
substrates,
and
usually
thethe
obtained
bisphosphonates
are
unstable,
and
phosphoryl
C-N
transferreaction
to compounds
54 is observed (Scheme 26), which may be considered
an example
of anC-N
aza-Perkov
[121–123].
and
phosphoryl
transfer
5454isisobserved
(Scheme
26),
which
may
be be
considered
an
phosphoryl
C-N
transfertotocompounds
compounds
observed
(Scheme
26),
which
may
considered
an example of an aza-Perkov reaction [121–123].
example
of an
reaction
[121–123].
an example
of aza-Perkov
an aza-Perkov
reaction
[121–123].
Cl
Cl
CCl3
CCl3
Cl Cl
HP(O)(OEt)2
(EtO)2(O)P CCl3 SO Ar
CCl3 SO2Ar
2
Cl
HP(O)(OEt)2
N
(EtO)
(O)P
(EtO)2(O)P CClN3
CClN3 SO Ar
2
(EtO)
(O)P
SO Ar
2
2
(EtO)2Cl
(O)P
H
HP(O)(OEt)2
N
(EtO)2(O)P
N
(EtO)2(O)P
N SO2 Ar
SO
Ar
(EtO)2(O)P H
2
(EtO)2(O)P 54
2
53 N
N
(EtO)2(O)P
N
(EtO)2(O)P H
(EtO)2(O)P
53
Ar = Ph, 4-Me-C6H4
54
53
54
Ar = Ph, 4-Me-C6H4
Ar = Ph, 4-Me-C
6H4 26. Addition of phosphites to iminophosphonates.
Scheme
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
SO2Ar
SO2Ar
SO2Ar
Scheme 26. Addition of phosphites to iminophosphonates.
Scheme 26.
26. Addition
of phosphites
phosphites to
to iminophosphonates.
iminophosphonates.
Scheme
Addition of
Finally, syntheses of rare aminomethyltrisphosphonates are presented in a recent review
Finally, syntheses
of rare
aminomethyltrisphosphonates
are presented in a recent
review
by Romanenko
and Kukhar
devoted
to applications of methylidynetrisphosphonates
[124].
Two
Finally, syntheses
of rare
aminomethyltrisphosphonates
are presented in a recent
review
by
Romanenko
and
Kukhar
devoted
to
applications
of
methylidynetrisphosphonates
[124].
Two
Finally,
syntheses
of
rare
aminomethyltrisphosphonates
are
presented
in
a
recent
review
procedures
for the
of bis- and
trisphosphonates
55 and 56 taken from this review
and
by Romanenko
andsynthesis
Kukhar devoted
to applications
of methylidynetrisphosphonates
[124]. Two
procedures
for
the
synthesis
of devoted
bisand to
trisphosphonates
and 56 taken from this review[124].
and
by
Romanenko
and
Kukhar
applications
of55 methylidynetrisphosphonates
described
in
patent
literature
are
depicted
in
Scheme
27.
procedures for the synthesis of bis- and trisphosphonates 55 and 56 taken from this review and
described
in patent
are depicted
Scheme
27.
Two
procedures
forliterature
the synthesis
of bis- in
and
trisphosphonates
55 and 56 taken from this review
described in patent literature are depicted in Scheme 27.
O 27.
and described in patent literature are depicted in Scheme
O
O
O
Ar
Ar N
Ar N
N
Cl
Cl
Cl
Cl
Cl
P(OEt)3/
P(OEt)
3/ 2
CH2Cl
P(OEt)
3/
CH2Cl
2
CH2Cl2
N
N
ClN
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
O N P(O)(OEt)2
P(OEt)3
N P(O)(OEt)2
0
P(OEt)
3
CH2Cl2/-40 C
N P(O)(OEt)2
P(OEt)
0 (EtO)2(O)P P(O)(OEt)2
3
CH2Cl2/-40 C
0 (EtO)2(O)P55P(O)(OEt)2
CH2Cl2/-40 C
(EtO)2(O)P55 P(O)(OEt)2
55
Ar
Ar N
Ar N
N
P(O)(OEt)2
Ar
Ar N P(O)(OEt)
P(O)(OEt)
2 2
H N P(O)(OEt)
Ar
2 2
P(O)(OEt)
P(O)(OEt)
2
H N P(O)(OEt)
P(O)(OEt)2
2
56
H
P(O)(OEt)2
56
56
aminomethyltrisphosphonates.
