Preparation of α-aminobenzylphosphonic acids with a stereogenic quaternary carbon atom via microscopically configurationally stable α-aminobenzyllithiums

Article abstract of DOI:10.1002/chem.200800475

The enantiomers of 1-phenylethylamine were phosphorylated with diethyl chlorophosphate/Et₃N and then Boc-protected (Boc = tert-butoxycarbonyl) at the nitrogen atom. These phosphoramidates were metalated by using sBuLi/N,N,N′,N′-tetramethylethy-lenediamine (TMEDA) to give α-aminobenzyllithiums that isomerised to αaminophosphonates in yields of up to 80% with retention of the configuration at the carbon atom. The intermediate tertiary organolithiums were found to be microscopically configurationally stable from -78 to 0°C in Et₂O. The protected a-aminophosphonates were deblocked by using boiling 6 M HCl or preferably Me₃SiBr/(allyl)SiMe₃. When the Boc group was replaced by the diethoxyphosphinyl group, the a-aminobenzyllithium intermediate partially enantiomerised even at -78°C and rearranged to yield an α- aminophosphonate with 50% ee (ee=enantiomeric excess). Similarly, N-Boc-protected phosphoramidates derived from racemates and/ or enantiomers of l-(1-naphthyl)ethyl-, 1-indanyl- and 1,2,3,4-tetrahydro-1-naphthylamine or 1-azidoindan- and 1-azido-1,2,3,4-tetrahydronaphthalene were converted to aminophosphonates in good yields. Deblocking gave α-aminophosphonic acids of excellent enantiomeric excess (97-99%), as determined by means of HPLC on a chiral ion-exchange stationary phase based on quinine carbamate. When racemic Boc-protected diethyl phosphoramidate derived from 1,2,3,4-tetrahydro-1- naphthylamine was metalated with LiTMP/TMEDA (TMP = 2,2,6,6- tetramethylpiperidine), 1-hydroxyethylphosphonamidates resulted. The configuration of the main isomer was determined by means of a single-crystal X-ray structure analysis.

Full text of DOI:10.1002/chem.200800475

FULL PAPER
DOI: 10.1002/chem.200800475
Preparation of a-Aminobenzylphosphonic Acids with a Stereogenic
Quaternary Carbon Atom via Microscopically Configurationally
Stable a-Aminobenzyllithiums
Edyta Kuliszewska, Martin Hanbauer, and Friedrich Hammerschmidt*[a]
Abstract: The enantiomers of 1-phenyl-
ethylamine were phosphorylated with
diethyl chlorophosphate/Et3N and then
Me3SiBr/
N
were converted to aminophosphonates
in good yields. Deblocking gave a-ami-
nophosphonic acids of excellent enan-
tiomeric excess (97–99%), as deter-
mined by means of HPLC on a chiral
ion-exchange stationary phase based
on quinine carbamate. When racemic
Boc-protected diethyl phosphorami-
date derived from 1,2,3,4-tetrahydro-1-
naphthylamine was metalated with
LiTMP/TMEDA (TMP=2,2,6,6-tetra-
methylpiperidine), 1-hydroxyethylphos-
phonamidates resulted. The configura-
tion of the main isomer was deter-
mined by means of a single-crystal X-
ray structure analysis.
group was replaced by the diethoxy-
phosphinyl group, the a-aminobenzyl-
lithium intermediate partially enantio-
merised even at À788C and rearranged
to yield an a-aminophosphonate with
50% ee (ee=enantiomeric excess).
