On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected o-aminoarylphosphonates

Article abstract of DOI:10.1007/s00706-017-2058-x

Abstract: Various arylamines were converted in two steps to N-Boc-N-arylphosphoramidates. LiTMP and LDA induced directed ortho-metalation at temperatures from ?78 to 0?°C. The ensuing [1,3]-migration of the phosphorus atom with its substituents from the n

Full text of DOI:10.1007/s00706-017-2058-x

Monatsh Chem (2018) 149:87–98
https://doi.org/10.1007/s00706-017-2058-x
ORIGINAL PAPER
On the rearrangement of N-aryl-N-Boc-phosphoramidates
to N-Boc-protected o-aminoarylphosphonates
Edyta Kuliszewska1 Friedrich Hammerschmidt1
•
Received: 7 August 2017 / Accepted: 4 September 2017 / Published online: 1 December 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract Various arylamines were converted in two steps
to N-Boc-N-arylphosphoramidates. LiTMP and LDA
induced directed ortho-metalation at temperatures from
-78 to 0 °C. The ensuing [1,3]-migration of the phos-
phorus atom with its substituents from the nitrogen to the
ortho-carbanionic carbon atom gave N-Boc-protected o-
aminoarylphosphonates. The nature of the substituent of
3-substituted phenylphosphoramidates strongly influenced
the regioselectivity of phosphonate formation. A crossover
experiment with a deuterated phosphoramidate proved the
intramolecular course of the rearrangement. Three repre-
Introduction
Phosphorus atoms in phosphonic and phosphoric acid
derivatives can be induced to migrate with their sub-
stituents within molecules. The most important
isomerization reactions are [1,2]- and [1,3]-rearrange-
ments. Pudovik and Konovalova discovered that a-
hydroxyphosphonates with certain structural requirements
isomerize to phosphates under basic conditions and they
named this reaction phosphonate–phosphate rearrangement
[1–3] (Scheme 1). They and others extended it to a-mer-
capto- and a-aminophosphonates (X = S, NR) [1]. These
isomerizations are reminiscent of the 1,2-Wittig [4] and
1,2-Brook rearrangement [5, 6]. When strong bases such as
LDA, LiTMP, n-BuLi, or s-BuLi are used to deprotonate 4
to give 3, the reverse process is induced. Then, the phos-
phorus atom migrates from the hetero- to the carbanionic
carbon atom in 3, a [1,2]-rearrangement as found by Sturtz
and Corbel [7] and preparatively and mechanistically
extensively studied by the group of Hammerschmidt
[8–10].
sentative
N-Boc-o-aminoarylphosphonates
were
deprotected to access the corresponding o-aminoarylphos-
phonic acids.
Graphical Abstract
Aryl phosphates 5 (X = O) can be isomerized to o-hy-
droxyarylphosphonates
8 with strong bases [11–15]
(Scheme 2). As the phosphate group effects directed ortho-
metalation [16, 17], aryl lithiums 6 are formed, which
undergo migration of the phosphorus atom from the oxygen
to the carbanionic carbon atom to give phosphonates 7 and
on workup 8. The driving force for the rearrangement is the
formation of the strong O–Li bond. A large variety of
dialkyl aryl phosphates and derivatives thereof were rear-
ranged. In analogy to the Fries-rearrangement this reaction
was named anionic phospho-Fries rearrangement [11]. We
prefer the more general term [1,3]-phosphate–hydrox-
yphosphonate rearrangement. The isomerization was
applied to S-aryl thiophosphates and their derivatives
Keywords Phosphorus compounds Á Rearrangements Á
Amines Á Carbanions Á Arenes
& Friedrich Hammerschmidt
friedrich.hammerschmidt@univie.ac.at
1
Institute of Organic Chemistry, University of Vienna,
Vienna, Austria
123

88
E. Kuliszewska, F. Hammerschmidt
nitrogen atom was protected with a Boc or dialkoxyphos-
phoryl group [22, 23]. Importantly, both Boc and
(RO)2P(O) at the nitrogen atom favor directed o-metalation
[16, 17] with lithium bases. In order to test this idea, aniline
was phosphorylated with diethyl chlorophosphate/pyridine
to give N-phenylphosphoramidate 10 in 83% yield
(Scheme 3). N-Boc protection was effected by deprotona-
tion of 10 at the nitrogen atom with s-BuLi at -78 °C,
followed by addition of Boc2O and allowing the reaction
mixture to slowly warm to room temperature. Bases n-
BuLi or s-BuLi were not used for metalation because of
possible attack at the carbonyl group of the Boc group,
which would regenerate phosphoramidate 10. Therefore,
we opted for strong encumbered amide bases such as
lithium 2,2,6,6-tetramethylpiperidide (LiTMP) and LDA.
When LiTMP was reacted with 11 in THF for 2 h at
-78 °C, phosphonate 12 was obtained in 55% yield by
flash chromatography. Surprisingly, even LiTMP removed
the Boc group from part of 11 so that phosphoramidate 10
was isolated in 30% yield as well. LDA as alternative base
in Et2O in combination with slowly warming the reaction
mixture for 18 h furnished the same phosphonate in 62%
yield and 10 as side product, too. These two experiments
demonstrate that N-Boc-protected N-phenylphosphorami-
date 11 can be rearranged by [1,3]-migration of phosphorus
from the nitrogen to the carbon atom induced by strong
lithium amide bases. Migration of the Boc group was not
detected. We tested also 14a, the isopropyl analog of 10, as
substrate for the rearrangement to optimize the reaction
conditions (Scheme 4). It was prepared from aniline and
diisopropyl bromophosphate [24] in 95% yield and then
Boc-protected as before (92% yield). The rearrangement
was performed in THF with three bases, s-BuLi/TMEDA,
LDA, and LiTMP at -78 °C. The combination of s-BuLi
with TMEDA delivered a mixture of recovered starting
material 14a and Boc-deprotected 13a as crude product,
which did not contain phosphonate 15a unexpectedly. The
Scheme 1
Scheme 1 .
Scheme 2
Scheme 2 .
[18–20]. Analogously, this isomerizations might be dubbed
[1,3]-thiophosphate–sulfanylphosphonate rearrangement.
Only one example for
a
[1,3]-phosphoramidate–
aminophosphonate rearrangement (X = NMe) has been
reported by Modro et al. [21]. Interestingly, they also
found, that diphenyl N-methyl-N-phenylphosphoramidate
underwent the first migration of phosphorus from the
oxygen to the carbon atom when treated with 1 equiv of
LDA, two migrations from O to C, when treated with 4
equiv of LDA and a third one from N to C with 8 equiv of
LDA. We reasoned that N-arylphosphoramidates with an
additional electron-withdrawing group on the nitrogen
atom could first facilitate o-metalation of the phenyl ring
and migration of the phosphorus atom from N to C and
second expand the scope of the P to O to the P to N
rearrangement.
Scheme 3
Results and discussion
We found recently that dialkyl N-benzylphosphoramidates
underwent a base-catalyzed [1,2]-phosphoramidate-a-
aminophosphonate rearrangement when the secondary
Scheme 3 .
123

On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected…
89
Table 1 [1,3]-Rearrangement of N-Boc-N-arylphosphoramidates
14b–14e to N-Boc-protected o-aminoarylphosphonates 15b–15e and
16b–16ea
Scheme 4
14
Base
T/ °C
t/h
Yield/ % 15/16
b
b
b
c
c
c
d
d
e
e
a
LiTMP
LiTMP
LDA
-78
0
1
1
55/35
55/32
96/0
19/60
23/66
4/78
40/0
67/0
0/5
-78
-78
0
1
LiTMP
LiTMP
LDA
1
1
-78
-78
-78
-78
-78
1
LiTMP
LDA
1
1
LiTMP
LiTMPb
20
1
0/6
All reactions were performed in THF
b
Two equiv of TMEDA were present as well
formation of phosphonates 15b is predetermined. When
chloride as substituent was replaced by iodide being larger
in size and lower in electronegativity compared to chloride,
the quantity of phosphonate 16c (60 and 66%, see Table 1)
outweighed those of 15c (19 and 23%) for LiTMP, inde-
pendent of the reaction temperature. Remarkably, LDA
delivered a yield of only 4% for 15c but 78% for 16c. The
next two N-Boc-protected phosphoramidates, 14d and 14e,
followed the expectations. The methoxy group with its
strong ortho directing metalation effect in combination
with the P=O group directed deprotonation exclusively to
carbon atom 2, leading to the exclusive formation of
phosphonate 15d. However, the methyl group which
reduces the acidity of the hydrogen atoms in the phenyl
ring and is additionally of significant size effected that the
rearrangement of 14e furnished low yields of 16e (5 and
6%), despite a reaction time of 20 h with slow warming to
room temperature. The main components of the crude
product were starting material 14e and its precursor 13e
formed by base-catalyzed removal of Boc.
Scheme 4 .
other two bases gave the desired phosphonate 15a in 25
and 79% yield, respectively. In summary, these results
demonstrated that N-Boc-protected N-arylphosphorami-
dates can be isomerized to N-Boc-protected o-
aminoarylphosphonates. As isopropyl protecting groups at
the phosphorus atom seemed to shield it better than the
ethyl groups and to give higher yields, all further experi-
ments were performed with diisopropyl phosphoramidates.
In order to address the regioselectivity of metalation and
expand the scope of the rearrangement, meta-substituted
anilines 9b–9e were transformed into N-Boc-protected
phosphoramidates 14b–14e by the previous methods in
combined unoptimized yields ranging from 58 to 90%
yield. All rearrangements were performed in THF with
LiTMP as well as LDA, normally at -78 °C, sometimes
for comparison reasons also at 0 °C, for 1 h in the majority
of experiments (Table 1). Yields could possibly be
increased by longer reaction times for certain substrates.
Varying amounts of starting material 14 and the corre-
sponding phosphoramidate 13 formed by base-catalyzed
removal of Boc from 14 were present (TLC) in the crude
reaction products, but were not isolated. In the case of the
N-Boc-N-(m-chlorophenyl)phosphoramidate 14b the two
phosphonates 15b and 16b were formed in yields of 55 and
35% for LiTMP as base at -78 °C and 55 and 32% for the
same base at 0 °C, respectively. LDA delivered exclusively
15b in 96% yield, surprisingly. The preferred deprotona-
tion ortho to both substituents might be explained by their
additive acidifying and o-directing effect, although the
bases were very encumbered. Consequently, the preferred
Two more amines were transformed into N-protected
phosphoramidates. 1-Naphthylamine was phosphorylated
and N-Boc protected in the usual way to give compound 19,
which was smoothly subjected to the [1,3]-phosphorami-
date–aminophosphonate rearrangement with LiTMP in Et2O
at -78 °C for 2 h (Scheme 5). The 2-napthylphosphonate 20
was isolated in 84% yield. The second amine was
2-aminopyridine (21), which was converted to diphospho-
ramidate 22 with 2 equiv of diisopropyl bromophosphate/
excess pyridine in 72% yield in one step (Scheme 6). We
found previously that two diethylphosphoryl groups at the
nitrogen atom of benzyl amine allowed to perform a [1,2]-
phosphoramidate-a-aminophosphonate rearrangement [22].
Here, LiTMP and LDA mediated a [1,3]-phosphoramidate-
123