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)22
P(O)(OEt)2
P(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
CH
2Cl2/NaOH
HP(O)(OEt)
2
CH2Cl2/NaOH
CH2Cl2/NaOH
Scheme 27. Syntheses of
Scheme 27. Syntheses of aminomethyltrisphosphonates.
Scheme 26. Addition of phosphites to iminophosphonates.
Finally, syntheses of rare aminomethyltrisphosphonates are presented in a recent review
by Romanenko and Kukhar devoted to applications of methylidynetrisphosphonates [124]. Two
procedures
the synthesis of bis- and trisphosphonates 55 and 56 taken from this review
and
Molecules
2016, for
21, 1474
14 of
26
described in patent literature are depicted in Scheme 27.
O
Cl
O
CH2Cl2/-400C
(EtO)2(O)P P(O)(OEt)2
55
Cl
Cl
Ar
Cl
Ar
P(OEt)3/
CH2Cl2
N
Cl
N P(O)(OEt)2
P(OEt)3
N
N
P(O)(OEt)2
HP(O)(OEt)2
Ar
P(O)(OEt)2
CH2Cl2/NaOH
H
N
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
56
Scheme 27.
27. Syntheses
of aminomethyltrisphosphonates.
aminomethyltrisphosphonates.
Scheme
Syntheses of
Molecules 2016, 21, 1474
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3. Functionalization
Functionalizationof
ofAminobisphosphonates
Aminobisphosphonates
Bisphosphonates are known for their affinity to bone tissue, and thus their conjugation to
various drugs has been quite intensively
intensively studied; they are expected to serve as system-targeting
system-targeting
drugs [6]. Because
Because dronic acids are produced at industrial scale and are thus readily available and
inexpensive, they are most frequently used for
for that
that purpose.
purpose. However, their extreme hydrophilic
which
limits
thethe
useuse
of
character means
means that
that they
theyare
arepractically
practicallyinsoluble
insolubleininmost
mostorganic
organicsolvents,
solvents,
which
limits
aqueous
media
or or
requires
of
aqueous
media
requirestheir
theirconversion
conversioninto
intophosphonate
phosphonateesters
esters prior
prior to
to functionalization.
functionalization.
Unfortunately, the methods for direct esterification of phosphonate moieties are scarce and usually
must generally
generally be
be synthesized
synthesized independently.
independently.
give unsatisfactory results; these esters must
Methods for functionalizing aminobisphosphonic acids with structurally variable molecules
were recently reviewed [12]; therefore, in this review,
review, the
the methods
methods arbitrarily chosen as the most
are reported.
reported.
representative are
3.1. Direct Acylation of Aminobisphosphonic Acids
Direct acylation of aminobisphosphonic acids is difficult because this reaction is accompanied
accompanied
by the possible competitive acylation of phosphonic groups [125,126] and hydroxylic groups when
amino-1-hydroxy-1,1-bisphosphonic acids are substrates [126,127]. A representative example of this
reaction is given in Scheme 28 for
for alendronic
alendronic acid
acid 57.
57.
O
Cl
+ H2N
57
PO3H2
OH
PO3H2
aq. NaOH
O
N
H
PO3H2
OH
PO3H2
+
O
N
H
O
O
O
PO3H2
PO3H2
O
+
H2N
O
OH
P
OH
PO3H2
Scheme
acid with
with indication
indication of
of possible
possible side-products.
side-products.
Scheme 28.