Similarly, N-Boc-protected phosphor-
Boc-protected
(Boc=tert-butoxycar-
bonyl) at the nitrogen atom. These
phosphoramidates were metalated by
using sBuLi/N,N,N’,N’-tetramethylethy-
lenediamine (TMEDA) to give a-ami-
nobenzyllithiums that isomerised to a-
aminophosphonates in yields of up to
80% with retention of the configura-
tion at the carbon atom. The inter-
mediate tertiary organolithiums were
found to be microscopically configura-
tionally stable from À78 to 08C in
Et2O. The protected a-aminophospho-
nates were deblocked by using boiling
amidates derived from racemates and/
or enantiomers of 1-(1-naphthyl)ethyl-,
1-indanyl- and 1,2,3,4-tetrahydro-1-
naphthylamine or 1-azidoindan- and 1-
azido-1,2,3,4-tetrahydronaphthalene
Keywords: aminophosphonic acids ·
carbanions
stability · lithium · rearrangement
6m
HCl
or
preferably
Introduction
effects.[2] N-Benzyl a-aminobenzylphosphonic acids were
found to be potent inhibitors of human prostatic acid phos-
phatase.[3] (R)-Phosphatyrosine (the phosphonic acid ana-
logue of l-tyrosine) is a component of naturally occurring
hypotensive tripeptides.[4]
Proteinogenic and non-proteinogenic amino acids, primarily
the a ones, play vital roles in biological systems. To interfere
with their metabolism and to block biosynthetic pathways, a
variety of analogues have been prepared and tested. As the
phosphonic acid group is considered an isosteric replace-
ment for the carboxyl group and it mimics the tetrahedral
intermediate of reactions of carboxylic acid derivatives, a-
aminophosphonic acids are an attractive group of analogues
for amino acids.[1] Therefore, racemic and preferably chiral,
non-racemic a-aminophosphonic acids and peptides contain-
ing them have been synthesised to address various biological
Not surprisingly, the widespread interest in aminophos-
phonic acids gave rise to the development of many methods
for their asymmetric preparation, but a limited number for
quaternary ones. For the first time, enantiomerically pure
quaternary a-aminophosphonic acids were prepared by
chemical resolution of racemic esters by using tartaric acid
or its dibenzoyl derivative as resolving agents.[5a] One abso-
lute configuration was assigned on the basis of a single-crys-
tal X-ray structure analysis.[5b] Methods are known for the
preparation of chiral, non-racemic individual compounds,
such as a-methylphosphaphenylalanine,[6] a-aminocyclopro-
pylphosphonic acids[7] and those obtainable by means of cat-
alytic asymmetric allylation of a-aminophosphonates[8] and
rhodium-catalysed enantioselective Michael addition[9] of di-
ethyl a-cyanoethylphosphonate to vinyl ketones. More gen-
[a]Dr. E. Kuliszewska, Dr. M. Hanbauer, Prof. Dr. F. Hammerschmidt
Department of Organic Chemistry
University of Vienna
Währingerstrasse 38, 1090 Vienna (Austria)
Fax : (+43)4277-9521
E-mail: friedrich.hammerschmidt@univie.ac.at
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8603

erally applicable accesses are based on the diastereoselec-
tive alkylation[10] of homochiral imidazolinylphosphonates
and the highly diastereoselective addition[11] of lithium di-
ethyl phosphite to a-ketosulfinimines.
N,N,N’,N’-tetramethylethylenediamine (TMEDA) in Et2O at
À788C, it rearranged smoothly to phosphonate (S)-(À)-6 in
73% yield. To determine its enantiomeric excess, we tried to
deblock the nitrogen atom and react it with a-methoxy-a-
trifluoromethyl phenylacetyl chloride ((S)-MTPACl). Even
harsh conditions (5m HCl, 608C; Scheme 2) did not cleave
We have found that N-protected N-benzylphosphorami-
dates undergo a phosphoramidate–a-aminophosphonate re-
arrangement induced by sBuLi or lithium amides at À788C
to give chiral, non-racemic a-aminobenzylphosphonates.[12]
The intermediary a-aminocarbanions are in part configura-
tionally stable. These are reminiscent of those obtained by
Beak et al. from N-Boc-protected pyrrolidines (Boc=tert-
butoxycarbonyl) and benzylamines by (À)-sparteine-mediat-
ed lithiation.[13] We reasoned that this method could serve as
a platform for the preparation of quaternary a-aminobenzyl-
phosphonic acids. These are potential inhibitors of the phe-
nylalanine ammonia-lyase.[14]
Results and Discussion
Scheme 2. Deblocking of quaternary a-aminophosphonate (S)-(À)-6.
