Synthesis of Pyridiniumboranephosphonate Diesters and Related Compounds using Trityl Cation as a Borane Hydride Acceptor

Article abstract of DOI:10.1055/s-0040-1706569

Boranephosphonate diesters react with pyridine and some tertiary amines in the presence of dimethoxytrityl chloride used as a borane hydride acceptor, to afford the boron-modified phosphodiester analogues containing a P-B-N structural motif. The reaction provides a convenient entry to pyridinium- and ammoniumboranephosphonates derived from the corresponding alkyl, aryl, or nucleoside boranephosphonate diesters. Some aspects of the synthetic protocol, mechanistic features related to a possible intermediate involved, and the role of the solvents used, are discussed.

Full text of DOI:10.1055/s-0040-1706569

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
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020, 52, A–I
feature
A
en
Synthesis
M. Rachwalak et al.
Feature
Synthesis of Pyridiniumboranephosphonate Diesters and Related
Compounds using Trityl Cation as a Borane Hydride Acceptor
Marta Rachwalak
O
P
B
H
1
OR2
N
R O
Justyna Gołębiewska
Tomasz Jakubowski
H
O
+
O
pyridine
Jacek Stawinski*
0
0
0
0
-
0
0
0
1
-
9
3
5
0
-
3
0
1
8
O
P
B
pyridiniumboranephosphonates
examples
P NMR yield: >95%
O
P
B
H
9
1
OR2
1
OR2
H
DCM
R O
31
R O
Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Noskowskiego 12/14, 61-704 Poznań, Poland
isolated yields: 55–85%
H
H
H
3° amine
O
1
OR2
N
R O
P
B
H
λ3-boranephosphonate
N
O
N
N
boranephosphonates
(1.2 equiv)
H
intermediate
=
eJI anMcs eta ikitCluSoj tstreatr aweo wsf i pnB@osi ionkb odic rihng . agp noAizcun tCahhnoe. pr ml istry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznań, Poland
1
2
R , R = various dialkyls, diaryls, alkyl deoxy- and ribonucleosides,
alkyl AZT, dinucleosides, alkyl cholesteryl
ammoniumboranephosphonates
examples
P NMR yield: >95%
isolated yields: 56%, 58%
2
3
1
Received: 01.09.2020
Accepted after revision: 06.10.2020
Published online: 09.11.2020
charged oligonucleotides endowed with such a structural
motif to cancer cells. It is expected that the P–B–N bond
6
DOI: 10.1055/s-0040-1706569; Art ID: ss-2020-z0454-fa
system present in pyridiniumboranephosphonates and re-
lated compounds will contribute to the development of
Abstract Boranephosphonate diesters react with pyridine and some
tertiary amines in the presence of dimethoxytrityl chloride used as a
borane hydride acceptor, to afford the boron-modified phosphodiester
analogues containing a P-B-N structural motif. The reaction provides a
convenient entry to pyridinium- and ammoniumboranephosphonates
derived from the corresponding alkyl, aryl, or nucleoside boranephos-
phonate diesters. Some aspects of the synthetic protocol, mechanistic
features related to a possible intermediate involved, and the role of the
solvents used, are discussed.
8
new boron-based pharmacophores and may find various
applications in the design of therapeutic nucleic acids.9
Until now there has been only one method for the syn-
thesis of pyridiniumboranephosphonate diesters, devel-
6
oped by Caruthers et al., which consisted of oxidation of
boranephosphonate diesters with iodine in the presence of
6
pyridine. Given the new perspectives and potential impor-
2
tance of this class of compounds in medicinal chemistry
6
,7
Key words H-phosphonates,
boranephosphonates,
pyridinium-
and in material sciences, we have been searching for new
synthetic alternatives for their preparation. In this work we
have been inspired by the known instability of boranephos-
phonates during removal of trityl protecting groups.4
This phenomenon was traced back to the generation of a tr-
ityl cation under the deprotection process, which caused
partial deboronation and decomposition of boranephos-
phonate diesters. To remedy this problem, the detritylation
protocol for protected boranephosphonates was modified
to include trityl cation scavengers in a form of borane-
boranephosphonates, trityl cation, nucleotide analogues
b,10
Boranephosphonates, analogues of natural phosphate
esters in which one of the non-bridging oxygen atoms is re-
placed with a -BH group, were introduced to nucleic acid
3
1
chemistry by Sood, Shaw and Spielvogel in 1990. Due to
their close structural and electronic resemblance to natural
phosphates (albeit with distinct differences), these com-
2
pounds can, on the one hand, serve as substrates for RNA
3
4b
10b,11
and DNA polymerizing enzymes, but, on the other hand,
amine complexes or alkylsilanes.
Working towards
1
2
biopolymers containing this functionality are resistant to
various RNA/DNA hydrolysing enzymes.4 This constitutes
the basis for the use of boranephosphonates as tools for
another goal, Wada et al. took advantage of the instability
of boranephosphonate in the presence of the trityl cation to
develop the -BH group as a protection for the P-H function-
3
5
reading, writing and modulating genetic information.
ality and demonstrated that boranephosphonate diesters
can be efficiently converted into the parent H-phosphonate
diesters using dimethoxytritanol and trifluoroacetic acid.
Since formation of pyridiniumboranephosphonates
from the boranephosphonates in the presence of iodine is
formally a simple substitution of a borane hydride by a pyr-
idine moiety, for our part, we attempted to use a trityl cat-
ion as the hydride acceptor to furnish this substitution pro-
cess. Our recent mechanistic studies on oxidative transfor-
mations of boranephosphonate diesters promoted by
Pyridiniumboranephosphonate diesters are a new class
2
of boranephosphonate analogues with a molecular com-
6
plexity built around the boron center. This new structural
and electronic P-B-N framework of a betaine type can open
new avenues for applications of nucleoside and nucleic ac-
ids boranephosphonate analogues in medicine, medicinal
diagnostic or material sciences; for example, for selective
deposition of metal nanostructures on the surface of oligo-
6
,7
nucleotides
or to facilitate the uptake of negatively
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
M. Rachwalak et al.
Feature
3
iodine suggested formation of highly electrophilic  -bora-
nephosphonate as a key intermediate13 in this process.
Here, we argue that trityl cation-promoted instability of
boranephosphonate diesters may involve an analogous re-
action pathway (shown in Scheme 1) with generation of an
In this paper we describe a novel synthesis of pyridini-
um- and ammoniumboranephosphonate diesters from the
corresponding boranephosphonates via a trityl cation-
mediated abstraction of the borane hydride in the presence
of pyridine and some 3° amines.
3
electrophilic  -boranephosphonate as an intermediate.
Such reaction, when carried out in the presence of pyridine
or 3° amines), should result in capture of the  -borane-
phosphonate intermediate and lead to the formation of pyr-
idiniumboranephosphonates (or the corresponding ammo-
niumboranephosphonates).
A general synthetic strategy for the preparation of pyri-
diniumboranephosphonate diesters 3 and related com-
pounds 4 (structures shown in Scheme 2, Scheme 3, and
Scheme 4) is depicted in Scheme 2. This consists of the syn-
thesis of boranephosphonate diesters 2 from readily avail-
able H-phosphonate precursors 1 by using reported proto-
3
(
2
cols (first step, boronation), followed by oxidative transfor-
Biographical Sketches
Marta Rachwalak graduated
from Adam Mickiewicz Universi-
ty in Poznań, Poland in 2014,
and in the same year started her
doctoral studies at the Institute
of Bioorganic Chemistry, Polish
Academy of Sciences, Poznań.