28. Direct
Direct acylation
acylation of
of alendronic
alendronic acid
Acylation of dronic acid salts with acyl chlorides in sodium hydroxide in water or in
Acylation of dronic acid salts with acyl chlorides in sodium hydroxide in water or in water/propanol
water/propanol solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the
solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the solution results in the
solution results in the precipitation of the desired acids or their monosodium salts. To conjugate
precipitation of the desired acids or their monosodium salts. To conjugate aminobisphosphonic acids
aminobisphosphonic acids with molecules bearing carboxylic groups, classical coupling protocols
with molecules bearing carboxylic groups, classical coupling protocols used in peptide synthesis have
used in peptide synthesis have also been used. These include the activation of carboxylic groups
also been used. These include the activation of carboxylic groups with N,N’-dicyclohexylcarbodiimide
with N,N’-dicyclohexylcarbodiimide (DCC) [129,130]; the use of previously prepared succinimidate
(DCC) [129,130]; the use of previously prepared succinimidate esters to obtain 21 extremely complex
esters to obtain 21 extremely complex fluorescent imaging probes (representative examples of a
fluorescent imaging probes (representative examples of a green fluorescent dye 58 and a red fluorescent
green fluorescent dye 58 and a red fluorescent dye 59 are shown in Scheme 29) [131]; and
dye 59 are shown in Scheme 29) [131]; and N,N’-dicarbonylimidazole, which was used to conjugate
N,N’-dicarbonylimidazole, which was used to conjugate pamidronate to pullan (polysaccharide
composed of maltotriose units) [132] to obtain a system for bone regeneration.
N
HO
O
O
N
O
SO3H
water/propanol solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the
solution results in the precipitation of the desired acids or their monosodium salts. To conjugate
aminobisphosphonic acids with molecules bearing carboxylic groups, classical coupling protocols
used in peptide synthesis have also been used. These include the activation of carboxylic groups
with N,N’-dicyclohexylcarbodiimide (DCC) [129,130]; the use of previously prepared succinimidate
Molecules 2016, 21, 1474
15 of 26
esters to obtain 21 extremely complex fluorescent imaging probes (representative examples of a
green fluorescent dye 58 and a red fluorescent dye 59 are shown in Scheme 29) [131]; and
pamidronate
to pullan (polysaccharide
composed
of maltotriose
units) [132]
to obtain
a system for
N,N’-dicarbonylimidazole,
which was used
to conjugate
pamidronate
to pullan
(polysaccharide
bone
regeneration.
composed of maltotriose units) [132] to obtain a system for bone regeneration.
N
HO
O
O
N
O
SO3H
COOH
O
O
PO3H
HN
HO
N
S
O
OH
PO3H2
O
NH
N
H
N
OH
PO3H
H2O3P
OH
59, derivative of Rhodamine Red -X
58, derivative of Carboxyfluorescein
Scheme 29.
29. Representative
Representative fluorescent
fluorescent imaging
imaging probes
probes obtained
obtained via
via acylation
acylation of
of bisphosphonic
bisphosphonic acids
acids
Scheme
(green—carboxyfluoresceine fragment,
Red-X
fragment).
(green—carboxyfluoresceine
fragment,red—rhodamine
red—rhodamine
Red-X
fragment).
Molecules
2016, 21, 1474
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Acylation of aminobisphosphonic acids with small acids, such as acrylic acid [133], chloroacetic
acid [134] or succinic acid [135], provided useful substrates for further functionalization of larger
molecules, such as macrocycles devised for lanthanide ion
ion complexation,
complexation, chitosan,
chitosan, and
and hyaluronan.
hyaluronan.
Tetraethyl Aminobisphosphonates
3.2. Direct Acylation of Tetraethyl
Aminobisphosphonates
Esters are far more suitable substrates for acylation than free phosphonic acids, with tetraethyl
aminomethylenebisphosphonate
being the
the most popular substrate. ItIt has
has been
been used
used to obtain
aminomethylenebisphosphonate being
structurallyvariable
variableconjugates
conjugates
with
estradiol
(compounds
60,
6162and
62 in Scheme
30)
using
structurally
with
estradiol
(compounds
60, 61
and
in Scheme
30) using
classical
classical synthesis
peptide synthesis
agents
DCC
and (diphenylphosphoryl
DPPA (diphenylphosphoryl
azide)These
[136].
peptide
couplingcoupling
agents such
as such
DCC as
and
DPPA
azide) [136].
These
conjugates
were
synthesized
as
bone-specific
estrogens
in
the
hope
that
they
will
protect
elderly
conjugates were synthesized as bone-specific estrogens in the hope that they will protect elderly
women from bone loss resulting
resulting from
from osteoporosis.
osteoporosis.