The commercially available (R)-1-phenylethylamine of
96% ee (ee=enantiomeric excess) was selected to study the
feasibility of the approach. It seemed to be convenient to
use a diethoxyphosphinyl group as a protecting group at the
nitrogen atom for the respective phosphoramidate
(Scheme 1). As the phosphorylation could not be performed
in one step, it had to be effected in two.[12] (R)-1-Phenyl-
À
the very stable N P bond in (S)-(À)-6. Consequently, all
protecting groups were removed by heating the solution at
reflux in 6m HCl to get the free a-aminophosphonic acid
(S)-(À)-8a to determine its enantiomeric excess by using
HPLC[15] on a chiral stationary phase based on quinine car-
bamate, after pre-column derivatisation with the Sanger re-
agent (2,4-dinitrofluorobenzene) to yield the N-2,4-dinitro-
phenyl (DNP) derivative (S)-9a. Surprisingly, its enantio-
meric excess was found to be 50% compared with 96% for
the starting (R)-1-phenylethylamine. We assigned the S con-
figuration to a-aminophosphonic acid (À)-8a on the basis
that 1) its levorotatory p-methyl and p-nitro analogues have
the S configuration,[11] 2) the binding model for DNP deriva-
tives of chiral a-aminophosphonic acids gives the S configu-
ration[15] for chiral stationary phases based on quinine carba-
mate and 3) migration of the dialkoxyphosphinyl group
from the oxygen or nitrogen atom to the carbon atom fol-
lowed, so far, a retentive course[16] consistently. Evidently,
the intermediate a-aminocarbanion (R)-4 was configuration-
ally unstable and partly enantiomerised (23%) resulting in
phosphonate (S)-(À)-6 with 50% ee, in which the S enantio-
mer predominated. This result, in combination with the tedi-
ous purification of the analytical sample of the starting
phosphoramidate by means of HPLC, convinced us to probe
the N-Boc-protected phosphoramidate next.
ACHTREUNG
ACHTREUNG
yield the N-protected phosphoramidate (R)-(+)-3, the ana-
lytical sample of which could be obtained only by means of
preparative HPLC. When it was treated with sBuLi/
Thus, (S)-1-phenylethylamine ((S)-(À)-1a, 98% ee) was
phosphorylated to give phosphoramidate (S)-(À)-2a in 85%
yield, which was metalated at the nitrogen atom with sBuLi
in Et2O at À788C. This was followed by addition of Boc2O
and then the reaction mixture was allowed to warm up to
room temperature (Scheme 3). The N-Boc-protected phos-
phoramidate (S)-(À)-10a isolated in 82% yield was metalat-
ed with sBuLi/TMEDA (1.5 equiv) in THF at À788C at the
benzylic position to induce a phosphoramidate–a-amino-
phosphonate rearrangement. The reaction mixture was
Scheme 1. Conversion of (R)-1-phenylethylamine to aminophosphonate
(S)-(À)-6.
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Chem. Eur. J. 2008, 14, 8603 – 8614

a-Aminobenzylphosphonic Acids via a-Aminobenzyllithiums
FULL PAPER
Table 1. Phosphoramidate–a-aminophosphonate rearrangement of (S)-
(À)-10a under various conditions and ee of a-aminophosphonic acid (R)-
(+)-8a.
Entry
Solvent[a]
T [8C]
t
Yield of
ee of
(R)-13a [%]
(R)-8a [%]
1
2
3
4
5
6
THF
Et2O
Et2O
Et2O
Et2O
Et2O
À78
À78
À78
À30
À30
0
1 h
3 h
45 min
1 h
10 min
3 min
80
65
76
39
75
59
98
[b]
[b]
[b]
97
98
[a] sBuLi/TMEDA (1.5 equiv) was used. [b]Not determined.