She received her Ph.D. in 2020
under the supervision of Prof.
Jacek Stawinski and Dr. Joanna
Romanowska. Her research in-
terests include biological chem-
istry, especially new nucleotide
analogues of biological impor-
tance.
Justyna Gołębiewska re-
ceived her M.Sc. from Adam
Mickiewicz University, Poznan,
Poland in 2015. In the same
year she joined the Institute of
Bioorganic Chemistry, Polish
Academy of Sciences in Poznań,
where, under the supervision of
Prof. Jacek Stawiński, received
her Ph.D. degree in 2020. Her
research focuses on the chemis-
try of nucleoside H-phospho-
nates
and
nucleoside
boranephosphonates.
Tomasz Jakubowski studied
chemistry at the University of
Wrocław, Poland, and obtained
his master’s degree in 2011. Af-
ter a few years in industry, in
dent at the Institute of Bioor-
His professional interests in-
clude bioorganic chemistry, in
particular the chemistry and bi-
ological properties of nucleotide
analogues, and teaching chem-
istry.
ganic
Chemistry,
Polish
Academy of Sciences in Poznań.
He received his Ph.D. degree in
2020 working under the super-
vision of Prof. Jacek Stawinski.
2014 he became a Ph.D. stu-
Jacek Stawinski is a Professor
of Chemistry at the Institute of
Bioorganic Chemistry, Polish
Academy of Sciences, Poznań,
Poland, and Professor Emeritus
at Stockholm University, Stock-
holm, Sweden. Since 1984, he
has been conducting research
and teaching in both institu-
tions. His main research inter-
ests are in the synthetic and
mechanistic chemistry of nucle-
ic acids, bioorganic phosphorus
chemistry (especially the chem-
istry of H-phosphates and nu-
cleotide analogues), and the
chemistry of lipids.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
Synthesis
M. Rachwalak et al.
Feature
O
1
To optimize this tentative protocol for preparative pur-
poses, additional experiments were carried out. First, we
were interested to find out whether the amount of pyridine
used in the reaction could be reduced without compromis-
O
P
R O
H
P
B
OR2
H
O
1
OR2
R O
O
1
2
pyridine
R
O
P
B
OR
B
H
H
N
–
DMTH
H
H
H
BP
PyBP
λ3-boranephosphonate
3
ing the capture efficiency of the postulated  -boranephos-
intermediate
phonate intermediate. To this end we reacted diethyl bora-
nephosphonate 2a in acetonitrile with the added pyridine
DMTr+
O
(
20 equiv) in the presence of DMTr-Cl (1.2 equiv). Under
BP = boranephosphonate; PyBP = pyridiniumboranephosphonate
DMTr = 4,4'-dimethoxytrityl cation; DMTH = phenyl-di(4-methoxyphenyl)methane
+
these conditions we observed only a slight drop in the effi-
ciency of formation of pyridiniumboranephosphonate 3a
(85% vs. 89%), and also the expected trend in the side prod-
ucts distribution; that is, more diethyl H-phosphonate (9%)
and less of the corresponding dimethoxytritylphosphonate
Scheme 1 A postulated mechanism for the formation of pyridinium-
boranephosphonate diesters PyBP from boranephosphonates BP pro-
moted by a trityl cation
(
5%). A further reduction in the amount of pyridine (10
mation of 2 into pyridiniumboranephosphonates 3. For the
latter step, we considered the use of a trityl cation as a bo-
rane hydride acceptor in the presence of pyridine or a 3°
amine, and this is the main focus of this paper.
equiv) led to a reduction in the yield of pyridinium borane-
phosphonate 3a by favoring the formation of diethyl H-
phosphonate (15%) and its P-dimethoxytritylated derivative
3
1
(6%) ( P NMR experiments). The replacement of DMTr-Cl
by trityl chloride (Tr-Cl) made the reaction of 2a with pyri-
dine (20 equiv) rather sluggish (3.5 h vs. 5 min to reach
completion) and more of the side product, diethyl H-phos-
phonate (20%), was observed. This apparently reflected the
lower ability of Tr-Cl vs. DMTr-Cl to form ionic pairs in ace-
tonitrile solution due to differences in the stability of the
corresponding trityl cations.
O
P
H
O
P
B
H
O
P
B
H
boronation
oxidant
pyridine
1
OR2
R O
1
OR2
H
R O
1
OR2
N
R O
H
H
1
(BP)
2
3 (PyBP)
1
2
R , R = alkyl, aryl, nucleoside moiety, etc.
Scheme 2 A synthetic scheme for the conversion of H-phosphonate
diesters 1 into the corresponding pyridiniumboranephosphonate deriv-
atives 3 via boranephosphonates 2 as synthetic intermediates
Since acetonitrile is a strongly participating solvent in
3
reactions involving the generation of electron-deficient  -
13
boranephosphonate species, we anticipated that its re-
placement by dichloromethane (DCM) as a reaction medi-
um may affect the outcome of this reaction. Indeed, we
found that in the reaction in DCM (2a, 20 equiv of pyridine,
1.2 equiv of DMTr-Cl) the extent of side product formation
was significantly suppressed (only 3% of the P-C side prod-
uct) but the rate of the reaction remained similar to that in
acetonitrile (completion within 5 min). With less pyridine
used (5–10 equiv), additional amounts of diethyl H-phos-
phonate (ca. 3%) were formed ( P NMR experiments).
Before proceeding to preparative runs, we briefly stud-
ied some mechanistic aspects of the investigated reaction,
relevant to its synthetic applications. First, we wanted to
find out what products are formed when a model borane-
phosphonate 2a reacts with DMTr-Cl in acetonitrile or di-
chloromethane without pyridine (the preactivation pro-
To provide a proof of principle for the mechanism-based
transformation shown in Scheme 1, we added to the reac-
tion mixture containing a model substrate, diethyl borane-
phosphonate 2a (for compounds numbering, see Scheme 3)
in pyridine, dimethoxytrityl chloride (DMTr-Cl, 1.2 equiv)
as a source of a trityl cation. It was rewarding to observe
3
1
that in the first P NMR spectrum recorded (after 5 min),
all the starting material 2a (resonating at ca. 92 ppm) had
disappeared, and a major signal at ca. 60 ppm due to pyri-
diniumboranephosphonate 3a emerged (ca. 90%). This was
3
1
1
1
confirmed by B NMR analysis of the reaction mixture in
which the signal from 2a at ca. –39 ppm was replaced with
a new resonance from 3a at ca. –13 ppm. Apart from this
desired product, small signals at ca. 27 ppm (9%) and 7.5
ppm (2%), assigned to diethyl dimethoxytritylphosphonate
and diethyl H-phosphonate, respectively, could be detected
cess), which, under normal reaction conditions, would cap-
3
1
3
by P NMR spectroscopy.
ture
the
incipient
electrophilic
species,
 -
+
This experiment clearly showed that DMTr is an effec-
tive borane hydride acceptor and could be a viable alterna-
tive to iodine used as an oxidant for this purpose. We spec-
ulated that formation of the side-products in this reaction
boranephosphonate intermediate. To this end, 2a was re-
acted with DMTr-Cl (2 equiv) in both of these solvents. We
found that the preactivation in acetonitrile (NMR experi-
ments) rapidly (ca. 30 sec) afforded an intermediate (ca.