90
E. Kuliszewska, F. Hammerschmidt
Scheme 7
Scheme 5
Scheme 5 .
Scheme 6
Scheme 7 .
rearrangement. A modified crossover experiment was car-
ried out by Heinicke et al. [26] demonstrating that aryl
dialkyl phosphates isomerize to o-hydroxyphenylphos-
phonates intramolecularly.
o-Aminophenylphosphonic acid was tested for its anti-
Scheme 6 .
cholesterinase
activity
[27]
and
2-amino-4-
methylphenylphosphonic acid for removing formaldehyde
adducts [28] from RNA and DNA bases. The protected o-
aminoarylphosphonates prepared by [1,3]-migration of
phosphorus can be deprotected to give o-aminoarylphos-
phonic acids as shown for three examples (Scheme 8). N-
Boc-o-aminophenylphosphonate 15a was deprotected by
refluxing with 6 M HCl or with TMSBr/allylTMS [29] in
CH2Cl2 under milder conditions, resulting in a higher yield.
The o-aminophenylphosphonic acid (25) was purified by
cation exchange chromatography (Dowex 50 W 9 8, H?)
and crystallization from water. 2-Naphthylphosphonate 20
had to be deprotected with TMSBr/allylTMS and crystal-
lized from methanol because of its lability in hot water,
where it decomposed to 1-naphthylamine (detected by
TLC) and H3PO4 (detected by 31P NMR). Pyridin-3-
ylphosphonate 23 was converted to 2-amino-3-pyridin-3-
ylphosphonic acid (27) using refluxing 6 M HCl, followed
by purification as for 25. Selective removal of the Boc
group with CF3CO2H would give dialkyl o-aminophos-
phonates. As the amino group in aromatic compounds can
be replaced by a variety of substituents, the globally or
partially deprotected N-Boc-o-aminophoshonates prepared
here are useful starting materials for other o-substituted
phosphonic acid derivatives.
aminophosphonate rearrangement of diphosphoramidate 22
to phosphonate 23 in yields of 36 and 72%, respectively.
When we started this project we surmised that the
migration of phosphorus from the nitrogen to the carbon
atom is an intramolecular process proceeding via a cyclic
four-membered transition state. As it is unfavorable, we
reasoned that the formal [1,3]-migration could also be
exclusively or in part an intermolecular process with
phenyllithium attacking at the electrophilic phosphorus
atom of a second molecule. We conceived a crossover
experiment with an equimolar mixture of deuterated and
nondeuterated N-Boc-N-(3-methoxyphenyl)phosphorami-
date, [D17]14d and 14d (Scheme 7). The latter was
synthesized from [D3]methyl tosylate [25] and tris(hep-
tadeuterioisopropyl) phosphite [24] by the methods used
for the unlabeled species. The rearrangement of the 1:1
mixture furnished a 1:1 mixture of phosphonates 15d and
[D17]15d in 98% yield. No phosphonates containing 3 or
14 deuterium atoms could be detected by EI-MS, indicative
of an intermolecular transfer of the phosphorus atom with
its labeled substituents. Therefore, the migration of the
phosphorus atom from the nitrogen to the ortho-carbon
atom in N-Boc-N-arylphosphoramidates proceeds exclu-
sively intramolecularly and represents a [1,3]-sigmatropic
123

On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected…
91
Flash (column) chromatography was performed with
Scheme 8
Merck silica gel 60 (230–400 mesh). Thin layer chro-
matography (TLC) was carried out on 0.25 mm thick
Merck plates, silica gel 60 F254. Spots were visualized by
UV and/or dipping the plate into a solution of (NH4)6-
Mo7O24Á4H2O (24.0 g) and Ce(SO4)2Á4H2O (1.0 g) in 10%
aqueous H2SO4 (500 cm3), followed by heating with a heat
gun. Pyridine was dried by refluxing over powdered CaH2,
˚
then distilled and stored over molecular sieves (4 A).
Dichloromethane was dried by storage over molecular
˚
sieves (3 A). All other chemicals and solvents were of the
highest purity available and used as received.
General procedure A—N-phosphorylation of aromatic
amines with diisopropyl bromophosphate
A solution of bromine (18 cm3, 18 mmol, 1 M in dry
CH2Cl2) was added dropwise to a stirred solution of
4.44 cm3 (i-PrO)3P (3.75 g, 18 mmol) in 10 cm3 dry
CH2Cl2 under Ar at -50 °C [24]. Stirring was continued
for 30 min at 0 °C. After cooling again to -50 °C, a
solution of aromatic amine (15 mmol) in 2 cm3 dry
CH2Cl2 and 4.18 cm3 Et3N (3.04 g, 30 mmol) was added.
The reaction mixture was allowed to warm to RT (18 h).
HCl (12 cm3, 2 M) and 20 cm3 water were added. The
organic layer was separated and the aqueous one was
extracted twice with CH2Cl2. The combined organic layers
were dried with Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography
and/or crystallization.
Scheme 8 .
Conclusion
In summary, we have shown that arylamines can be easily
converted to N-Boc-N-arylphosphoramides. Treatment
with LiTMP or LDA mediated [1,3]-phosphoramidate-
aminophosphonate rearrangements. Three phosphonates
were globally deprotected. This approach extends the scope
for the synthesis of 2-amino-substituted phosphonic acids
derived from aromatic and heteroaromatic amines. Addi-
tionally, selective removal of the Boc-protecting group will
give a free amino group amenable to fuctional group
manipulation and incorporation of the 2-aminophospho-
nates into peptides.
General procedure B—conversion of N-arylphosphorami-
dates to N-Boc-N-arylphosphoramidates
s-BuLi (5.14 cm3, 7.2 mmol, 1.4 M in cyclohexane) was
added to a stirred solution of phosphoramidate (6 mmol) in
10 cm3 dry THF (or Et2O) under Ar at -78 °C. After
15 min a solution of 1.44 g Boc2O (6.6 mmol) in 5 cm3
dry THF (or Et2O) was added. The reaction mixture was
allowed to slowly warm to RT in the cooling bath (18 h).
After the addition of 3 cm3 solution of AcOH in Et2O
(2 M) and 10 cm3 H2O the organic phase was separated
and the aqueous one extracted with CH2Cl2 (3 9 10 cm3).
The combined organic layers were washed with a saturated
aqueous solution of NaHCO3, dried with Na2SO4, and
concentrated under reduced pressure. The residue was
purified by flash chromatography.
Experimental
NMR pectra (1H, 13C, and 31P) were recorded in CDCl3 or
D2O on a Bruker DRX 400 (1H: 400.13 MHz, 13C:
100.61 MHz, 31P: 161.98 MHz), spectrometer at 25 °C,
respectively. Chemical shifts d (ppm) were referenced to
residual CHCl3 (dH = 7.24), CDCl3 (dC = 77.00), HDO
(dH = 4.67), and external H3PO4 (85%; dP = 0.00). IR
spectra of compounds soluble in CDCl3 or CH2Cl2 were
recorded on a Perkin-Elmer FT 1600 IR Spectrometer. The
solution was applied to a silicon disc [30] and the solvent
was allowed to evaporate before the measurement. IR
spectra of the aminophosphonic acids were recorded on a
Perkin-Elmer Spectrum 2000 IR spectrometer in ATR
mode. Melting points were determined on a Reichert
Thermovar instrument. New compounds were checked for
purity by means of appropriate combustion analysis results.
General procedure C—rearrangement of N-Boc-N-
arylphosphoramidates with lithium tetramethylpiperidide
(LiTMP)
n-BuLi (0.94 cm3, 1.50 mmol, 1.6 M in hexane) was added
to
a
stirred solution of 0.25 cm3 2,2,6,6-tetram-
ethylpiperidine (0.212 g, 1.5 mmol) in 8 cm3 dry THF
(or Et2O) at 0 °C under Ar. Stirring was continued for
30 min at 0 °C. Subsequently, the mixture was cooled at
123