Surprisingly, the enantiomeric excesses for entries 5 and 6
were 97 and 98%, respectively. This result reflects the mi-
croscopic configurational stability of the short-lived a-ami-
nobenzyllithium (S)-11a, even at 08C, relative to the dieth-
oxyphosphinyl analogue (R)-4. If the methyl group is re-
placed by a hydrogen atom as reported previously, the re-
spective secondary benzyllithiums were much less configura-
tionally stable.[12] At À788C they yielded phosphonates of 4
and 43% ee, respectively. It is well known that a-aminocar-
banions[17] are less stable than a-oxyanions and that the con-
figurational stability increases from secondary to tertiary.
Finally, we tried to secure the absolute configuration of
(R)-(+)-13a by an additional independent method, that is,
Scheme 3. Conversion of 1-phenyl- and 1-(1-naphthyl)ethylamines into
quaternary a-aminophosphonic acids 8a,b.
quenched with AcOH after 1 h and worked up by using
standard procedures. The crude product contained a small
amount of phosphoramidate (S)-(À)-2a (determined by
using TLC), formed by deprotection of starting material at
the nitrogen atom with sBuLi, and a-aminophosphonate
(R)-(+)-13a obtained by means of flash chromatography in
80% yield. The free acid (R)-(À)-8a was obtained by fully
deprotecting (R)-13a by heating the solution in 6m HCl at
reflux and purification by means of ion-exchange chroma-
tography using Dowex 50W,H+ as before. The HPLC data
showed it to have 97% ee and to be of the opposite configu-
ration to the a-aminophosphonic acid prepared from the N-
phosphorylated analogue (S)-(À)-6. As the enantiomeric
1
by use of H NMR spectroscopy of the Mosher amide. Its
Boc group was selectively removed with CF3CO2H and the
amine (R)-(+)-14a was derivatised with (S)-MTPACl[18] to
give amide (R)-(+)-14a·MTPA-(R) (Scheme 4). The
1H NMR spectrum showed four significant resonances, two
strong ones (d=3.45 (q, J
(d, J(H,P)=16.2 Hz; CH3)) and two weak ones (d=3.57 (q,
(H,F)=1.6 Hz; OMe), 2.13 ppm (d, (H,P)=16.2 Hz;
A
AHCTREUNG
excess of the starting (R)-1-phenylethyl
A
J
A
J
ACHTREUNG
that of the phosphonic acid agreed within experimental
error, the dipole-stabilised tertiary intermediate a-amino-
benzyllithium 11a had to be microscopically configurational-
ly stable at À788C. We assume that it is a short-lived species
that isomerised with migration of the diethoxyphosphinyl
group from the nitrogen atom to the carbon atom with re-
tention of configuration.
CH3)) in a ratio of 98:2, respectively. This corresponds to an
enantiomeric excess of 96% for the underlying amine (R)-
(+)-14a. When racemic 14a was prepared and derivatised
similarly to the enantiomer, the two sets of signals were of
equal intensity. The determination of absolute configura-
tions of alcohols and amines with a quaternary centre is not
well established and is problematic, especially for the
To study the configurational stability of lithium-com-
plexed carbanion 11a, the phosphoramidate–a-amino-
phosphonate rearrangement was also performed in Et2O
and at various temperatures (À78, À30 and 08C; Table 1,
which also contains the above-described reaction in THF for
comparison). The isomerisation could be effected nearly
equally well in Et2O and in THF at À788C in 45 min. At a
longer reaction time (3 h), side reactions such as removal of
an ethyl group by excess sBuLi from the phosphorus atom
by E2 elimination consumed product. The same effect was
even more pronounced at À308C, where the yield doubled
when the reaction time was shortened from 1 h to 10 min.
The rearrangement yielded 59% of phosphonate (R)-(+)-
13a at 08C at the very short reaction time of 3 min. In the
latter two cases, the phosphonate was deblocked for the de-
termination of the enantiomeric excess by means of HPLC.