O
O
O
O
PO3H2
N
H
O
PO3H2
60
HO
H2O3P
O
PO3H2
NH
61
HO
OH
O
H2O3P
H2O3P
N
H
O
O
62
Scheme
estrogens.
Scheme 30.
30. Representative
Representative structures
structures of
of bone-specific
bone-specific estrogens.
A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using a suitable
A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using
acid chloride as substrate [137], whereas radioligands, which are selectively bound to bone tissue,
a suitable acid chloride as substrate [137], whereas radioligands, which are selectively bound to
have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138] and antibacterial
bone tissue, have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138]
bisphosphonated benzoxazinorifamycin prodrugs using EDCl (1-ethyl-3-(3-dimethylaminopropyl)
and antibacterial bisphosphonated benzoxazinorifamycin prodrugs using EDCl (1-ethyl-3-(3carbodiimide) [139].
dimethylaminopropyl)carbodiimide) [139].
In this case, acylation of aminobisphosphonic acids with small acids was also applied as a
In this case, acylation of aminobisphosphonic acids with small acids was also applied as a starting
starting step to produce antibacterial agents against osteomyelitis [88] and bone imaging macrocycles
step to produce antibacterial agents against osteomyelitis [88] and bone imaging macrocycles [81],
[81], using acid chlorides as acylating agents.
using acid chlorides as acylating agents.
H
N
BnO
COOH
+
O
BnO
H2N
22
P(O)(OEt)2
OH
P(O)(OEt)2
HBTU
BnO
H
N
O
N
P(O)(OEt)2
OH
O
H2O3P
H2O3P
O
N
H
O
62
Scheme 30. Representative structures of bone-specific estrogens.
Molecules 2016, 21, 1474
16 of 26
A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using a suitable
DCC
as a coupling
diethyl
1-(2-aminoethylamino)-1,1-ethylbisphosphonate
was
acid Using
chloride
as substrate
[137],agent,
whereas
radioligands,
which are selectively bound to bone tissue,
acylated
by
structurally
variable
natural
acids,
such
as
folic
acid
[140,141],
ursulonic
and
betulinic
have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138] and antibacterial
acids
[142], and trolox
[141,143].
bisphosphonated
benzoxazinorifamycin
prodrugs using EDCl (1-ethyl-3-(3-dimethylaminopropyl)
Acylation[139].
of pamidronic acid ester 22 by using HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3carbodiimide)
tetramethyluronium
hexafluorophosphate)
was usedacids
to prepare
a catecholic
derivative,
which as
wasa
In this case, acylation
of aminobisphosphonic
with small
acids was
also applied
then
bound
surfaceantibacterial
of magneticagents
iron oxide
nanoparticles
(Scheme
31)bone
[144].
The particle
63 has
starting
steptotothe
produce
against
osteomyelitis
[88] and
imaging
macrocycles
been
designed
to
remove
uranyl
ions
from
blood.
[81], using acid chlorides as acylating agents.
H
N
BnO
COOH
+
O
BnO
H2N
22
P(O)(OEt)2
OH
P(O)(OEt)2
HBTU
BnO
O
H
N
N
H
O
BnO
P(O)(OEt)2
OH
P(O)(OEt)2
1./ H2/Pd-C
2./ TMSBr
HO
Molecules 2016, 21, 1474
HO
O
H
N
O
PO3H2
OH
PO3H2
N
H
16 of 25
Using DCC as a coupling agent, diethyl 1-(2-aminoethylamino)-1,1-ethylbisphosphonate was
Fe3O4
acylated by structurally variable natural acids, such as folic acid [140,141], ursulonic and betulinic
acids [142], and trolox [141,143].
O
PO3H2
H
O
OH
N
Acylation of pamidronic acid Feester
22
by
using
HBTU
(2-(1H-benzotriazol-1-yl)-1,1,3,3N
3O4
PO3H2
H
tetramethyluronium hexafluorophosphate) Owas used 63
to Oprepare a catecholic derivative, which was
then bound to the surface of magnetic iron oxide nanoparticles (Scheme 31) [144]. The particle 63 has
Scheme
31. Synthesis
of
bisphosphonate
functionalized magnetic
magnetic nanoparticles.
nanoparticles.