90%;  = 59 ppm and  = –25 ppm) identified as an aceto-
3
was due to incomplete capture of  -boranephosphonate
P
B
3
13
intermediate by pyridine. This could lead to a partial debor-
onation and liberation of the corresponding H-phosphonate
diester (see below) that, under the reaction conditions, re-
acted further with DMTr-Cl to produce diethyl dimethoxy-
tritylphosphonate as another side product.12
nitrile–diethyl  -boranephosphonate adduct (formed via
capture of an electrophilic  -boranephosphonate interme-
3
diate by acetonitrile), and diethyl H-phosphonate (10%,  =
P
1
4
3
7.5 ppm). Upon addition of pyridine, the acetonitrile– -
boranephosphonate adduct ( = 59 ppm) underwent con-
P
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
Synthesis
M. Rachwalak et al.
Feature
version into the desired product, pyridiniumboranephos-
phonate 3a. The analogous reaction in dichloromethane
was less efficient and gave a complex mixture of products
containing unreacted starting material 2a (ca. 20%), vari-
able amounts of mono-, di- and trichloroboranephospho-
nates (ca. 60%), and diethyl H-phosphonate (ca. 20%). These
remained practically unchanged upon addition of pyridine,
indicating that chloroboranephosphonate diesters are ap-
parently not intermediate in the formation of pyridinium-
boranephosphonates 3. An interesting observation was that
when the preactivation reaction in dichloromethane was
carried out in the presence of the added chloride anions
O
P
B
H
2
O
DMTr-Cl
(1.2 equiv)
O
P
H
1
OR2
1
OR2
boronation
see the
experimental)
R O
R O
P
B
H
1
OR2
+
R O
(
H
H
DCM
H
N
N
(
20 equiv)
3
(PyBP)
1
2
1a, 2a, 3a; R
b, 2b, 3b; R = R = iPr
c, 2c, 3c; R = R = Bn
1d, 2d, 3d; R = R2 = Ph
= R = Et
1
2
1
1
1
2
1
1e, 2e, 3e
= Et
R2 = AZT =
1f, 2f, 3f
1
R
g, 2g, 3g
1
R
R
1
= Et
1
R
O
O
= Et
=
O
2
R2
=
NH
O
NH
NH
O
N
N
O
DMTrO
N
O
O
O
N
3
AcO
OAc
O-TBDMS
(
tetra-n-butylammonium chloride, 3 equiv) only unreacted
1
h, 2h, 3h
O
O
starting material 2a (60%) and diethyl H-phosphonate (40%)
could be detected. This supported the view that generation
of H-phosphonate diesters in the preactivation process and
in the regular reaction with pyridine, was due to formation
of chloroboranephosphonate derivatives, which collapsed
to the parent H-phosphonate and the borane part1 due to
R1
=
R2
=
NH
O
NH
O
TrO
N
N
Ac = acetyl
O
O
AZT = 3’-azido-3’-deoxythymidine
DMTr = 4,4’-dimethoxytrityl
TBDMS = tert-butyldimethylsilyl
Tr = trityl
TrO
3
1
i, 2i, 3i
= Et
R2 = cholesteryl =

-donation from the chlorine to the boron atom. In line
R
1
with this, the addition of chloride anions (tetra-n-butylam-
monium chloride, 3 equiv) to the generated acetonitrile– -
3
boranephosphonate adduct ( = 59 ppm) caused a com-
plete deboronation to diethyl H-phosphonate.
P
Scheme 3 A synthetic scheme for the preparation of pyridiniumborane-
phosphonate diesters 3 from the corresponding boranephosphonates 2
mediated by dimethoxytrityl chloride (DMTr-Cl)
As to the preferred solvent for the reaction under study,
DCM vs. MeCN, the above experiments pointed to DCM be-
cause of the slower oxidation of 2 by DMTr-Cl in DCM (low-
>95% in all instances. One should note, however, that isolat-
+
1
2
er polarity and less efficient ionization to DMTr than in
ed yields of 3 depended on R and R (55–85%), and this we
3
acetonitrile); a  -boranephosphonate intermediate appar-
ascribed to losses during chromatography, and, possibly, a
1
5
ently could be more easily trapped by the pyridine present
in the reaction mixture, resulting in less side products for-
mation. In addition, since for more bulky substrates (e.g.,
nucleoside boranephosphonate diesters) in dichlorometh-
partial instability during the purification process.
Since in both reaction steps in Scheme 2 and Scheme 3,
the boronation of H-phosphonates 1 and oxidative transfor-
mation of boranephosphonates 2 were usually clean and ef-
3
1
31
ane we did not observe ( P NMR spectroscopy) any side
product formation, we used DCM as a solvent, pyridine (20
equiv) and DMTr-Cl (1.2 equiv) for our synthetic protocol
for the preparation of pyridiniumphosphonate diesters 3
ficient ( P NMR experiments), we attempted to combine
them into a one-pot reaction to further simplify and short-
en the synthesis of pyridiniumboranephosphonates 3. To
check the efficacy of this approach, H-phosphonate diester
1e (ethyl, AZT derivative) or 1h (a dinucleoside derivative)
was silylated in DCM using trimethylsilyl chloride (TMS-Cl,
3 equiv) to convert it into the corresponding tervalent bis-
(
Scheme 3).
As synthetic targets for testing the generality of this ap-
+
proach and the utility of DMTr as a borane hydride accep-
tor, we chose pyridiniumboranephosphonate diesters 3
with diverse structural features (Scheme 3).
silyl phosphite, and then treated with BH -dimethylsulfide
3
complex (2 equiv). After quenching of the reaction mixture
with aq. ammonia and evaporation to dryness, the crude
product (2e or 2h) was reacted in DCM with DMTr-Cl (1.2
equiv) in the presence of pyridine (20 equiv). In both in-
Thus, as substrates for our reaction we selected (i) sym-
metrical boranephosphonate diesters 2 with simple alkyls
(
(
ethyl, 2a), branched alkyls (isopropyl, 2b), reactive alkyls
benzyl, 2c), simple aryls (phenyl, 2d), and (ii) mixed bora-
3
1
stances, the P NMR spectrum showed that formation of 2
and 3 was virtually quantitative, and the desired products,
pyridiniumboranephosphonates 3e and 3h, were isolated in
total 50 and 72% yields, respectively.
nephosphonate diesters 2 all bearing ethyl group and an
antiviral nucleoside (AZT derivative, 2e), a protected 5′-ri-
bonucleoside (2f), a protected 3′-ribonucleoside (2g), a cho-
lesteryl moiety (2i), or two nucleoside groups (5′- and 3′-
tritylated thymidine, 2h). The entire synthesis was rather
straightforward and uneventful, and proved to be effective
for all compounds investigated. Progress of each of the reac-
tions was checked by 31P NMR spectroscopy, which indicat-
ed that yields of pyridiniumboranephosphonates 3 were
+
To explore a possible application of a DMTr -mediated
oxidation of boranephosphonate diesters 2 for the prepara-
3
tion of complexes of  -boranephosphonate with 3°
16
amines, that is, ammoniumboranephosphonate deriva-
31
tives of type 4, we carried out P NMR studies on the reac-
tion shown in Scheme 4, in which pyridine was replaced
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

E
Synthesis
M. Rachwalak et al.
Feature
with a 3° amine. For this purpose we reacted simple diethyl
boranephosphonate 2a and N-methylmorpholine or bora-
nephosphonate 2e bearing a known antiviral nucleoside
moiety (AZT) with bicylic diamine DABCO, in the presence
of DMTr-Cl in DCM.
distinction to this, the premixing of DMTr-Cl with pyridine,
did not affect the oxidation efficiency of the added borane-
phosphonate 2a. This apparently pointed to higher equilib-
rium concentration of a dimethoxytrityl cation in complex-
es with unsubstituted pyridine and 4-CNPy vs. pyridines
with electron-donating substituents (e.g., 4-MeOPy). These
studies will be the subject of further investigations in this
laboratory.