Scheme 4. Transformation of (R)-13a into (R)-Mosher amide.
Chem. Eur. J. 2008, 14, 8603 – 8614
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8605

F. Hammerschmidt et al.
[20]
latter.[18] Assuming that the predominant conformations of
the two diastereomeric Mosher amides are A and B
(Scheme 4) with the methyl and the carbonyl groups being
syn periplanar, the methoxy group of the (R)-MTPA portion
should be shielded in A, but deshielded in B, which is in
agreement with the shifts found (d=3.45 vs. 3.57 ppm).
Therefore, this finding also supported the assigned R config-
uration, which necessitates a retentive course for the phos-
phoramidate–a-aminophosphonate rearrangement. On the
other hand, the phosphorus atom is shielded in A, but de-
shielded in B. However, the shift difference is too small to
be of relevance and opposite to expectation (31P NMR:
major diastereomer: d=24.98 ppm, with a shoulder at
24.96 ppm for the minor one).
by using Ph3P/diisopropyl azodicarboxylate (DIAD)/HN3
was treated with triethyl phosphite (Staudinger reaction) in
toluene (Scheme 6). The iminophosphorane (Æ)-16a was
Similarly, the (R)-1-phenylethylamine ((R)-(+)-1a) and
its racemic and S-configured 1-naphthyl analogue 1b were
converted to the corresponding a-aminophosphonic acids 8a
and 8b (see Scheme 3). The rearrangements were performed
under the optimised conditions, that is, by using sBuLi/
TMEDA in THF at À788C. A small amount of the N-Boc-
protected phosphoramidate was deprotected at the nitrogen
atom by removal of Boc. All protecting groups (Boc; ethyl
at the phosphorus atom) could be removed by heating the
solution at reflux in 6m HCl followed by ion-exchange chro-
matography (Dowex 50W,H+) or under milder conditions
using bromotrimethylsilane/allylsilane at 508C in 1,2-di-
chloroethane (Scheme 5).[19] After removal of volatile com-
Scheme 6. Conversion of (Æ)- and (R)-1-azidoindan to a-aminophos-
phonic acids (Æ)- and (S)-(+)-23.
hydrolysed[21] to give phosphoramidate (Æ)-19a, which was
protected at the nitrogen atom with a Boc group in high
yield (91%). N-Boc-protected phosphoramidate (Æ)-17a
was then subjected to the phosphoramidate–a-amino-
phosphonate rearrangement under our standard conditions
(sBuLi/TMEDA/THF/À788C) to furnish aminophosphonate
(Æ)-22a in 54% yield, which was deprotected. The low
yield for the rearrangement, in part caused by removal of
the Boc group, induced us to probe the more bulky isopro-
pyl group as protecting groups at the phosphorus atom in
the optically active series. (S)-1-Indanol (98% ee)[22] was
converted to azide (R)-(+)-15 by using diphenylphosphoryl
Scheme 5. Deblocking of N-Boc-protected aminophosphonates 13a,b.
ponents under reduced pressure, hydrolysis of the silyl
esters furnished the free acids 8a,b, which were crystallised
from water. The enantiomeric excesses were determined by
means of HPLC from samples taken from the crude prod-
ucts. The yields of the individual steps and the enantiomeric
excesses of the free acids are compiled in Table 2. The two
steps, the conversion of 2 to 13 via 10, can also be per-
formed as a one-pot reaction in 66% yield.
To show that cyclic benzylic amines can be similarly trans-
formed into a-aminophosphonic acids, we selected 1-indan-
yl- and 1,2,3,4-tetrahydro-1-naphthylamine. In the case of
the 1-indanyl derivatives we demonstrate that the corre-
sponding alcohols can be used as starting materials as well
as the amines. Thus, (Æ)-1-azidoindan ((Æ)-15a) prepared
azide/1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU)[23] giving a
A
higher enantiomeric excess than the Mitsunobu method.