92
E. Kuliszewska, F. Hammerschmidt
ꢀ
-78 °C and a solution of N-Boc-N-arylphosphoramidate
(1 mmol) dissolved in 2 cm3 dry THF (or Et2O) was added.
After stirring for 2 h at -78 °C the reaction was quenched
with 1 cm3 AcOH (2 M in Et2O) and 5 cm3 H2O. The
organic layer was separated and the aqueous one was
extracted twice with CH2Cl2. The combined organic layers
were dried with Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography.
V = 2982, 1728, 1492, 1369, 1302, 1160, 1099, 1028,
983 cm-1
.
Diethyl 2-(t-butoxycarbonylamino)phenylphosphonate
(12, C15H24NO5P)
Diethyl N-Boc-N-phenylphosphoramidate (11, 0.329 g,
1 mmol) was rearranged according to general procedure
C in THF and flash chromatogaphed (hexanes/EtOAc = 3/
1, Rf = 0.45) to give 0.182 g 2-(N-Boc-amino)phenylphos-
phonate 12 (55%) as a colorless oil and 0.078 g
phosphoramidate 10 (30%). When 11 (0.329 g, 1 mmol)
was rearranged according to general procedure D in Et2O
and flash chromatographed (hexanes/EtOAc = 3/1), the
yield of phosphonate 12 was 0.203 g (62%). 1H NMR
(400.13 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 6H), 1.49
(s, 9H), 4.03 (m, 2H), 4.12 (m, 2H), 7.01 (ddt, J = 1.0, 3.0,
7.7 Hz, 1H), 7.47 (ddt, J = 1.5, 7.3, 7.7 Hz, 1H), 7.52
(ddd, J = 1.5, 7.7, 14.4 Hz, 1H), 8.32 (ddd, J = 1.0, 7.3.
7.8 Hz, 1H), 9.61 (br. s, 1H) ppm; 13C NMR (100.61 MHz,
CDCl3): d = 16.2 (d, J = 6.9 Hz, 2C), 28.3 (3C), 63.2 (d,
J = 5.5 Hz, 2C), 80.4, 112.9 (d, J = 179.7 Hz), 119.2 (d,
J = 11.5 Hz), 121.7 (d, J = 13.8 Hz), 132.6 (d,
J = 6.1 Hz), 133.9 (d, J = 2.2 Hz), 143.4 (d,
J = 7.7 Hz), 153.0 ppm; 31P NMR (161.98 MHz, CDCl3):
General procedure D—rearrangement of N-Boc-N-
arylphosphoramidates with LDA
s-BuLi (1.07 cm3, 1.5 mmol, 1.4 M in hexane) was added
to a stirred solution of 0.21 cm3 diisopropylamine (0.152 g,
1.5 mmol) in 5 cm3 dry Et2O (or THF) at -20 °C under
Ar. Stirring was continued for 20 min. Subsequently, a
solution of N-Boc-N-arylphosphoramidate (1 mmol) dis-
solved in 2 cm3 dry Et2O was added. The stirred solution
was allowed to slowly warm to RT (20 h) and then the
reaction was quenched with 2 cm3 AcOH (2 M in Et2O)
and 5 cm3 H2O. The organic layer was separated and the
aqueous one was extracted twice with CH2Cl2. The
combined organic layers were dried with Na2SO4 and
concentrated under reduced pressure. The residue was
purified by flash chromatography.
ꢀ
d = 34.1 ppm; IR (Si, CDCl3): V = 3247, 3117, 2981,
1732, 1587, 1538, 1443, 1305, 1243, 1160, 1094, 1044,
Diethyl N-phenylphosphoramidate (10)
Diethyl chlorophosphate (3.451 g, 2.89 cm3, 20 mmol)
was added to a stirred solution of 1.83 cm3 aniline
(1.862 g, 20 mmol) and 3.35 cm3 Et3N (2.429 g,
24 mmol) in 36 cm3 dry CH2Cl2 under Ar at RT. After
stirring for 19 h at RT the reaction was quenched with
20 cm3 H2O. The organic layer was separated and the
aqueous one was extracted twice with CH2Cl2. The
combined organic layers were dried with Na2SO4 and
concentrated under reduced pressure. The residue was
purified by crystallization from hexanes to give 3.79 g
phosphoaramidate 10 (83%) as colorless crystals. M.p.:
93–94 °C (Ref. [31] 94–95 °C).
1022, 972 cm-1
.
Diisopropyl N-phenylphosphoramidate
(13a, C12H20NO3P)
Aniline (1.40 g, 1.37 cm3, 15 mmol) was phosphorylated
according to general procedure A and flash chro-
matographed (hexanes/EtOAc = 1/1, Rf = 0.68) to yield
3.65 g phosphoramidate 13a (95%) as colorless crystals.
M.p.: 120–121 °C (hexanes); 1H NMR (400.13 MHz,
CDCl3): d = 1.19 (d, J = 6.3 Hz, 6H), 1.36 (d,
J = 6.3 Hz, 6H), 4.66 (dsept, J = 6.3, 7.6 Hz, 2H), 6.22
(br. s, 1H), 6.90 (tt, J = 1.0, 7.6 Hz, 1H), 6.97 (m, 2H),
7.20 (br. t, J = 7.6 Hz, 2H) ppm; 13C NMR (100.61 MHz,
CDCl3): d = 23.5 (d, J = 5.4 Hz, 2C), 23.9 (d,
J = 4.6 Hz, 2C), 71.6 (d, J = 5.4 Hz, 2C), 117.4 (d,
J = 7.7 Hz, 2C), 121.2, 129.0 (2C), 140.2 ppm; 31P NMR
Diethyl N-(t-butoxycarbonyl)-N-phenylphosphoramidate
(11, C15H24NO5P)
Diethyl N-phenylphosphoramidate (10, 1.15 g, 5 mmol)
was converted to the N-Boc derivative in THF and purified
ꢀ
(161.98 MHz, CDCl3): d = 1.3 ppm; IR (Si): V = 3161,
by
flash
chromatography
(hexanes/EtOAc = 1/2,
2981, 2919, 1604, 1504, 1426, 998, 963 cm-1
.
Rf = 0.45) to give 1.55 g N-Boc-phosphoramidate 11
1
(94%) as a colorless oil. H NMR (400.13 MHz, CDCl3):
Diisopropyl N-(t-butoxycarbonyl)-N-phenylphosphorami-
date (14a, C17H28NO5P)
d = 1.253 (dt, J = 1.0, 7.1 Hz, 3H), 1.251 (dt, J = 1.0,
7.1 Hz, 3H), 1.47 (br. s, 9H), 4.07 (m, 2H), 4.17 (m, 2H),
7.23 (m, 2H), 7.29 (m, 1H), 7.36 (m, 2H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 15.8 (d, J = 7.7 Hz, 2C), 27.8
(3C), 63.7 (d, J = 6.1 Hz, 2C), 82.6, 127.5 (d,
J = 1.5 Hz), 128.7 (2C), 128.8 (d, J = 2.3 Hz, 2C),
138.1, 153.2 (d, J = 8.4 Hz) ppm; 31P NMR
(161.98 MHz, CDCl3): d = 0.2 ppm; IR (Si, CDCl3):
Diisopropyl N-(phenyl)phosphoramidate (13a, 2.01 g,
7.81 mmol) was converted to the N-Boc derivative in
15 cm3 dry Et2O according to general procedure B. The
crude product was purified by flash chromatography
(CH2Cl2/EtOAc = 7/1, Rf = 0.40) to give 2.57 g N-Boc-
N-phenylphosphoramidate 14a (92%) as a colorless oil. 1H
NMR (400.1 MHz, CDCl3): d = 1.16 (d, J = 6.3 Hz, 6H),
123