O
P
B
H
2
O
P
B
DMTr-Cl
(1.2 equiv)
1
OR2
1
OR2
R O
R O
+
3° amine
20 equiv)
H
H
DCM
H
N
(
H
To sum up, we have developed a new synthetic protocol
for the preparation of pyridiniumboranephosphonates 3
under mild conditions that consists of oxidation of borane-
phosphonate diesters 2 in the presence of pyridine using di-
methoxytrityl cation as a borane hydride acceptor. This
protocol is also applicable to the synthesis of ammonium-
boranephosphonate diesters 4 bearing 3° amines in place of
a pyridine residue. The method is simple, efficient, and thus
DMTr-Cl can be considered as a viable alternative to the io-
dine-promoted synthesis of this class of compounds. This
protocol can be further simplified by combining the prepa-
ration of boranephosphonates 2 and their oxidative trans-
formations towards the P-B-N derivatives of type 3 and 4
into a one-pot reaction to make the transformation more
effective in terms of both time and the chemicals used.
Further studies exploring scope and limitations of
4
1
4a, R1 = R2 = Et; 3° amine = N-methylmorpholine
4b, R = Et; R2 = AZT; 3° amine = DABCO
2
2
a, R = R2 = Et
1
e, R = Et; R2 = AZT
1
DABCO = 1,4-diazabicyclo[2.2.2]octane
Scheme 4 Exemplary syntheses of ammoniumboranephosphonates 4
from boranephosphonates 2 and selected 3° amines
In both instances 31P and 11B NMR spectroscopy showed
rapid (<5 min) and efficient formation of the expected am-
moniumboranephosphonates 4a and 4b, respectively
(
>95%;  = 59 and  = –17 ppm for 4a, and  = 61 and  =
P B P B
–
13 ppm for 4b), which were isolated in >50% yields by sili-
ca gel chromatography.
Finally, some comments related to the possible sub-
strate scope of the investigated reaction. On mechanistic
grounds, the reaction relies on the ability of a trityl cation
to accept a borane hydride and thus it can be of crucial im-
portance for any process that may be affected by the con-
centration of a free trityl cation or its reactivity under the
reaction conditions. In this context, of significance could be
+
DMTr as an acceptor of borane hydrides for oxidative trans-
formations of boranephosphonates, and its underlying
mechanism, are in progress in this laboratory.
1
7
formation of trityl cation complexes with pyridines (or 3°
amines used for the reaction) that can deplete effective con-
All reagents were of analytical grade, obtained from commercial sup-
pliers, and used without further purification. The anhydrous solvents
used for the reactions were stored over molecular sieves 4 Å. TLC
analyses were carried out on Merck silica gel 60 F 254 precoated
plates using a DCM–MeOH 9:1 (v/v) solvent system. All evaporations
were carried out on rotatory evaporators under reduced pressure at
centration of a trityl cation and may themselves have differ-
ent borane hydride acceptor properties.17a To address this
issue we reacted a model boranephosphonate diester 2a in
DCM with 10 equiv of 2,6-lutidine (2,6-Lu), 3-hydroxypyri-
dine (3-OHPy), 4-methoxypyridine (4-MeOPy), or 4-cyano-
pyridine (4-CNPy) in the presence of DMTr-Cl (1.2 equiv).
4
0 °C.
The NMR spectra were recorded with a Bruker Avance II 400 MHz in-
strument. The chemical shifts are reported in ppm, relative to solvent
3
1
Preliminary P NMR experiments (spectra recorded after 5
min) showed that only for 4-cyanopyridine the reaction
was almost as efficient as that for pyridine. For the other
pyridine derivatives, the corresponding diethyl pyridinium-
boranephosphonates of type 3 (structures not shown),
were formed as minor products (20% for 2,6-Lu, 38% for 3-
OHPy, and 10% for 4-MeOPy), with a significant portion of
unreacted starting material 2a (40, 25 and 60%, respective-
ly), and the deboronation product, diethyl H-phosphonate
1
H, 13C NMR), 2% H PO solution in D O (31P NMR), and BF -di-
peaks (
3 4 2 3
1
1
ethyl etherate ( B NMR). Assignment of the NMR signals was accom-
plished based on the expected chemical shift values, splitting pattern
of the signals, and 2D correlation experiments. High-resolution mass
spectra (HRMS) were recorded with a Thermo Fisher Scientific Q-Ex-
active Orbitrap mass spectrometer.
For compounds 3e–i and 4b, due to the presence of two P-diastereo-
mers and similar chemical shifts of the protons in the 3′- and 5′-nu-
cleoside units, multiplicity and overlapping of the resonances were
(
40, 38, and 30%, respectively). The reaction mixtures re-
observed in the 1H NMR spectra. For this reason, only selected diag-
mained unchanged within an hour, indicating that appar-
ently the DMTr-Cl was completely consumed. We interpret-
ed these results as indicating the formation of stable com-
plexes between dimethoxytrityl cation and 2,6-Lu, 3-OHPy
and 4-MeOPy that could not act as efficient borane hydride
acceptors. In line with this, no reaction was observed when
nostic signals are listed. Purity of the isolated compounds was >97%
( H NMR spectroscopy).
1
H-Phosphonate diesters 1a–d are commercial products and 1e–i were
obtained by condensation of the corresponding H-phosphonate mon-
1
9
oesters with suitable alcohols using standard reported procedures.
Synthesis of Boranephosphonate Diesters 2; General Procedure
2
,6-lutidine was mixed in dichloromethane with DMTr-Cl
1
8
All boranephosphonate diesters 2 were obtained by using modified
prior to the addition of boranephosphonate 2a. In contra-
reported procedures.1
3a,20
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

F
Synthesis
M. Rachwalak et al.
Feature
H-Phosphonate diester 1 (1a–i; 1 mmol) was placed in a 250 mL pear-
shaped flask and dried by evaporation of the added anhydrous DCM
5′-O-Tritylthymidin-3′-yl 3′-O-Tritylthymidin-5′-yl Boranephos-
phonate (2h)1
3a
(2 × 20 mL), and dissolved in the same solvent (30 mL). To this,
31
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 92.8–96.2 (br).
3
trimethylsilyl chloride (3 equiv) and triethylamine (3 equiv) were
added. The reaction mixture was stirred for 5 min, then dimethyl sul-
fide borane (BH -SMe , 2 equiv) was added to the generated silyl
1
1
B NMR (128 MHz, CDCl , 25 °C):  = –38.9 to –41.8 (br).
3
HRMS: m/z [M–] calcd for C58H57BN O P : 1027.3860; found:
1
–
4
11
3
2
027.3879.
phosphite derivative. The reaction mixture was stirred for another 15
3
1
min, and progress of the reaction was monitored by P NMR spec-
troscopy. After completion, the reaction was quenched with 25% aq.
ammonia (10 mL) and the mixture was concentrated to a gum. The
residue was dissolved in a small amount of DCM, applied on a silica
gel column and eluted with a gradient of MeOH in DCM (0–5%, v/v).