The azide was reacted with triisopropyl phosphite and then
with water to give phosphoramidate (R)-(+)-19b in high
yield. The remaining steps were similar to those with the
racemic compounds. Alternatively, we tried to directly use
the iminophosphorane (R)-16b for the protection at the ni-
trogen atom with Boc by reaction with Boc2O. As the yield
was merely 58% after heating for 72 h at 808C, this ap-
proach was abandoned in favour of the method via 19b. The
yield for the rearrangement was only marginally higher
(60%) compared with the ethyl analogue in the racemic
series. The enantiomeric excess of a-aminophosphonic acid
(S)-(+)-23, the first quaternary cyclic one known, was 96%,
which reflects complete inversion of configuration at the
benzylic position for the introduction of the azide group
Table 2. Conversion of amines 1a,b into a-aminophosphonic acids 8a,b.
Amine/ee [%] 2/Yield [%] 10/Yield [%] 13/Yield [%] 8/Yield/ee [%]
(R)-1a/96
(Æ)-1b/–
(S)-1b/99
(R)-2a/96
(Æ)-2b/89
(S)-2b/90
(R)-10a/96
(Æ)-10b/96
(S)-10b/95
(S)-13a/79
(Æ)-13b/75
(R)-13b/61
(S)-8a/74/92
(Æ)-13b/90/–
(R)-13b/53/99
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Chem. Eur. J. 2008, 14, 8603 – 8614

a-Aminobenzylphosphonic Acids via a-Aminobenzyllithiums
FULL PAPER
(SN2 reaction) and stereospecificity for the rearrangement,
for which we assume a retentive course by analogy to the
open-chain amines.
As the Boc protecting group proved insufficiently stable
towards sBuLi used for metalation, there were two options:
1) replacing it by the lithiocarboxyl group or 2) using a
strong and sterically demanding lithium amide as a base. We
reasoned that the former group should be more stable to al-
kyllithiums than Boc, although possibly less activating for
metalation. Phosphoramidate (Æ)-19a was lithiated and re-
acted with CO2 to give lithium salt (Æ)-24 (Scheme 7). Re-
moval of excess CO2 under reduced pressure and addition
of sBuLi/TMEDA to effect rearrangement and workup after
1 h furnished the desired phosphonate (Æ)-25, but in low
yield (26%).
Scheme 8. Conversion of racemic 1,2,3,4-tetrahydro-1-naphthylamine to
a-aminophosphonate (Æ)-30 and hydroxyphosphonates (Æ)-32a–d.
Scheme 7. Use of N-lithiooxycarbonyl-protected phosphoramidate (Æ)-
24 for phosphoramidate–a-aminophosphonate rearrangement.
CHN (d=5.20 ppm) was still present. These characteristic
features are in agreement with the tentatively assigned
structures (Æ)-32a–d of isomeric a-hydroxyphosphonates
with three stereogenic centres. When the sample was kept
for a while, crystals of isomer (Æ)-32a formed that corre-
sponded to the predominant phosphonamidate in the mix-
As we wanted to prepare the a-aminophosphonic acid de-
rived from 1,2,3,4-tetrahydro-1-naphthylamine ((Æ)-26) as
well, we used LiTMP/TMEDA (TMP=2,2,6,6-tetramethyl-
piperidine) as base and compared it with sBuLi/TMEDA.
The amine was protected to furnish N-Boc-protected phos-
phoramidate (Æ)-28, which was metalated and rearranged
to give a-aminophosphonate (Æ)-30 in 38% yield, so far the
lowest for the rearrangement (Scheme 8). To minimise re-
moval of the Boc group, (Æ)-28 was also metalated with
LiTMP/TMEDA at À788C in Et2O and the progress of the
reaction was followed by TLC analyses. As expected, re-
moval of the Boc group was insignificant, but surprisingly
no a-aminophosphonate was formed. Instead, a new spot
appeared, increasing with reaction time. After 4 h the TLC
results obtained from withdrawn samples did not change
any more. The crude product was a complex mixture of
compounds. Flash chromatography furnished starting mate-
rial (37%) and a product (37%), which seemed to be nearly
homogeneous according to the TLC data, but was heteroge-
neous according to the spectroscopy data (1H, 31P NMR).