31.
Synthesis
of bisphosphonate
been designedScheme
to remove
uranyl ions
from blood. functionalized
3.3. Synthesis of Building Blocks for Polymer Chemistry
Self-etching adhesives are polymeric materials containing phosphonate groups that have become
popular in restorative dentistry because they allow strong bonds between dental hard tissues (enamel
and dentin). One
One possibility
possibility for
for their
their preparation
preparation is to obtain monomers containing phosphonic
groups [145].
Such
methacrylamide
monomers
64 and
65 were
by acylation
with suitable
[145]. Such methacrylamide monomers
64 and
65 synthesized
were synthesized
by acylation
with
acryloylchlorides
(Scheme 32)
[146]. Studies
of their
photopolymerization
indicated that
they maythat
be
suitable acryloylchlorides
(Scheme
32) [146].
Studies
of their photopolymerization
indicated
suitable
usepotential
in dentistry.
they mayfor
bepotential
suitable for
use in dentistry.
O
PO3H2
N
H
PO3H2
64
O
H2O3P
H2O3P
H
N
H
N
O
65
PO3H2
PO3H2
O
Scheme
32. Bisphosphonylated
monomers.
Scheme 32.
Bisphosphonylated methacrylamide
methacrylamide monomers.
A similar monomer, acryloylated pamidronate, has been used to obtain a hyaluronic acid
A similar monomer, acryloylated pamidronate, has been used to obtain a hyaluronic acid
derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate
derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate
ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic
ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic
acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as
acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as
a mediator for fast bone regeneration.
a mediator for fast bone regeneration.
By dispersion copolymerization of three monomers (methacrylate bisphosphonate 66,
By dispersion copolymerization of three monomers (methacrylate bisphosphonate 66, N-(3N-(3-aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33),
aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33), polymeric
polymeric nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing
nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing various
various polymerization parameters. By covalent attachment of a drug and/or a dye to amino groups
(such as a near IR fluorescent dye), a theranostic system may be obtained.
O
O
O
66
x
PO3H2
OH
PO3H2
H2O3P
PO3H2
O
NH2
PO3H2
derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate
ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic
acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as
a mediator for fast bone regeneration.
By 2016,
dispersion
copolymerization of three monomers (methacrylate bisphosphonate
Molecules
21, 1474
17 of66,
26
N-(3-aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33),
polymeric nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing
polymerization
parameters.
By covalent
attachment
of a drugofand/or
dye to aamino
as
various polymerization
parameters.
By covalent
attachment
a drugaand/or
dye togroups
amino(such
groups
a(such
nearas
IRafluorescent
dye),
a
theranostic
system
may
be
obtained.
near IR fluorescent dye), a theranostic system may be obtained.
O
O
O
PO3H2
OH
PO3H2
x
66
PO3H2
H2O3P
O
PO3H2
NH2
O
H2O3P H2N
NH2
H2O3P
O
H2N
H2O3P
67
O
O
O
H2O3P
O
PO3H2
NH2
O
O
H2N
H2O3P
4
68
O
PO3H2
PO
3H2
NH2
PO3H2
69
Scheme
potential dye
dye and
and drug
drug carriers.
carriers.
Scheme 33.
33. Synthesis
Synthesis of
of polymeric
polymeric nanoparticles
nanoparticles as
as potential
Macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized by means
Macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized by means
of Michael addition copolymerization of methylenebisacrylamide (MBA) with primary amines-6of Michael addition copolymerization of methylenebisacrylamide (MBA) with primary amines-6amino-1-hydroxyhexylidene-1,1-bisphosphonate and 4-ferrocenyl-butamidopropylamine [149]. The
amino-1-hydroxyhexylidene-1,1-bisphosphonate and 4-ferrocenyl-butamidopropylamine [149].
mass percentage incorporation of ferrocene analogues was found to be between 4%–5%, and 10%–12%
The mass percentage incorporation of ferrocene analogues was found to be between 4%–5%,
for bisphosphonate. Such polymers could be selectively bound to bone tissue and slowly release
and 10%–12% for bisphosphonate. Such polymers could be selectively bound to bone tissue and
anticancer ferrocene derivatives at this target site.