Fractions containing the desired compound were collected and evap-
Cholester-3-yl Ethyl Boranephosphonate (2i)
31
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 98.5–102.4 (br).
3
1
1
B NMR (128 MHz, CDCl , 25 °C):  = –39.2 to –43.6 (br).
3
–
–
HRMS: m/z [M ] calcd for C29H BO P : 491.3831; found: 491.3834.
53
3
orated, to yield 2a–i as white, amorphous solids (Et N salts, 70–90%
3
yield).
Synthesis of Pyridiniumboranephosphonate Diesters 3; General
Procedure
Diethyl Boranephosphonate (2a)13a
Boranephosphonate diester 2 (2a–i; 0.5 mmol) was dried by evapora-
tion of the added anhydrous DCM (2 × 20 mL) and dissolved in the
same solvent (3 mL). To this, pyridine (20 equiv), followed by dime-
thoxytrityl chloride (1.2 equiv), were added. After stirring for 5 min, a
3
1
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 93.0 (br q, J = 138.2 Hz).
3
P–B
1
1
1
= 138.3 Hz, 1J
B NMR (128 MHz, CDCl , 25 °C):  = –40.3 (dq, J
3
P–B
B–H
=
91.3 Hz).
3
1
P NMR spectrum was recorded (a broad signal at  ~60 ppm corre-
P
–
–
HRMS: m/z [M ] calcd for C H BO P : 151.0701; found: 151.0688.
4
13
3
sponding to the expected pyridiniumboranephosphonate diester 3).
After completion, the reaction mixture was evaporated to dryness,
the residue was dissolved in a small amount of acetonitrile and ap-
plied on a silica gel column. Products 3 were isolated using a gradient
of water in acetonitrile (0–3%, v/v). Fractions containing the desired
products were collected and evaporated, to yield 3a–i as white, amor-
phous solids.
Diisopropyl Boranephosphonate (2b)
3
1
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 96.6 (br q, J = 128.4 Hz).
3
P–B
1
1
B NMR (128 MHz, CDCl , 25 °C):  = (dq, J = 129.8 Hz, 1JB–H = 91.5
1
3
P–B
Hz).
HRMS: m/z [M ] calcd for C H BO P : 179.1014; found: 179.1003.
–
–
6
17
3
Diethyl Pyridiniumboranephosphonate (3a)
Dibenzyl Boranephosphonate (2c)
Yield: 55% (63 mg).
3
1
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 97.7 (br q, J = 121.4 Hz).
3
P–B
1
3
H NMR (400 MHz, CDCl , 25 °C):  = 1.03 (t, J
= 7.1 Hz, 6 H, 2 ×
H–H
3
1
1
B NMR (128 MHz, CDCl , 25 °C):  = –39.6 to –42.6 (br).
3
3
-CH ), 3.77 (q, J
= 6.3 Hz, 4 H, 2 × -CH -), 7.47–7.53 (m, 2 H, H2Py,
3
H–H 2
–
–
HRMS: m/z [M ] calcd for C14H17BO P : 275.1014; found: 275.1017.
H6Py), 7.91–7.98 (m, 1 H, H4Py), 8.48–8.51 (m, 2 H, H3Py, H5Py).
3
1
3
3
C NMR (100 MHz, CDCl , 25 °C):  = 16.6 (d, J = 5.6 Hz), 58.6 (d,
3
P–C
Diphenyl Boranephosphonate (2d)
2JP–C = 6.5 Hz), 125.9 (d, J = 2.1 Hz), 140.6 (d, J = 3.2 Hz), 148.1 (d, J = 6.8
3
1
1
1
Hz).
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 90.3 (br q, J = 124.1 Hz).
3
P–B
3
1
1
1
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 60.2 (br q, J = 184.9 Hz).
B NMR (128 MHz, CDCl , 25 °C):  = –37.2 to –41.2 (br).
3
P–B
3
1
1
1
1
–
–
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –13.2 (d, J = 183.1 Hz).
3 P–B
HRMS: m/z [M ] calcd for C12H13BO P : 247.0701; found: 247.0700.
3
+
+
HRMS (ESI+): m/z [M + H] calcd for C H BNO P : 230.1117; found:
9
18
3
3
′-Deoxy-3′-azidothymidin-5′-yl Ethyl Boranephosphonate (2e)
230.1102.
3
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 93.0–99.5 (br).
3
1
1
Diisopropyl Pyridiniumboranephosphonate (3b)
B NMR (128 MHz, CDCl , 25 °C):  = –38.8 to –43.9 (br).
3
Yield: 63% (81 mg).
–
–
HRMS: m/z [M ] calcd for C12H20BN O P : 372.1250; found: 372.1250.
5
6
1
3
H NMR (400 MHz, CDCl , 25 °C):  = 1.07 (d, J
= 6.2 Hz, 6 H, 2 ×
H–H
3
3
-
-
8
CH iPr), 1.14 (d, J
= 6.2 Hz, 6 H, 2 × -CH ), 4.44–4.57 [m, 2 H, 2 ×
CH(OH)-], 7.52–7.59 (m, 2 H, H2Py, H6Py), 7.96–8.04 (m, 1 H, H4Py),
.57–8.63 (m, 2 H, H3Py, H5Py).
3
H–H 3
2
3
′,3′-O,O-Diacetyluridine-5′-yl Ethyl Boranephosphonate (2f)
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 98.5–102.9 (br).
3
1
1
B NMR (128 MHz, CDCl , 25 °C):  = –39.3 to –41.5 (br).
13
3
3
C NMR (100 MHz, CDCl , 25 °C):  = 24.3 (d, J = 3.2 Hz), 66.1 (d,
3
P–C
HRMS: m/z [M–] calcd for C15H23BN O P : 433.1189; found:
–
2JP–C = 7.00 Hz), 125.8 (d, J = 2.3 Hz), 140.7 (d, J = 3.5 Hz), 147.9 (d, J =
2
10
433.1190.
6.9 Hz).
3
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 58.3 (br).
3
5
′-O-Dimethoxytrityl-2′-O-tert-butyldimethylsilyuridin-3′-yl Eth-
1
1
1
1
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –12.5 (d, J = 183.9 Hz).
3
P–B
yl Boranephosphonate (2g)
+
P+: 258.1430; found:
3
1
1
HRMS (ESI+): m/z [M + H] calcd for C11
58.1412.
H22BNO
3
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 94.0–98.6 (br).
3
2
1
1
1
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –38.2 to –42.8 (br).
3
HRMS: m/z [M–] calcd for C38H51BN O10PSi–: 765.3149; found:
2
Dibenzyl Pyridiniumboranephosphonate (3c)
765.3156.
Yield: 87% (154 mg).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
Synthesis
M. Rachwalak et al.
Feature
1
2
= 12.4 Hz, 3JP–H
H–H
H NMR (400 MHz, CDCl , 25 °C):  = 4.88 (dd, J
=
2.59 Hz), 126.22 (d, J = 2.59 Hz), 139.6, 139.65, 140.9 (d, J = 3.45 Hz),
140.99 (d, J = 3.46 Hz), 148.0 (J = 7.15 Hz), 148.1 (J = 6.78 Hz), 150.7,
163.3, 169.5, 169.5, 169.54, 169.6, 169.65.