On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected…
93
1.31 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.70 (dsept,
J = 6.3, 7.3 Hz, 2H), 7.19 (m, 2H), 7.27 (m, 1H), 7.33
(m, 2H) ppm; 13C NMR (100.6 MHz, CDCl3): d = 23.3 (d,
J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.0 (3C), 72.8
(d, J = 6.1 Hz, 2C), 82.7, 127.5 (d, J = 1.5 Hz, 2C),
128.8, 129.1 (d, J = 2.3 Hz, 2C), 138.8, 153.6 ppm; 31P
NMR (161.98 MHz, CDCl3): d = 11.6 ppm; IR (Si,
Diisopropyl N-(t-butoxycarbonyl)-N-(3-chlorophenyl)phos-
phoramidate (14b, C17H27ClNO5P)
Diisopropyl N-(3-chlorophenyl)phosphoramidate (13b,
1.46 g, 5 mmol) was converted to N-Boc derivative 14b
in Et2O, using general procedure B. The crude product was
purified by flash chromatography (hexanes/EtOAc = 1/1,
Rf = 0.48) to give 1.36 g N-Boc-phosphormadiate 14b
(69%) as colorless crystals. M.p.: 80 °C (hexanes); 1H
NMR (400.13 MHz, CDCl3): d = 1.21 (d, J = 6.3 Hz,
6H), 1.33 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.71 (dsept,
J = 6.3, 7.1 Hz, 2H), 7.11 (m, 1H), 7.21 (m, 1H), 7.26 (m,
2H) ppm; 13C NMR (100.65 MHz, CDCl3): d = 23.4 (d,
J = 5.4 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C), 28.0 (3C), 73.0
(d, J = 6.1 Hz, 2C), 83.1, 127.5 (d, J = 2.3 Hz), 127.8,
129.5 (d, J = 2.3 Hz), 129.7, 134.1, 139.9, 153.2 (d,
J = 7.7 Hz) ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
CDCl3): V = 2981, 1729, 1492, 1386, 1370, 1299, 1259,
1161, 1097, 1002 cm-1
.
Diisopropyl 2-(t-butoxycarbonylamino)phenylphosphonate
(15a, C17H28NO5P)
Diisopropyl N-(t-butoxycarbonyl)-N-phenylphosphorami-
date (14a, 0.514 g, 1.44 mmol) was converted to
phenylphosphonate 15a by general procedure C in THF.
The crude product was purified by flash chromatography
(hexanes/EtOAc = 5/1, Rf = 0.64) to give 0.404 g phos-
phonate 15a (79%) as a colorless oil. Rearrangement of
0.514 g phosphoramidate 14a (1.44 mmol) according to
general procedure D in THF and flash chromatography
(hexanes/EtOAc = 3/1, Rf = 0.60) of the crude product
furnished 0.128 g phosphonate 15a (25%). 1H NMR
(400.13 MHz, CDCl3): d = 1.20 (d, J = 6.3 Hz, 6H),
1.36 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H), 4.64 (dsept,
J = 6.3, 7.6 Hz, 2H), 7.00 (ddt, J = 1.0, 3.0, 7.7, 1H),
7.45 (ddt, J = 1.5, 7.3, 7.7 Hz, 1H), 7.55 (ddt, J = 1.5, 7.7,
14.6 Hz, 1H), 8.28 (ddd, J = 1.0, 7.3, 7.5 Hz, 1H), 9.56 (br.
s, 1H) ppm; 13C NMR (100.63 MHz, CDCl3): d = 23.7 (d,
J = 4.6 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C), 28.3 (3C), 71.4
(d, J = 5.4 Hz, 2C), 80.3, 114.8 (d, J = 181.3 Hz), 119.2
(d, J = 11.5 Hz), 121.6 (d, J = 13.8 Hz), 132.8 (d,
J = 6.1 Hz), 133.6 (d, J = 2.3 Hz), 142.8 (d,
J = 6.9 Hz), 153.0 ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
d = -2.4 ppm; IR (Si, CDCl3): V = 2981, 1729, 1302,
1267, 1159, 1000 cm-1
.
Diisopropyl (2-t-butoxycarbonylamino-6-chlorophenyl)phos
phonate and diisopropyl (2-t-butoxycarbonylamino-4-
chlorophenyl)phosphonate (15b and 16b, C17H27ClNO5P)
N-(t-Butoxycarbonyl)-N-(3-chlorophenyl)phosphoramidate
(14b, 0.392 g, 1 mmol) was rearranged in THF according
to general procedure C for 1 h at -78 °C. The crude
product was purified by flash chromatography (hexanes/
EtOAc = 5/1, 15b: Rf = 0.70, 16b: Rf = 0.60) to give
0.216 g phosphonate 15b (55%) as colorless crystals, m.p.:
70–75 °C (hexanes), and 0.137 g phosphonate 16b (35%)
as colorless oil. When the same experiment was performed
according to general procedure C for 1 h at 0 °C, 0.215 g
15b (55%) and 0.125 g 16b (32%) were obtained. When
392 mg N-(t-butoxycarbonyl)-N-(3-chlorophenyl)phospho-
ramidate (14b, 1 mmol) was rearranged according to
general procdure D in THF for 1 h at -78 °C, 0.377 g
phosphonate 15b (96%) was obtained.
ꢀ
d = 31.9 ppm; IR (Si, CDCl3): V = 3247, 1732, 1587,
1305, 1243, 1160, 985 cm-1
.
Diisopropyl N-(3-chlorophenyl)phosphoramidate
(13b, C12H19ClNO3P)
15b: 1H NMR (400.13 MHz, CDCl3): d = 1.23 (d,
J = 6.3 Hz, 6H), 1.38 (d, J = 6.3 Hz, 6H), 1.50 (s, 9H),
4.68 (dsept, J = 6.3, 7.8 Hz, 2H), 7.01 (ddd, J = 1.0, 4.3,
7.8 Hz, 1H), 7.33 (br. t, J = 8.3 Hz, 1H), 8.41 (ddd,
J = 1.0, 5.6, 8.6 Hz, 1H), 11.11 (s, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.5 (d, J = 4.6 Hz, 2C), 23.9
(d, J = 4.6 Hz, 2C), 28.3 (3C), 72.2 (d, J = 6.1 Hz, 2C),
80.4, 112.1 (d, J = 179.7 Hz), 117.2 (d, J = 10.7 Hz),
124.0 (d, J = 9.9 Hz), 133.7 (d, J = 1.5 Hz), 137.9, 146.3
(d, J = 6.1 Hz), 153.2 ppm; 31P NMR (161.98 MHz,
3-Chloroaniline (1.021 g, 0.84 cm3, 8 mmol) was con-
verted to (3-chlorophenyl)phosphoramidate 13b according
to general procedure A. The crude product was purified by
flash chromatography (hexanes/EtOAc = 2/1, Rf = 0.18)
to give 2.22 g phosphoramidate 13b (95%) as colorless
crystals. M.p.: 121–122 °C (hexanes); 1H NMR
(400.13 MHz, CDCl3): d = 1.21 (d, J = 6.3 Hz, 6H),
1.37 (d, J = 6.3 Hz, 6H), 4.66 (dsept, J = 6.3, 7.6 Hz,
2H), 6.87 (m, 2H), 6.90 (br. s, 1H), 7.01 (t, J = 2.0 Hz,
1H), 7.11 (t, J = 8.1 Hz, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.5 (d, J = 5.4 Hz, 2C),
23.8 (d, J = 4.6 Hz, 2C), 71.9 (d, J = 5.4 Hz, 2C), 115.5
(d, J = 7.6 Hz), 117.4 (d, J = 7.6 Hz), 121.2, 130.0,
134.7, 141.7 ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
CDCl3): d = 15.4 ppm; IR (Si, CDCl3): V = 2981, 1732,
1582, 1444, 1397, 1298, 1269, 1239, 1160, 1124, 1061,
995 cm-1
.
16b: 1H NMR (400.13 MHz, CDCl3): d = 1.18 (d,
J = 6.1 Hz, 6H), 1.33 (d, J = 6.1 Hz, 6H), 1.47 (s, 9H),
4.61 (dsept, J = 6.1, 7.8 Hz, 2H), 6.96 (dt, J = 1.8,
8.3 Hz, 1H), 7.43 (dd, J = 8.3, 14.4 Hz, 1H), 8.40 (dd,
ꢀ
d = 0.8 ppm; IR (Si): V = 3153, 2980, 1599, 1498,
1481, 1388, 1225, 995 cm-1
.
123