On the basis of the 31P NMR spectrum, it was determined to
be a mixture of four phosphonamidates (d=34.1, 32.9, 32.5,
and 31.7 ppm) in a ratio of 3:2:27:68. The 1H NMR spec-
trum showed that one of the CH3 groups of the ethyl groups
resonated as a doublet of a doublet (J=7.1, 18.7 Hz), which
indicated a P-CH-CH3 group. The signal of the benzylic
1
ture (d=31.7 ppm). Its H and 13C NMR spectrum support-
ed the assignment, but did not give the configuration at the
stereogenic centres. Single-crystal X-ray structure analysis
secured the proposed structure (Æ)-32a with the relative
configurations (Figure 1, Table 3). Clearly, LiTMP did not
metalate (Æ)-28 in the position a to the nitrogen atom at
the benzylic position, but instead in the position a to the
oxygen atom at the ethyl group. The a-oxyethyllithium in-
termediates (Æ)-31a–d isomerised to a-hydroxyphosphon-
amidates (Æ)-32a–d (phosphate–a-hydroxyphosphonate re-
arrangement). This result shows that the sterically encum-
bered base LiTMP removed the more easily accessible hy-
drogen atom from the methylene group rather than from
the benzylic position, which should be of roughly equal acid-
ity. For the first time, this allows the acidity of hydrogen
atoms in the position a to the oxygen atom in phosphorami-
dates (and phosphates) and in the position a to the nitrogen
atom in N-benzyl phosphoramidates to be estimated. Their
pKa should be about 37, the pKa of 2,2,6,6-tetramethylpiper-
idine.[24] The low yield of (Æ)-32a–d is very likely caused by
elimination of ethylene from the phosphoramidate (Æ)-28
by LiTMP, giving water-soluble salts. It was therefore not
surprising that N-alkyl phosphoramidates could not yet be
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F. Hammerschmidt et al.
Figure 1. Structural views of two of the four independent molecules in
the solid-state structure of (Æ)-32a (50% thermal ellipsoids). Note the
difference in the orientation of the Boc group of the two molecules.
Scheme 9. Conversion of (Æ)- and (S)-1,2,3,4-tetrahydro-1-naphthol to a-
aminophosphonic acids (Æ)- and (S)-(À)-38.
Table 3. Selected bond lengths [Š]and angles [ 8]for ( Æ)-32a. The
Conclusion
values given are averages of the four independent molecules.
À
P1 O1
À
P1 O2
1.475(2)
1.575(2)
1.697(2)
1.824(2)
2.731(2)
119.8(1)
120.0(1)
119.3(1)
N1-C1
1.495(2)
1.397(2)
1.455(3)
1.418(2)
We have shown that secondary benzylic amines and azides
can be transformed easily first into N-benzyl phosphorami-
dates and then into N-Boc-protected derivatives. These
could then be lithiated with sBuLi/TMEDA in THF or Et2O
to give at À788C microscopically configurationally stable
tertiary a-amino carbanions. These carbanion intermediates
were stable up to 08C as proven for the reaction in Et2O
before rearranging to a-aminophosphonates (phosphorami-
date–aminophosphonate rearrangement), as demonstrated
for 1-phenylethylamine. Removal of protecting groups with
bromotrimethylsilane/allytrimethylsilane followed by hy-
drolysis, gave crystalline quaternary benzylic a-aminophos-
phonic acids. In one case, when LiTMP was used as base to
induce the rearrangement of the diethyl phosphoramidate
derived from (Æ)-1,2,3,4-tetrahydro-1-naphthylamine, a hy-
drogen atom in the position a to the oxygen atom in the
ethyl protecting group was removed. The ensuing phosphor-
amidate–a-hydroxyphosphonate rearrangement furnished a
mixture of four a-hydroxyphosphonates. The predominating
diastereomer was isolated as a crystalline product amenable
to X-ray structure analysis. This enabled us to secure the rel-
ative configurations of the three stereogenic centres. This
product allowed the pKa of the respective hydrogen atoms
in the position a to the oxygen atom in phosphates to be es-
timated to be below 37.