3
2
3
7
.2 Hz, 2 H, -CH -), 4.97 (dd, J
= 12.35 Hz, J = 7.8 Hz, 2 H, -CH2-
2
H–H P–H
)
(
1
, 7.15–7.28 (m, 10 H, Bz), 7.35–7.41 (m, 2 H, H2Py, H6Py), 7.83–7.89
m, 1 H, H4Py), 8.38–8.44 (m, 2 H, H3Py, H5Py).
31
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 62.3 (br).
3
3
2
C NMR (100 MHz, CDCl , 25 °C):  = 64.1 (d, J = 6.6 Hz), 125.6 (d, J
11
1
3
P–C
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –15.8 (br).
3
=
1
2.5 Hz), 127.1, 127.2, 127.9, 137.9 (d, J = 5.8 Hz), 140.5 (d, J = 3.5 Hz),
HRMS (ESI–): m/z [M–H] calcd for C20H26BN O10P–: 510.1449; found:
–
3
47.5 (d, J = 6.7 Hz).
5
10.1462.
3
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 61.4 (br).
3
1
1
1
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –15.7 (br).
3
5′-O-Dimethoxytrityl-2′-O-tert-butyldimethylsilyluridin-3′-yl Ethyl
Pyridiniumboranephosphonate (3g)
+
+
HRMS (ESI+): m/z [M + H] calcd for C19H22BNO P : 354.1430; found:
3
354.1422).
Yield: 38% (161 mg).
1
H NMR (400 MHz, CDCl , 25 °C, diagnostic signals):  = 0.23 (m, 6 H,
3
Diphenyl Pyridiniumboranephosphonate (3d)
2
× -CH tBDMS), 0.98 (s, 9 H, 3 × -CH tBDMS), 3.89 (s, 6 H, 2 × -CH
3
3
3
3
Yield: 85% (138 mg).
DMTr), 5.3–5.37 (m, 1 H, =C5-H), 6.02 (d, JH–H = 5.2 Hz, 1 H, C1′-H),
1
7.75–7.82 (m, 2 H, H2Py, H6Py), 8.16–8.23 (m, 1 H, H4Py), 8.72–8.81
H NMR (400 MHz, CDCl , 25 °C):  = 6.99 (m, 2 H, 2 × H4Ph), 7.11 (m,
3
(
m, 2 H, H3Py, H5Py), 9.82 (s, 1 H, N3-H).
4
(
H, 2 × H2Ph, 2 × H6Ph), 7.17 (m, 4 H, 2 × H3Ph, 2 × H5Ph), 7.39–7.47
m, 2 H, H2Py, H6Py), 7.87–7.94 (m, 1 H, H4Py), 8.38–8.43 (m, 2 H,
H3Py, H5Py).
1
3
C NMR (100 MHz, CDCl , 25 °C):  = –4.96, 16.7, 18.0, 18.2, 25.3,
3
25.6, 25.7, 55.2, 58.1, 59.1, 59.4, 62.4, 62.7, 64.2, 70.7, 71.8, 75.3, 75.4,
82.95, 83.2, 8.2, 87.8, 87.9, 102.3, 113.2, 126.0, 127.1, 127.9, 128.1,
1
3
3
C NMR (100 MHz, CDCl , 25 °C):  = 120.7 (d, J = 3.9 Hz), 123.5,
3
P–C
1
30.16, 130.24, 135.0, 135.1, 140.2, 141.9, 144.2, 148.1, 148.2, 150.9,
1
1
3
1
25.9 (d, J = 2.3 Hz), 129.3, 141.0 (d, J = 3.5 Hz), 147.6 (d, J = 6.7 Hz),
2
158.6, 163.3.
51.3 (d, J = 8.9 Hz).
P–C
3
1
1
1
1
1
1
P{ H} NMR (162 MHz, CDCl
3
, 25 °C):  = 60.55 (br).
, 25 °C):  = –13.0 (br).
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 57.1 (br).
3
1
1
1
1
B{ H} NMR (128 MHz, CDCl
3
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –15.2 (d, J = 159.6 Hz).
3
P–B
HRMS (ESI–): m/z [M–H]– calcd for C43
H54BN O10PSi : 842.3409;
–
+
+
3
HRMS (ESI–): m/z [M + H] calcd for C17H18BNO P : 326.1117; found:
3
3
found: 842.3434.
26.1100.
5
′-O-Tritylthymidin-3′-yl 3′-O-Tritylthymidin-5′-yl Pyridinium-
3
′-Deoxy-3′-azidothymidin-5′-yl Ethyl Pyridiniumboranephos-
boranephosphonate (3h)
phonate (3e)
Yield: 61% (337 mg).
Yield: 71% (160 mg).
1H NMR (400 MHz, CDCl
, 25 °C, diagnostic signals):  = 1.46 and 1.48
s, 3 H, C5-CH ), 1.94–1.98 (s, 3 H, C5-CH ), 6.36–6.46 (m, 1 H, C1′-H),
1
3
H NMR (400 MHz, CDCl , 25 °C):  = 1.14–1.22 (m, 3 H, -CH Et), 1.86–
3
3
(
1
.93 (m, 3 H, C5-CH ), 2.14–2.27 (m, 1 H, C2′-H ), 2.27–2.37 (m, 1 H,
3
3
3
A
6
.51–6.61 (m, 1 H, C1′-H).
C2′-H ), 3.89–3.99 (m, 2 H, C5′-CH -), 4.00–4.04 (1 H, C3′-H), 4.06–
B
2
1
3
4.14 (1 H, C4′-H), 4.21–4.29 (m, 1 H, -CH -H Et), 4.36–4.41 (m, 1 H, -
C NMR (100 MHz, CDCl , 25 °C):  = 11.5, 11.6, 12.3, 39.2, 39.4, 39.9,
3
2
A
CH -H Et), 6.23–6.30 (m, 1 H, C1′-H), 7.57 (s, 1 H, C6-H), 7.59–7.67
62.6, 62.65, 63.1, 63.15, 63.8, 73.7, 75.0, 75.2, 84.2, 84.3, 84.75, 84.8,
84.9, 885.0, 85.18, 85.2, 87.56, 87.6, 87.88, 87.9, 111.1, 111.2, 111.5,
126.2, 126.3, 127.4, 127.9, 128.0, 128.1, 128.6, 128.7, 128.73, 135.3,
135.4, 135.9, 141.3, 141.4, 143.1, 143.9, 144.0, 147.7, 147.8, 147.83,
2
B
(m, 2 H, H2Py, H6Py), 8.02–8.10 (m, 1 H, H4Py), 8.61–8.68 (m, 2 H,
H3Py, H5Py), 9.86 (s, 1 H, N3-H).
1
3
C NMR (100 MHz, CDCl , 25 °C):  = 12.3, 16.6, 37.5, 37.6, 58.8, 59.2,
3
1
47.9, 150.5, 150.8, 163.9.
6
1
3
0.9, 61.0, 62.1, 62.4, 83.1, 83.3, 84.4, 111.2, 111.3, 127.1, 135.3,
40.9, 148.0, 150.5, 164.1.
3
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 61.5 (br).
3
1
1
11
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 62.04 (br).
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –13.7 (br).
3
3
1
1
1
HRMS (ESI–): m/z [M–H]– calcd for C63H60BN O11P–: 1104.4120;
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –15.9 (br).
3
5
+
+
found: 1104.4142.
HRMS (ESI+): m/z [M + H] calcd for C17H25BN O P : 451.1666; found:
6
6
451.1642.