94
E. Kuliszewska, F. Hammerschmidt
J = 1.8, 5.8 Hz, 1H), 9.71 (br.s, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.6 (d, J = 5.4 Hz, 2C), 23.9
(d, J = 3.8 Hz, 2C), 28.2 (3C), 71.6 (d, J = 5.4 Hz, 2C),
80.8, 112.8 (d, J = 183.6 Hz), 118.9 (d, J = 11.5 Hz),
121.8 (d, J = 14.5 Hz), 133.8 (d, J = 6.9 Hz), 139.9 (d,
J = 3.8 Hz), 143.9 (d, J = 8.4 Hz), 152.6 ppm; 31P NMR
(162.0 MHz, CDCl3): d = 17.7 ppm; IR (Si, CDCl3):
J = 1.0, 1.7, 7.8 Hz, 1H), 7.55 (dt, J = 1.0, 1.7 Hz, 1H),
7.61(dq, J = 1.0, 7.8 Hz, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.4 (d, J = 6.1 Hz, 2C),
23.9 (d, J = 3.8 Hz, 2C), 28.0 (3C), 73.1 (d, J = 6.1 Hz,
2C), 83.1, 93.3, 128.6 (d, J = 2.3 Hz), 130.2, 136.6, 138.1
(d, J = 2.3 Hz), 139.9, 153.2 (d, J = 7.6 Hz) ppm; 31P
NMR (161.98 MHz, CDCl3): d = -2.4 ppm; IR (Si):
-1
ꢀ
ꢀ
V = 2980, 2930, 1727, 1300, 1159, 1098, 1002 cm
.
V = 3233, 2981, 1732, 1599, 1577, 1520, 1411, 1275,
1240, 1160, 1077, 987 cm-1
.
Diisopropyl (2-t-butoxycarbonylamino-6-iodophenyl)- and
diisopropyl (2-t-butoxycarbonylamino-4-iodophenyl)phos-
phonate (15c and 16c, C17H27INO5P)
Diisopropyl N-(3-iodophenyl)phosphoramidate
(13c, C12H19INO3P)
Iodoaniline (1.752 g, 0.95 cm3, 8 mmol) was converted to
N-(2-iodophenyl)phosphoramidate 13c. The crude product
was purified by flash chromatography (hexanes/
EtOAc = 1/1, Rf = 0.51) to give 2.60 g phosphoramidate
13c (85%) as colorless crystals. M.p.: 136–137 °C (hex-
anes); 1H NMR (400.13 MHz, CDCl3): d = 1.22 (d,
J = 6.3 Hz, 6H), 1.37 (d, J = 6.3 Hz, 6H), 4.67 (dsept,
J = 6.3, 7.6 Hz, 2H), 6.24 (br. d, J = 8.8 Hz, 1H), 6.90
(dt, J = 1.8, 7.8 Hz, 1H), 7.03 (dt, J = 1.8, 7.8 Hz, 1H),
7.06 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 1.8 Hz, 1H) ppm;
13C NMR (100.61 MHz, CDCl3): d = 23.6 (d, J = 5.4 Hz,
2C), 23.8 (d, J = 4.6 Hz, 2C), 72.0 (d, J = 4.6 Hz, 2C),
116.0 (d, J = 7.7 Hz), 120.3 (d, J = 7.7 Hz), 122.8, 124.3,
130.4, 141.6 ppm; 31P NMR (161.98 MHz, CDCl3):
N-(t-Butoxycarbonyl)-N-(3-iodophenyl)phosphoramidate
(14c, 0.483 g, 1.0 mmol) was rearranged according to
general procedure C in THF at -78 °C for 1 h. The crude
product was purified by flash chromatography (hexanes/
EtOAc = 5/1, 15c: Rf = 0.62, 16c: Rf = 0.53) to give
0.093 g 15c (19%) as colorless crystals, m.p.: 75–77 °C
(hexanes), and 0.288 g 16c (60%) as a colorless oil. When
this experiment was repeated except that the rearrangement
was perfomed at 0 °C for 1 h, 0.112 g 15c (23%) and
0.319 g 16c (66%) were obtained. When 0.483 g N-Boc-
phosphoramidate 14c (1 mmol) was rearranged according
to general procedure D in THF at -78 °C for 1 h, 0.019 g
15c (4%) and 0.376 g 16c (78%) were obtained.
ꢀ
d = 0.4 ppm; IR (Si): V = 3148, 2979, 1581, 1480,
15c: 1H NMR (400.13 MHz, CDCl3): d = 1.28 (d,
J = 6.3 Hz, 6H), 1.41 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H),
4.71 (dsept, J = 6.3, 7.3 Hz, 2H), 7.01 (dd = *t, J = 7.8,
8.6 Hz, 1H), 7.66 (ddd, J = 1.0, 3.4, 7.8 Hz, 1H), 8.48
1220, 994, 974 cm-1
.
Diisopropyl N-(t-butoxycarbonyl)-N-(3-iodophenyl)phos-
phoramidate (14c, C17H27INO5P)
(ddd, J = 1.0, 5.6, 8.6 Hz, 1H), 11.16 (br. s, 1H) ppm; 13
C
n-BuLi (1.63 cm3, 2.6 mmol, 1.6 M in hexane) was added
to a stirred solution of 0.44 cm3 TMP (0.367 g, 2.6 mmol)
in 4.5 cm3 dry THF at 0 °C under argon. After stirring for
15 min at 0 °C a solution of 0.39 cm3 TMEDA (0.302 g,
2.6 mmol) was added and stirring was continued for
15 min. Then, the mixture was cooled at -78 °C and a
solution of 0.990 g N-(3-iodophenyl)phosphoramidate 13c
(2.6 mmol) dissolved in 2 cm3 dry THF was added,
followed 15 min later by 0.567 g Boc2O (2.6 mmol)
dissolved in 2 cm3 dry THF. The stirred solution was
allowed to warm to RT (20 h) and then the reaction was
quenched with 1.5 cm3 AcOH (2 M in dry Et2O) and
5 cm3 H2O. The organic layer was separated and the
aqueous one was extracted twice with CH2Cl2. The
combined organic layers were dried with Na2SO4 and
concentrated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2/EtOAc = 7/1,
Rf = 0.31) to give 0.850 g N-Boc-phospharamidate 14c
NMR (100.61 MHz, CDCl3): d = 23.7 (d, J = 4.6 Hz,
2C), 24.0 (d, J = 4.6 Hz, 2C), 28.4 (3C), 72.5 (d,
J = 4.4 Hz, 2C), 80.4, 99.1 (d, J = 1.5 Hz), 116.8 (d,
J = 182.8 Hz), 118.8 (d, J = 10.7), 133.8 (d, J = 2.3 Hz),
135.9 (d, J = 11.5 Hz), 146.4 (d, J = 7.7 Hz), 153.2 ppm;
31P NMR (161.98 MHz, CDCl3): d = 15.1 ppm; IR (Si,
ꢀ
CDCl3): V = 2980, 1731, 1577, 1437, 1388, 1252, 1160,
1116, 1059, 993 cm-1
.
16c: 1H NMR (400.13 MHz, CDCl3): d = 1.19 (d,
J = 6.3 Hz, 6H), 1.35 (d, J = 6.3 Hz, 6H), 1.49 (s, 9H),
4.62 (dsept, J = 6.3, 7.8 Hz, 2H), 7.13 (*dt, J = 2.0, 8.3,
1H), 7.37 (dd, J = 8.3, 14.4, 1H), 8.57 (dd, J = 1.5, 5.8,
1H), 9.70 (bs, 1H, NH) ppm; 13C NMR (100.61 MHz,
CDCl3): d = 24.1 (d, J = 5.4 Hz, 2C), 24.4 (d,
J = 3.8 Hz, 2C), 28.7 (3C), 71.7 (d, J = 5.4 Hz, 2C), 80.8,
113.3 (d, J = 183.6 Hz), 121.8 (d, J = 11.5 Hz), 124.7 (d,
J = 14.5 Hz), 128.5 (d, J = 3.8 Hz), 133.8 (d,
J = 6.9 Hz), 143.8 (d, J = 7.7 Hz), 152.7 ppm; 31P NMR
(161.98 MHz, CDCl3): d = 17.8 ppm; IR (Si, CDCl3):
1
(68%) as colorless crystals. M.p.: 75–77 °C (hexanes); H
NMR (400.13 MHz, CDCl3): d = 1.20 (d, J = 6.3 Hz,
6H), 1.32 (d, J = 6.3 Hz, 6H), 1.45 (s, 9H), 4.71 (dsept,
J = 6.3, 7.1 Hz, 2H), 7.06 (t, J = 7.8 Hz, 1H), 7.18 (ddt,
ꢀ
V = 3233, 2980, 1731, 1594, 1575, 1408, 1274, 1238,
1160, 1073, 987 cm-1
.
123