Moleculesrelease
2016, 21,anticancer
1474
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slowly
ferrocene derivatives at this target site.
3.4.
3.5. Miscellaneous
Other means to functionalize
functionalize amino
amino moieties
moieties are
are quite
quite scarce
scarce and
and dispersed.
dispersed. Classical ones
include
the
formation
of
Schiff
bases,
which
are
then
alkylated
[150]
or
reduced
[126],
and
synthesis
of
include the formation of Schiff bases, which are then alkylated [150] or reduced
[126],
and
synthesis
thioureido
derivatives
as intermediates
in the
preparation
of heterocyclic
compounds
[151–153].
of thioureido
derivatives
as intermediates
in the
preparation
of heterocyclic
compounds
[151–153].
The functionalization
functionalization
of polysaccharides
is the gateway
of aminobisphosphonates
into
of polysaccharides
is the gateway
of aminobisphosphonates
into nanoscience.
nanoscience.
For
example,
phosphonated
cellulose
was
utilized
to
obtain
nanocellulose
with
good
For example, phosphonated cellulose was utilized to obtain nanocellulose with good thermal
thermal
and potential
intumescent
properties.
It was synthesized
pulp via
stability stability
and potential
intumescent
properties.
It was synthesized
from birchfrom
pulp birch
via sequential
sequential
periodate and
oxidation
and reductive
using alendronate
57 as a phosphonating
periodate oxidation
reductive
aminationamination
using alendronate
57 as a phosphonating
reagent
reagent
34) After
[154]. high-pressure
After high-pressure
homogenization,
bisphosphonate
cellulose
nanofibers
(Scheme(Scheme
34) [154].
homogenization,
bisphosphonate
cellulose
nanofibers
or
or
nanocrystals
general
formula
were
obtained,
depending
initial
oxidation
degree.
nanocrystals
of of
thethe
general
formula
70 70
were
obtained,
depending
onon
thethe
initial
oxidation
degree.
OH
OH
O
HO
O
OH
NaIO4
O
O
O
+ H2N
O
H2O3P
OH
PO3H2
57
N
BH3
OH
O
HN
H2O3P
HO
H2O3P
O
HO
70
Scheme
reductive amination
aminationwith
withsodium
sodiumalendronate.
alendronate.
Scheme34.
34.Periodate
Periodateoxidation
oxidationof
ofcellulose
cellulose followed
followed by
by reductive
Alendronate was also bound to conjugates of pullulan and paclitaxel, which were bound to the
polysaccharide by a cathepsin K-sensitive tetrapeptide spacer. This should ensure release of paclitaxel
in bones. Then, bisphosphonate was covalently conjugated to the sugar chain via a polyethyleneglycol
chain, using a technique similar to that described above (identical to those shown in Scheme 34)
[155]. This system exhibited strong antiproliferative action against several cancer cell lines.
Molecules 2016, 21, 1474
18 of 26
Alendronate was also bound to conjugates of pullulan and paclitaxel, which were bound to the
polysaccharide by a cathepsin K-sensitive tetrapeptide spacer. This should ensure release of paclitaxel
in bones. Then, bisphosphonate was covalently conjugated to the sugar chain via a polyethyleneglycol
chain, using a technique similar to that described above (identical to those shown in Scheme 34) [155].
This system exhibited strong antiproliferative action against several cancer cell lines.
4. Conclusions
Aminobisphosphonic acids are gaining significant interest as a class of compounds with promising
physiologic activity, with some representatives already commercialized as bone resorption inhibitors,
and therefore useful drugs against osteoporosis and related bone disorders. This leads to both the
modification of existing and the elaboration of novel procedures for their preparation. There are
several commonly used reactions for this purpose; however, they have also been modified in the last
decade to be tailored to specific biological needs. A few novel procedures have also been developed.
Functionalization of simple aminobisphosphonic acids is a difficult task because of their strongly
polar character. However, successful examples of functionalization of the amino moieties of these
compounds have provided promising diagnostics and novel therapeutic agents.
Acknowledgments: This work was supported by a statuary activity subsidy from the Polish Ministry of Science
and Higher Education.
Conflicts of Interest: The authors declare no conflict of interest.
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