Cholester-3-yl Ethyl Pyridiniumboranephosphonate (3i)
2
′,3′-O,O-Diacetyluridine-5′-yl Ethyl Pyridiniumboranephospho-
Yield: 55% (157 mg).
nate (3f)
1
H NMR (400 MHz, CDCl , 25 °C, diagnostic signals):  = 3.85–4.02 (m,
3
Yield: 63% (161 mg).
2 H, -CH -Et), 4.07–4.20 (m, 1 H, C3-H), 5.24–5.35 (m, 1 H, =C6-H),
2
1
3
7.57–7.66 (m, 2 H, H2Py, H6Py), 8.00–8.08 (m, 1 H, H4Py), 8.63–8.72
(m, 2 H, H3Py, H5Py).
H NMR (400 MHz, CDCl , 25 °C, diagnostic signals):  = 1.16 (t, J
=
H–H
3
3
6
.4 Hz, 3 H, -CH Et), 1.19 (t, J
6.4 Hz, 3 H, -CH Et), 1.99–2.02 (m, 6
3
H–H 3
3
13
3
H, -CH Ac), 2.06 (s, 3 H, -CH Ac), 2.08 (s, 3 H, -CH Ac), 5.61 (d, J
8
6
=
=
C NMR (100 MHz, CDCl , 25 °C):  = 11.8, 16.6 (d, J = 5.9 Hz), 18.6,
3 P–C
3
3
3
3
H–H
H–H
3
3
.2 Hz, 1 H, =C5-H), 5.68 (d, J
.9 Hz, 1 H, C1′-H), 6.22 (d, J
= 8.2 Hz, 1 H, =C5-H), 6.18 (d, J
19.3, 20.95, 22.5, 22.8, 23.7, 24.2, 27.9, 28.2, 30.3, 31.8 (d, JP–C = 3.7
Hz), 35.7, 36.1, 36.4, 37.1, 39.4, 39.7, 40.7 (d,
H–H
3
3
= 6.0 Hz, 1 H, C1′-H), 7.59–7.65 (m, 4
J
= 5.6 Hz), 42.2,
H–H
P–C
3
3
2
2
H, H2Py, H6Py), 7.76 (d, J
= 8.2 Hz, =C6-H), 7.83 (d, J
= 8.2 Hz,
49.95, 56.04, 56.6, 58.4 (d, J = 6.5 Hz), 72.9 (d, J = 6.8 Hz), 121.9
H–H
H–H
P–C
P–C
=
C6-H), 7.98–8.08 (m, 2 H, H4Py), 8.61–8.68 (m, 4 H, H3Py, H5Py).
(d, J = 2.6 Hz), 125.8, 140.4, 140.5 (d, J = 3.3 Hz), 148.1 (d, J = 6.95 Hz).
1
3
31
1
C NMR (100 MHz, CDCl , 25 °C):  = 16.5, 16.55, 16.6, 16.65, 20.3,
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 59.1 (br).
3
3
2
0.46, 20.49, 59.3, 59.36, 59.6, 59.7, 61.3, 61.4, 61.7, 61.8, 71.2, 71.4,
11
1
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –15.3 (br).
3
772.9, 81.9, 81.97, 82.0, 82.1, 85.1, 85.3, 103.1, 103.2, 126.19 (d, J =
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
Synthesis
M. Rachwalak et al.
Feature
+
+
HRMS (ESI–): m/z [M + H] calcd for C34H58BNO P : 570.4247; found:
Funding Information
3
570.4237.
Financial support from the National Science Centre, Poland (Naro-
dowe Centrum Nauki, Preludium Grant Nr 2018/31/N/STP/03589 to
One-Pot Synthesis of Pyridiniumboranephosphonates 3e and 3h
from the Corresponding H-Phosphonate Diesters 1e and 1h
J.G.), is greatly acknowledged.Naro
d
o
w
ym Ce
n
tru
m
Nau
k
i2(
0
1
8
/3
1
/N/STP/0
3
5
8
9)
This synthetic protocol is a combination of a general procedure for
the synthesis of boranephosphonate diesters 2 (see above) and a gen-
eral procedure for the synthesis of pyridiniumboranephosphonate di-
esters 3 (see above), with the exception that the crude reaction mix-
tures containing boranephosphonates 2 were evaporated to dryness
and directly subjected to the reaction with dimethoxytrityl chloride
in the presence of pyridine.
Acknowledgment
We would like to thank Prof. Zofia Gdaniec and Dr. Witold Andrałojć
from our Institute for their help with B NMR measurements.
11
Supporting Information
After silica gel chromatography, 3′-deoxy-3′-azidothymidin-5′-yl eth-
yl pyridiniumboranephosphonate (3e) was obtained in 50% yield
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706569. Su
(from 1e), and 5′-O-tritylthymidin-3′-yl 3′-O-tritylthymidin-5′-yl pyr-
p
p
orting Inform atio
n
Su
p
p
orting Inform atio
n
idiniumboranephosphonate (3h), in 72% yield (from 1h). For spectral
characterization of these compounds, see above.
References and Notes
Synthesis of Ammoniumboranephosphonates 4
Ammoniumboranephosphonates 4a and 4b were obtained analo-
gously to compounds 3 with the exception that pyridine was replaced
with N-methylmorpholine (for 4a, obtained from 2a) or 1,4-diazabi-
cyclo[2.2.2]octane (DABCO, for 4b, obtained from 2e).
(1) Sood, A.; Shaw, B. R.; Spielvogel, B. F. J. Am. Chem. Soc. 1990, 112,
9000.
(2) Li, P.; Sergueeva, Z. A.; Dobrikov, M.; Shaw, B. R. Chem. Rev.
2007, 107, 4746.
(
3) (a) He, K.; Porter, K. W.; Hasan, A.; Briley, J. D.; Shaw, B. R.
Nucleic Acids Res. 1999, 27, 1788. (b) Porter, K. W.; Briley, J. D.;
Shaw, B. R. Nucleic Acids Res. 1997, 25, 1611. (c) Li, H.; Porter, K.;
Huang, F. Q.; Shaw, B. R. Nucleic Acids Res. 1995, 23, 4495.
Diethyl N-Methylmorpholiniumboranephosphonate (4a)
Yield: 56% (70 mg).
1
3
H NMR (400 MHz, CDCl , 25 °C):  = 1.22 (t, J
= 7.1 Hz, 6 H, 2 × -
3
H–H
(4) (a) Kandimalla, E. R.; Manning, A.; Zhao, Q. Y.; Shaw, D. R.; Byrn,
R. A.; Sasisekharan, V.; Agrawal, S. Nucleic Acids Res. 1997, 25,
370. (b) Sergueeva, Z. A.; Sergueev, D.; Shaw, B. R. Nucleosides,
Nucleotides Nucleic Acids 2001, 20, 941. (c) Hall, A. H.; Wan, J.;
Shaughnessy, E. E.; Ramsay Shaw, B.; Alexander, K. A. Nucleic
Acids Res. 2004, 32, 5991.
CH ), 2.78–2.87 (m, 2 H, -CH -N), 2.92 (s, 3 H, -CH N-methylmorpho-
line), 3.31–3.38 (m, 2 H, -CH -N, N-methylmorpholine), 3.69–3.76 (m,
2
4
3
2
3
2
H, -CH -O, N-methylmorpholine), 3.86–4.00 (m, 4 H, 2 × -CH -Et),
.01–4.09 (m, 2 H, -CH -O, N-methylmorpholine).