On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected…
95
Diisopropyl N-(3-methoxyphenyl)phosphoramidate
(13d, C13H22NO4P)
24.0 (d, J = 4.6 Hz, 2C), 28.4 (3C), 55.5, 71.0 (d,
J = 5.4 Hz), 79.9, 101.8 (d, J = 175.2 Hz), 104.1(d,
J = 8.4 Hz), 111.3 (d, J = 11.5 Hz), 134.6, 145.7 (d,
J = 5.4 Hz), 153.3, 162.2 ppm; 31P NMR (161.98 MHz,
3-Methoxyaniline (0.985 g, 0.90 cm3, 8 mmol) was con-
verted to phosphoramidate 13d according to general
procedure A. The crude product was purified by flash
chromatography (CH2Cl2/EtOAc = 10/1, Rf = 0.08) to
give 2.21 g 13d (96%) as colorless crystals. M.p.: 139–
141 °C (hexanes); 1H NMR (400.13 MHz, CDCl3):
d = 1.22 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H),
3.75 (s, 3H), 4.66 (dsept, J = 6.3, 7.6 Hz, 2H), 5.55 (br. d,
J = 9.1 Hz, 1H), 6.47 (ddd, J = 1.0, 2.0, 8.0 Hz, 1H), 6.53
(m, 2H), 7.10 (t, J = 8.1 Hz, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.6 (d, J = 5.4 Hz, 2C),
23.9 (d, J = 4.6 Hz, 2C), 55.2, 71.8 (d, J = 4.6 Hz, 2C),
103.4 (d, J = 7.7 Hz), 106.9, 110.0 (d, J = 7.7 Hz), 129.9,
141.2, 160.4 ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
CDCl3): d = 17.9 ppm; IR (Si, CDCl3): V = 3172, 3085,
2980, 1729, 1603, 1586, 1469, 1413, 1268, 1241, 1204,
1161, 1046, 995 cm-1
.
Diisopropyl N-(3-methylphenyl)phosphoramidate
(13e, C13H22NO3P)
m-Toluidine (0.857 g, 0.86 cm3, 8 mmol) was converted to
phosphoramidate 13e by general procedure A. The crude
product was flash chromatographed (CH2Cl2/EtOAc = 1/
1, Rf = 0.56) and gave 1.98 g 13e (91%) as colorless
crystals. M.p.: 90–93 °C (hexanes); 1H NMR
(400.13 MHz, CDCl3): d = 1.20 (d, J = 6.3 Hz, 6H),
1.36 (d, J = 6.3 Hz, 6H), 2.27 (s, 3H), 4.65 (dsept,
J = 6.3, 7.8 Hz, 2H), 5.68 (br. d, J = 9.1 Hz, 1H), 6.73
(d, J = 7.3 Hz, 1H), 6.76 (s, 1H), 6.77 (d, J = 7.3 Hz,
1H), 7.09 (t, J = 7.3 Hz, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 21.5, 23.6 (d, J = 5.4 Hz,
2C), 23.9 (d, J = 3.8 Hz, 2C), 71.6 (d, J = 4.6 Hz, 2C),
114.4 (d, J = 6.9 Hz), 118.1 (d, J = 7.4 Hz), 122.2, 128.9,
139.0, 139.9 ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
d = 0.7 ppm; IR (Si): V = 3169, 2979, 1608, 1488,
1408, 1277, 1233, 1161, 1054, 982 cm-1
.
Diisopropyl N-(t-butoxycarbonyl)-N-(3-methoxyphenyl)phos-
phoramidate (14d, C18H30NO6P)
Diisopropyl N-(3-methoxyphenyl)phosphoramidate (13d,
1.436 g, 5 mmol) was converted to N-Boc derivative 14d
by general procedure B in Et2O at -78 °C. The crude
product was flash chromatographed (EtOAc, Rf = 0.60) to
give 1.78 g 14d (92%) as a colorless oil. 1H NMR
(400.13 MHz, CDCl3): d = 1.17 (d, J = 6.3 Hz, 6H), 1.32
(d, J = 6.3 Hz, 6H), 1.46 (s, 9H), 3.77 (s, 3H), 4.70 (dsept,
J = 6.3, 7.6 Hz, 2H), 6.75 (m, 1H), 6.81 (m, 2H), 7.23 (t,
J = 8.1 Hz, 1H) ppm; 13C NMR (100.61 MHz, CDCl3):
d = 23.3 (d, J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C),
28.0 (3C), 55.3, 72.9 (d, J = 6.1 Hz, 2C), 82.8, 113.3,
115.1 (d, J = 2.3 Hz), 121.5 (d, J = 1.5 Hz), 129.4, 139.7
(d, J = 2.3 Hz), 153.5 (d, J = 8.4 Hz), 159.9 ppm; 31P
NMR (161.98 MHz, CDCl3): d = -1.9 ppm; IR (Si,
ꢀ
d = 1.2 ppm; IR (Si): V = 3172, 2980, 1610, 1595,
1487, 1387, 1231, 1176, 990 cm-1
.
Diisopropyl-N-(t-butoxycarbonyl)-N-(3-methylphenyl)phos-
phoramidate (14e, C18H30NO5P)
Diisopropyl N-(3-methylphenyl)phosphoramidate (13e,
1.36 g, 5 mmol) was converted to N-Boc phosphoramdiate
14e by general procedure B in Et2O. The crude product was
flash chromatographed (hexanes/EtOAc = 1/1, Rf = 0.55)
and delivered 1.69 g 14e (91%) as colorless crystals. M.p.:
54–55 °C (hexanes); 1H NMR (400.13 MHz, CDCl3):
d = 1.17 (d, J = 6.3 Hz, 6H), 1.32 (d, J = 6.3 Hz, 6H),
1.46 (s, 9H), 2.32 (s, 3H), 4.69 (dsept, J = 6.3, 7.1 Hz,
2H), 6.99 (br. d, J = 7.6 Hz, 1H), 7.00 (br. s, 1H), 7.07 (br.
d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H) ppm; 13C
NMR (100.61 MHz, CDCl3): d = 21.2, 23.3 (d,
J = 6.1 Hz, 2C), 23.9 (d, J = 3.8 Hz, 2C), 28.1 (3C),
72.7 (d, J = 5.4 Hz, 2C), 82.6, 126.0 (d, J = 1.5 Hz),
128.4, 128.6, 129.7 (d, J = 2.3 Hz), 138.6 (d, J = 2.3 Hz),
138.7, 153.7 ppm; 31P NMR (161.98 MHz, CDCl3):
ꢀ
CDCl3): V = 2981, 1729, 1605, 1492, 1370, 1302, 1257,
1163, 1097, 1008 cm-1
.
Diisopropyl (2-t-butoxycarbonylamino-6-methoxyphenyl)phos-
phonate (15d, C18H30NO6P)
N-(t-Butoxycarbonyl)-N-(3-methoxyphenyl)phosphorami-
date (14d, 0.387 g, 1 mmol) was rearranged by general
procedure C in THF at -78 °C for 1 h. The crude product
was flash chromatographed (hexanes/EtOAc = 5/1,
Rf = 0.61) to give 0.156 g 15d (40%) as colorless crystals,
m.p.: 85–87 °C (hexanes). When 0.387 g 14d (1 mmol)
was rearranged by general procedure D in THF at -78 °C
ꢀ
d = -1.7 ppm; IR (Si, CDCl3): V = 2981, 1729, 1386,
1369, 1300, 1256, 1160, 1098, 1001 cm-1
.
Diisopropyl (2-t-butoxycarbonylamino-4-methylphenyl)phos-
phonate (16e, C18H30NO5P)
1
for 1 h 0.260 g phosphonate 15d (67%) was obtained. H
NMR (400.13 MHz, CDCl3): d = 1.15 (d, J = 6.1 Hz,
6H), 1.34 (d, J = 6.1 Hz, 6H), 1.49 (s, 9H), 3.80 (s, 3H),
4.59 (dsept, J = 6.1, 8.3 Hz, 2H), 6.50 (ddd, J = 0.8, 5.3,
8.4 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 8.06 (ddd, J = 0.8,
5.8, 8.4 Hz, 1H), 11.00 (s, 1H) ppm; 13C NMR
(100.61 MHz, CDCl3): d = 23.5 (d, J = 4.6 Hz, 2C),
Diisopropyl N-(t-butoxycarbonyl)-N-(3-methylphenyl)phos-
phoramidate (14e, 0.743 g, 2 mmol) was rearranged to N-
Boc phosphonate 16e according to general procedure C in
THF for 5 h. The crude product, which contained a large
amount of starting material, was flash chromatographed
123