2
2
2
1
3
C NMR (100 MHz, CDCl , 25 °C):  = 16.6 (d, J = 5.8 Hz), 51.5, 58.4 (d,
3
J = 6.7 Hz), 59.6 (d, J = 9.7 Hz), 61.4.
(5) (a) Summers, J. S.; Shaw, B. R. Curr. Med. Chem. 2001, 8, 1147.
(b) Shaw, B. R.; Dobrikov, M.; Wang, X. I. N.; Wan, J.; He, K.; Lin,
J.-L.; Li, P.; Rait, V.; Sergueeva, Z. A.; Sergueev, D. Ann. N. Y. Acad.
Sci. 2003, 1002, 12.
(6) Roy, S.; Paul, S.; Roy, M.; Kundu, R.; Monfregola, L.; Caruthers,
M. H. J. Org. Chem. 2017, 82, 1420.
3
1
1
1
P{ H} NMR (162 MHz, CDCl , 25 °C):  = 59.2 (br q, J = 179.2 Hz).
3
P–B
1
1
1
1
B{ H} NMR (128 MHz, CDCl , 25 °C):  = –16.7 (d, J = 189.5 Hz).
3
P–B
HRMS (ESI+): m/z [2M + H]+ calcd for (C H BNO P) +H : 503.2994;
found: 503.2988.
+
9
23
4
2
(7) Ganguly, S.; Paul, S.; Yehezkeli, O.; Cha, J.; Caruthers, M. H.
3
′-Deoxy-3′-azidothymidin-5′-yl Ethyl (1,4-Diazabicyclo[2.2.2]-
Chem. Mater. 2017, 29, 2239.
octane-1-ium)boranephosphonate (4b)
(8) (a) Coulthurst, S. J.; Whitehead, N. A.; Welch, M.; Salmond, G. P.
C. Trends Biochem. Sci. 2002, 27, 217. (b) Issa, F.; Kassiou, M.;
Rendina, L. M. Chem. Rev. 2011, 111, 5701. (c) Niziol, J.; Rode,
W.; Ruman, T. Mini-Rev. Org. Chem. 2012, 9, 418. (d) Diaz, D. B.;
Yudin, A. K. Nat. Chem. 2017, 9, 731.
Yield: 58% (130.5 mg).
1
3
H NMR (400 MHz, D O, 25 °C):  = 1.31 (t, J
= 6.8 Hz, 3 H, -CH Et),
3
2
H–H
1
.97 (s, 3 H, C5-CH ), 2.53–2.61 (m, 2 H, -C2′H -), 3.01–3.08 (m, 6
3
2
H, -CH -DABCO), 3.13–3.21 (m, 6 H, -CH -DABCO), 3.98–4.10 (m, 2 H,
2
2
(
9) (a) Ni, S.; Yao, H.; Wang, L.; Lu, J.; Jiang, F.; Lu, A.; Zhang, G. Int. J.
Mol. Sci. 2017, 18. (b) Hara, R. I.; Saito, T.; Kogure, T.;
Hamamura, Y.; Uchiyama, N.; Nukaga, Y.; Iwamoto, N.; Wada, T.
J. Org. Chem. 2019, 84, 7971. (c) Smith, C. I. E.; Zain, R. Annu. Rev.
Pharmacol. Toxicol. 2019, 59, 605.
-
CH -Et), 4.14–4.24 (m, 3 H, C5′-CH -), 4.46–4.54 (m, 1 H, C3′-H),
2
2
6.24–6.29 (m, 1 H, C1′-H), 7.63–7.66 (s, 1 H, C6-H).
1
3
C NMR (100 MHz, D O, 25 °C):  = 11.74, 11.78, 15.77, 15.83, 36.05,
2
3
1
3
6.1, 44.3, 51.3, 51.4, 60.0, 60.2, 60.3, 60.5, 62.4, 62.6, 82.7, 82.8, 85.2,
11.37, 111.4, 137.26, 137.3, 151.8, 166.8.
(10) (a) Higson, A. P.; Sierzchala, A.; Brummel, H.; Zhao, Z. Y.;
Caruthers, M. H. Tetrahedron Lett. 1998, 39, 3899. (b) Wada, T.;
Shimizu, M.; Oka, N.; Saigo, K. Tetrahedron Lett. 2002, 43, 4137.
1
1
P{ H} NMR (162 MHz, D O, 25 °C):  = 60.9 (br).
2
1
1
1
B{ H} NMR (128 MHz, D O, 25 °C):  = –12.8 (br).
2
(
(
(
11) Ravikumar, V. T.; Krotz, A. H.; Cole, D. L. Tetrahedron Lett. 1995,
+
+
HRMS (ESI+): m/z [M + H] calcd for C18H32BN O P : 484.2245; found:
7
6
36, 6587.
484.2221.
12) Shimizu, M.; Tamura, K.; Wada, T.; Saigo, K. Tetrahedron Lett.
2
004, 45, 371.
13) (a) Golebiewska, J.; Rachwalak, M.; Jakubowski, T.;
Romanowska, J.; Stawinski, J. J. Org. Chem. 2018, 83, 5496.
(
b) Golebiewska, J.; Stawinski, J. J. Org. Chem. 2020, 85, 4312.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
Synthesis
M. Rachwalak et al.
Feature
(
14) Within 15 min, the signal at  = 59 ppm disappeared and was
(17) (a) Lyle, R. L.; Boyce, C. B. J. Org. Chem. 1974, 39, 3708.
(b) Redmore, D. J. Org. Chem. 1976, 41, 2148. (c) Kers, A.;
Stawinski, J. Tetrahedron Lett. 1999, 40, 4263. (d) Kers, A.;
Dembkowski, L.; Kraszewski, A.; Stawinski, J. Heteroat. Chem.
1999, 10, 492.
P
replaced with a broad resonance at ca. P = 72 ppm (B = –21
ppm), tentatively assigned to the corresponding chloroborane-
phosphonate (MS analysis). This was accompanied by a gradual
conversion of diethyl H-phosphonate into its P-dimethoxytri-
tylated derivative (signal at ca.  = 27 ppm).
15) At this stage of the investigations, no attempt was made to max-
imize the isolated yields of compounds 3 and 4.
(18) Upon addition of 2,6-lutidine to the DMTr-Cl solution in DCM,
the orange color due to the presence of the dimethoxytrityl
cation changed to pale-yellow, indicating consumption of
DMTr-Cl. For the reaction with pyridine, the color change from
orange to yellow took place only after the addition of borane-
phosphonate 2a to the reaction mixture.
(19) Stawinski, J.; Strömberg, R. Di- and oligonucleotide Synthesis
Using H-Phosphonate Chemistry, In Oligonucleotide Synthesis:
Methods and Applications, Vol. 288; Herdewijn, P., Ed.; Humana
Press: Totowa, 2004, 81–100.
P
(
(
16) For 1° or 2° amines, no reaction was observed with boranephos-
phonate diesters in the presence of DMTr-Cl, apparently due to
the rapid conversion of the trityl reagent into inactive trityl-
amine derivatives. This is in contrast to the analogous reactions
of 1° and 2° amines with boranephosphonates promoted by
iodine, in which a rapid deboronation occurs leading ultimately
to the formation of the corresponding phosphoramidate
diesters (see also ref. 13 and references cited therein).
(20) Strenkowska, M.; Wanat, P.; Ziemniak, M.; Jemielity, J.;
Kowalska, J. Org. Lett. 2012, 14, 4782.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I