96
E. Kuliszewska, F. Hammerschmidt
(hexanes/EtOAc = 7/1, Rf = 0.27) and furnished 0.038 g
16e (5%) as a colorless oil. When this experiment (1 mmol)
was repeated, except that 0.3 cm3 TMEDA (2 mmol) was
added before cooling to -78 °C and that the reaction mixture
was allowed to warm to RT within 5 h, 0.024 g N-Boc
phosphonate 16e (6%) was obtained as colorless oil. 1H NMR
(400.13 MHz, CDCl3): d = 1.18(d, J = 6.3 Hz, 6H), 1.34 (d,
J = 6.3 Hz, 6H), 1.49 (s, 9H), 2.33 (s, 3H), 4.60 (dsept,
J = 6.3, 7.8 Hz, 2H), 6.81 (br. d, J = 7.8 Hz, 1H), 7.42 (dd,
J = 7.8 Hz, 1H), 8.12 (d, J = 6.3 Hz, 1H), 9.55 (s, 1H) ppm;
13C NMR (100.61 MHz, CDCl3): d = 22.0, 23.6 (d,
J = 5.4 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C), 28.3 (3C), 71.2
(d, J = 5.4 Hz, 2C), 80.2, 111.6 (d, J = 184.3 Hz), 120.9 (d,
J = 11.5 Hz), 122.6 (d, J = 14.5 Hz), 132.7 (d, J = 6.9 Hz),
J = 6.1 Hz), 82.6, 123.0, 125.4, 126.0, 126.6 (d,
J = 3.1 Hz), 126.7, 128.1, 128.3 (d, J = 1.5 Hz), 131.7,
134.3, 135.4, 153.6 (d, J = 9.2 Hz) ppm; 31P NMR
(161.98 MHz, CDCl3): d = -1.5 ppm; IR (Si, CDCl3):
-1
ꢀ
V = 2980, 1727, 1301, 1159, 1002 cm
.
Diisopropyl (1-t-butoxycarbonylamino-2-naphthyl)phos-
phonate (20, C21H30NO5P)
Diisopropyl N-(t-butoxycarbonyl)-N-(1-naphthyl)phospho-
ramidate (19, 0.469 g, 1.15 mmol) was rearranged to N-
Boc phosphonate 20 according to general procedure C in
Et2O at -78 °C for 2 h. The crude product was flash
chromatographed (hexanes/EtOAc = 2/1, Rf = 0.54) and
gave 0.393 g 20 (84%) as a colorless oil. 1H NMR
(400.13 MHz, CDCl3): d = 1.21 (d, J = 6.1 Hz, 6H), 1.38
(d, J = 6.1 Hz, 6H), 1.50 (s, 9H), 4.72 (dsept, J = 6.1,
8.1 Hz, 2H), 7.53 (m, 2H), 7.76 (m, 3H), 8.0 (m, 1H), 8.17
(br. s, 1H) ppm; 13C NMR (100.61 MHz, CDCl3):
d = 23.8 (d, J = 4.6 Hz, 2C), 24.0 (d, J = 3.8 Hz, 2C),
28.3 (s, 3C), 71.4 (d, J = 5.4 Hz, 2C), 80.4, 119.7 (d,
J = 183.6 Hz), 125.8, 126.0, 126.3, 127.1 (d, J = 7.7 Hz),
127.8, 128.1, 129.3 (d, J = 13.0 Hz), 136.3, 139.2 (d,
J = 5.4 Hz), 154.0 ppm; 31P NMR (161.98 MHz, CDCl3):
142.7 (d, J = 7.6 Hz), 144.5 (d, J = 2.3 Hz), 153.0 ppm; 31
P
NMR (161.98 MHz, CDCl3): d = 19.1 ppm; IR (Si, CDCl3):
-1
.
ꢀ
V = 3247, 2980, 1731, 1580, 1244, 1162, 1089, 985 cm
Diisopropyl N-(1-naphthyl)phosphoramidate
(18, C16H22NO3P)
1-Naphthylamine (1.146 g, 8.0 mmol) was converted to
phosphoramdiate 18 by general procedure A. The crude
product was purified by flash chromatography (hexanes/
EtOAc = 2/1, Rf = 0.30) and delivered 1.21 g 18 (49%) as
colorless crystals. M.p.: 149 °C (hexanes); 1H NMR
(400.13 MHz, CDCl3): d = 1.18 (d, J = 6.1 Hz, 6H),
1.38 (d, J = 6.1 Hz, 6H), 4.71 (dsept, J = 6.1, 7.6 Hz,
2H), 5.71 (d, J = 7.8 Hz, 1H), 7.36 (m, 2H), 7.49 (m, 3H),
7.82 (m, 1H), 7.90 (m, 1H) ppm; 13C NMR (100.61 MHz,
CDCl3): d = 23.6 (d, J = 5.4 Hz, 2C), 23.9 (d,
J = 3.8 Hz, 2C), 71.9 (d, J = 5.4 Hz, 2C), 114.0 (d,
J = 2.3 Hz), 120.0, 122.3, 125.1 (d, J = 9.9 Hz), 125.9,
125.9, 126.0, 128.8, 134.3, 135.0 ppm; 31P NMR
ꢀ
d = 17.0 ppm; IR (Si, CDCl3): V = 3401, 3271, 2979,
2930, 1733, 1243, 1161, 986 cm-1
.
Tetraisopropyl N-(pyridin-2-yl)diphosphoramidate
(22, C17H32N2O6P2)
2-Aminopyridine (0.753 g, 8 mmol) was converted to
diphosphoramidate 22 by general procedure A except that
19.2 mmol bromine and 19.2 mmol (i-PrO)3P, 32 mmol
Et3N and 3 cm3 2 N HCl were used. The crude product was
purified by flash chromatography (EtOAc/EtOH = 10/1,
1
Rf = 0.55) to give 3.13 g 22 (93%) as a colorless oil. H
ꢀ
(161.98 MHz, CDCl3): d = 1.5 ppm; IR (Si): V = 2979,
NMR (400.13 MHz, CDCl3): d = 1.23 (d, J = 6.3 Hz,
12H), 1.30 (d, J = 6.3 Hz, 12H), 4.83 (m, 4H), 7.16 (m,
1H), 7.32 (br. d, J = 7.8 Hz, 1H), 7.66 (dt, J = 1.8,
7.8 Hz, 1H), 8.46 (dd, J = 1.8, 4.8 Hz, 1H) ppm; 13C
NMR (100.61 MHz, CDCl3): d = 23.4 (d, J = 3.2 Hz,
2C), 23.4 (d, J = 3.1 Hz, 2C), 23.8 (dd, J = 2.3 Hz, 2C),
23.8 (d, J = 1.5 Hz, 2C), 72.8 (d, J = 3.2 Hz, 2C), 72.8
(dd, J = 3.1 Hz, 2C), 122.2, 123.2 (t, J = 2.7 Hz), 138.0,
148.9, 152.3 ppm; 31P NMR (161.98 MHz, CDCl3):
1470, 1244, 991 cm-1
.
Diisopropyl N-(t-butoxycarbonyl)-N-(1-naphthyl)phosphor-
amidate (19, C21H30NO5P)
Diisopropyl N-(1-naphthyl)phosphoramidate (18, 0.922 g,
3.0 mmol) was converted to Boc derivative 19 by general
procedure B in Et2O. The crude product was purified by
flash chromatography (CH2Cl2/EtOAc = 10/1, Rf = 0.35)
and gave 0.960 g 19 (79%) as brownish oil. 1H NMR
(400.13 MHz, CDCl3): d = 0.89 (d, J = 6.1 Hz, 3H), 1.11
(d, J = 6.1 Hz, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.28 (d,
J = 6.1 Hz, 3H), 1.40 (s, 9H), 4.62 (dsept, J = 6.1,
7.1 Hz, 1H), 4.72 (dsept, J = 6.1, 7.1 Hz, 1H), 7.38 (td,
J = 7.3, 1.5 Hz, 1H), 7.44 (dd, J = 7.7, 7.3 Hz, 1H), 7.46
(ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.52 (ddd, J = 8.3, 6.8,
1.5 Hz, 1H), 7.79 (br. d, J = 8.3 Hz, 1H), 7.82 (br. d,
J = 7.7 Hz, 1H), 8.02 (br. d, J = 8.6 Hz, 1H) ppm; 13C
NMR (100.61 MHz, CDCl3): d = 22.9 (d, J = 6.9 Hz),
23.3 (d, J = 6.9 Hz), 23.8 (d, J = 3.1 Hz), 24.0 (d,
J = 3.1 Hz), 27.9 (3C), 73.0 (d, J = 6.1 Hz), 73.1 (d,
ꢀ
d = -1.5 ppm; IR (Si): V = 2980, 2936, 1589, 1467,
1433, 1386, 1375, 1279, 1179, 1143, 1109, 1000 cm-1
.
Diisopropyl
(2-(diisopropylphosphorylamino)pyridin-3-
yl)phosphonate (23, C17H32N2O6P2)
Tetraisopropyl N-(pyridin-2-yl)diphosphoramidate (22,
1.27 g, 3 mmol) was rearranged to pyridin-3-ylphospho-
nate 23 by general procedure D in THF for 20 h. The crude
product was flash chromatographed (CH2Cl2/EtOH = 20/
1, Rf = 0.38) to give 0.920 g 23 (72%) as an oil. When this
experiment was repeated with LiTMP according to general
123

On the rearrangement of N-aryl-N-Boc-phosphoramidates to N-Boc-protected…
97
1
procedure C, 0.460 g 23 (36%) was obtained. H NMR
(400.13 MHz, CDCl3): d = 1.20 (d, J = 6.1 Hz, 6H), 1.30
(d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.36 (d,
J = 6.1 Hz, 6H), 4.65 (dsept, J = 6.1 Hz, 7.8 Hz, 2H),
4.83 (dsept, J = 6.1, 7.8 Hz, 2H), 6.83 (ddd, J = 2.0, 4.8,
7.3 Hz, 1H), 7.76 (ddt, J = 2.0, 7.3, 14.9 Hz, 1H), 8.40 (dt,
J = 2.0, 4.8 Hz, 1H), 8.56 (br. d, J = 10.9 Hz, 1H) ppm;
13C NMR (100.61 MHz, CDCl3): d = 23.6 (d, J = 5.4 Hz,
2C), 23.7 (d, J = 4.6 Hz, 2C), 23.9 (d, J = 4.6 Hz, 2C),
24.0 (d, J = 4.6 Hz, 2C), 71.7 (d, J = 5.4 Hz, 2C), 72.1
(d, J = 6.1 Hz, 2C), 108.8 (dd, J = 10.3, 185.9 Hz), 115.8
(d, J = 9.9 Hz), 142.1 (d, J = 6.9 Hz), 152.4, 156.1 (d,
J = 10.7 Hz) ppm; 31P NMR (161.98 MHz, CDCl3):
d = -1.1 (d, J = 2.0 Hz), 16.9 (d, J = 2.0 Hz) ppm; IR
(161.98 MHz, CDCl3): d = -1.9 ppm; IR (Si, CDCl3):
ꢀ
V = 2980, 1728, 1604, 1491, 1289, 1156, 1112, 990,
914 cm-1
.
Crossover experiment with a 1:1 mixture of deuterated and
nondeuterated diisopropyl N-(t-butoxycarbonyl)-N-(3-
methoxyphenyl)phosphoramidate
A mixture of 0.202 g deuterated N-(t-butoxycarbonyl)-N-
(3-methoxyphenyl)phosphoramidate [D17]14d (0.5 mmol)
and 0.194 g nondeuterated N-(3-methoxyphenyl)-N-(t-bu-
toxycarbonyl)phosphoramidate 14d (0.5 mmol) was
rearranged in the same way (LDA, THF, 1 h, 78 °C) as
phosphoramidate 14d and gave 0.390 g 1:1 mixture of
deuterated phosphonate [D17]15d and nondeuterated 15d
1
(98%) as colorless crystals. M.p.: 87–89 °C (hexanes); H
ꢀ
(Si, CDCl3): V = 3218, 2980, 2935, 1575, 1445, 1262,
1231, 998 cm-1
NMR (400.13 MHz, CDCl3): d = 1.15 (d, J = 6.1 Hz,
6H), 1.34 (d, J = 6.1 Hz, 6H), 1.49 (s, 18H), 3.81 (s, 3H),
4.60 (dsept, J = 6.1, 8.3 Hz, 2H), 6.50 (dddd, J = 0.8, 2.8,
5.3, 8.3 Hz, 2H), 7.38 (t, J = 8.6, 2H), 8.06 (dd, J = 5.8,
8.6, 2H), 11.01 (br. s, 1H) ppm; 31P NMR (161.98 MHz,
CDCl3): d = 17.88 (P(O)(Oi-Pr)2), 17.93 (br. s,
.
Crossover experiment
3-[Methyl-D3]methoxyaniline ([D3]9d, C7H6D3NO)
To a stirred mixture of 0.546 g 3-aminophenol (5 mmol)
and 0.786 g t-BuOK (7 mmol) in 8 cm3 dry THF under
argon at RT was added 1.136 g [D3]methyl p-toluenesul-
fonate (6 mmol) [25] dropwise. After stirring for 18 h
5 cm3 H2O and CH2Cl2 were added. The organic phase
was separated and the aqueous one was extracted with
CH2Cl2. The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (CH2Cl2,
Rf = 0 42) to give 0.400 g labeled 3-methoxyaniline
ꢀ
P(O)(OCD(CD3)2)2) ppm; IR (Si, CDCl3): V = 3503,
3172, 3085, 2980, 2933, 1729, 1603, 1586, 1534, 1469,
1439, 1413, 1387, 1368, 1309, 1268, 1241, 1204, 1161,
1127, 1109, 1066, 1046, 995 cm-1. MS before rearrange-
ment: EI-MS (70 eV, 50 °C): m/z (%) = 404 (6.3,
MD17?), 387 (5.5, M?), 203 (94), 208 (100); after
rearrangement: EI-MS (70 eV, 50 °C): m/z (%) = 404
(23.7, MD17?), 387 (25.3, M?), 203 (100), 208 (94). There
were no signals with m/z = 401 or 390.
1
[D3]9d (63%) as a colorless oil. H NMR (250.13 MHz,
2-Aminophenylphosphonic acid (25)
CDCl3): d = 3.63 (br. s, 2H), 6.22 (d, J = 2.2 Hz, 1H),
6.28 (ddd, J = 0.9, 2.2, 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz,
1H).
Method A: A mixture of 0.335 g diisopropyl 2-(t-butoxy-
carbonylamino)phenylphosphonate (15a, 0.94 mmol) and
10 cm3 HCl (6 M) was refluxed for 7 h. The cooled solution
was concentrated under reduced pressure and the residue
was dried over KOH in a vacuum desiccator. Then, it was
dissolved in H2O and applied to an ion exchange column
(Dowex 50 W 9 8; H?) and eluted with H2O. Fractions
containing product (TLC: i-PrOH/H2O/NH3 = 6/3/1,
Rf = 0.38) were pooled and concentrated to give 0.138 g
phosphonic acid 24 (85%) as a brownish crystalline product
Di-[D7]isopropyl N-(3-[methyl-D3]methoxyphenyl)phos-
phoramidate ([D17]13d, C13H5D17NO4P)
3-[Methyl-D3]methoxyaniline (0.630 g, 5 mmol) was con-
verted to 1.28 g phosphoramidate [D17]13d (84%) as
colorless crystals by the method used for the unlabled
compound except that (i-PrO)3P was replaced by the
deuterated species [24]; m.p.: 141–143 °C (hexanes). The
1H and 13C NMR spectrum of [D17]13d were identical to
those of the unlabeled compound except for the missing
signals because of deuteration.
1
containing an impurity (6%, by NMR); m.p.: 186 °C
(water) [Ref. [27] 199–200 °C (water/ethanol)].
Method B: A solution of 0.530 g diisopropyl 2-(t-bu-
toxycarbonylamino)phenylphosphonate (15a, 1.48 mmol),
0.48 cm3 allyltrimethylsilane (0.343 g, 3 mmol), and
1.73 cm3 bromotrimethylsilane (2.050 g, 13.4 mmol) [29]
in 5 cm3 dry CH2Cl2 was refluxed under Ar for 20 h.
Volatiles were removed under reduced pressure (0.5 mbar),
CH2Cl2 (2 9 10 cm3) was added and removed again under
reduced pressure. Water (15 cm3) was added and the
reaction mixture was stirred for 15 min. The solvent was
Di-[D7]isopropyl N-(t-butoxycarbonyl)-N-(3-[methyl-D3]
methoxyphenyl)phosphoramidate ([D17]14d, C18H13D17NO6P)
Di-[D7]isopropyl N-(3-[methyl-D3]methoxyphenyl)phos-
phoramidate ([D17]13d) (0.609 g, 2 mmol) was converted
to 0.760 g N-Boc phosphoramidate [D17]14d (94%) as a
1
colorless oil. The H and 13C NMR spectrum of [D17]14d
were identical to those of the unlabeled compound except
for the missing signals because of deuteration. 31P NMR
123

98
E. Kuliszewska, F. Hammerschmidt
3297, 3079, 2627, 2325, 1650, 1615, 1593, 1554, 1456,
1401, 1334, 1244, 1169, 1144, 1011, 908 cm-1
removed under reduced pressure and the residue was dried.
Crystallization of the crude product from H2O gave
0.240 g 24 (95%) of brownish crystals, m.p.: 198–201 °C.
1H NMR (400.13 MHz, D2O/NaOD): d = 6.70 (dd,
J = 4.8, 7.6 Hz, 1H), 6.73 (br. t, J = 7.6 Hz, 1H), 7.13 (t,
.
Acknowledgements Open access funding provided by University of
Vienna. We thank S. Felsinger for recording NMR spectra and J.
Theiner for combustion analyses.
J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6, 12.9 Hz, 1H) ppm; 13
C
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
NMR (100.63 MHz, D2O/NaOD): d = 117.3 (d,
J = 10.0 Hz), 118.6 (d, J = 12.2 Hz), 125.3 (d,
J = 162.9 Hz), 130.7, 132.8 (d, J = 6.9 Hz), 147.8 (d,
J = 5.4 Hz) ppm; 31P NMR (161.98 MHz, D2O/NaOD):
ꢀ
d = 11.7 ppm; IR (ATR): V = 2325, 1580, 1538, 1483,
1446, 1168, 1148, 1124, 1074, 1007, 903 cm-1
.
1-Amino-2-naphthylphosphonic acid (26, C10H10NO3P)
Diisopropyl [1-N-(t-butoxycarbonylamino)-2-naphthyl]phos-
phonate (20, 0.618 g, 1.52 mmol) was deblocked by method
B used for the preparation of 25 for the phenyl analog, except
that the final procedure was different. After removing all
volatiles under reduced pressure the residue was dissolved in
90 cm3 MeOH. Slow concentration of the reddish-brown
solution on the rotary evaporator at RT to about 7 cm3 gave
reddish crystals, which were collected by centrifugation. They
were washed with 3 cm3 MeOH and dried for 1 h (50 °C/
0.5 mbar) to give 0.204 g analytically pure naphthylphospho-
nic acid 26 (60%); m.p.: 236–239 °C; from the mother liquor a
second crop (0.085 g, 95% pure by 31P NMR) was obtained. 1-
Amino-2-naphthylphosphonic acid seemed to be stable for
short periods of time in refluxing MeOH. It could not be
crystallized from hot H2O, as it decomposed to phosphoric
acid (by 31P NMR) and 1-naphthylamine (by TLC after
extraction) within 30 min. 1H NMR (400.13 MHz, D2O/
NaOD): d = 7.20 (m, 1H), 7.37 (m, 1H), 7.56 (m, 1H), 7.69
(m, 2H), 7.86 (m, 1H) ppm; 13C NMR (100.61 MHz, D2O/
NaOD): d = 118.0 (d, J = 12.2 Hz), 120.0 (d,
J = 164.5 Hz), 122.2, 124.6 (d, J = 10.7 Hz), 125.7, 127.0,
128.5, 130.3 (d, J = 7.7 Hz), 134.6, 143.7 (d, J = 6.1 Hz)
ppm; 31P NMR (161.98 MHz, D2O/NaOD): d = 12.5 ppm;
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2-Aminopyridin-3-ylphosphonic acid (27, C5H7N2O3P)
Diisopropyl 2-(diisopropylphosphorylamino)pyridin-3-
ylphosphonate (23, 0.887 g, 2.10 mmol) was deblocked
with refluxing HCl by method A used for the preparation of
25. Fractions containing product (TLC: i-PrOH/H2O/
NH3 = 6/3/1, Rf = 0.43) were pooled and concentrated
to give 0.319 g 27 (87%) as nearly colorless crystals. M. p.:
1
256–259 °C (H2O/EtOH); H NMR (400.13 MHz, D2O):
d = 6.72 (ddd, J = 1.7, 6.3, 7.1 Hz, 1H), 7.60 (dt, J = 1.7,
6.3 Hz, 1H), 7.99 (ddd, J = 1.7, 7.1, 13.1 Hz, 1H) ppm;
13C NMR (100.61 MHz, D2O): d = 130.1 (d,
J = 11.5 Hz), 123.7 (d, J = 163.7 Hz), 136.6, 146.9 (d,
J = 5.4 Hz), 154.4 (d, J = 12.2 Hz) ppm; 31P NMR
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ꢀ
(161.98 MHz, D2O): d = 5.9 ppm; IR (ATR): V = 3401,
123