À
N1 C15
À
À
P1 N1
O2 C11
À
À
P1 C13
O3 C13
À
O3 (H)···O1’
P1-N1-C1
P1-N1-C15
C1-N1-C15
O1-P1-O2
P1-O2-C11
P1-C13-O3
115.0(1)
119.8(2)
109.0(2)
metalated at the position a to the nitrogen atom to get a-
aminophosphonates, because the pKa of the hydrogen atoms
in the position a to the nitrogen atom will be significantly
higher than those in the position a to the oxygen atom.
When the experiment was repeated, except that the temper-
ature was kept between À50 and À458C, only 4% of start-
ing material was recovered and the yield (39%) of the mix-
ture of the a-hydroxyphosphonates with minor changes in
their ratio was virtually the same as before (37%). The
higher reaction temperature increased elimination relative
to rearrangement. This reaction could form the basis for the
preparation of optically active a-hydroxyphosphonates start-
ing from phosphoramidates derived from optically active
amines.
To improve the yield for the phosphoramidate–amino-
phosphonate rearrangement in the 1,2,3,4-tetrahydro-1-
naphthylamine series, we switched from the ethyl to the iso-
propyl protecting groups (Scheme 9). The racemic and (S)-
1-tetralol[22] 33 were first converted in high yield via azides
34 into phosphoramidates 35 and then into N-Boc-protected
amides 36. Base-induced rearrangement furnished a-amino-
phosphonates 37 in acceptable yields of 59 and 53%, respec-
tively. Complete removal of protecting groups gave the free
a-aminophosphonic acids (Æ)- and (S)-(À)-38, the latter
with an enantiomeric excess of 97% as determined by using
HPLC after pre-column derivatisation with the Sanger re-
agent. The configuration was assigned on the basis of assum-
ing retention for the rearrangement.
ExperimentalSection
General: Reactions were carried out under argon in oven-dried glass-
ware. 1H, 13C and 31P NMR spectra were usually measured in CDCl3 at
300 K on a Bruker Avance DRX 400 at 400.1, 100.6 and 162 MHz, re-
spectively, or on a Bruker DPX 250 (1H: 250.1 MHz; 13C: 62.9 MHz) in
rare cases. Chemical shifts were referenced to residual CHCl3 (dH =
7.24 ppm), CDCl3 (dC =77.00 ppm) or H3PO4 (external). Additional 1H
and 13C (J modulated) spectra were measured at 360 K in [D8]toluene on
a DRX 400 at 400.1 and 100.6 MHz, respectively, and referenced to the
8608
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8603 – 8614

a-Aminobenzylphosphonic Acids via a-Aminobenzyllithiums
FULL PAPER
CHD2 (dH =2.09 ppm) and the CD3 group (dC =21.04 ppm). IR spectra
were run as films on a silicon disc on a Perkin-Elmer 1600 FTIR spec-
trometer.[25] IR spectra of the ground aminophosphonic acids were re-
corded on an attenuated total internal reflection (ATR) diamond on a
Perkin-Elmer Spektrum 2000 IR spectrometer. Optical rotations were
measured at 208C on a Perkin-Elmer 351 polarimeter in a 1 dm cell.
TLC analyses were carried out on 0.25 mm-thick Merck plates of silica
gel 60 F254. Flash column chromatography was performed with Merck
silica gel 60 (230–400 mesh). Spots were visualised by using UV and/or
dipping the plate into a solution of (NH4)6Mo7O24·4H2O (23.0 g) and of
in cyclohexane) were added to a solution of an N-Boc-protected phos-
phoramidate (1.0 mmol) in dry Et2O (or THF) (5 mL) under argon at
À788C. When the product did not increase anymore (monitored by TLC,
up to 1 h), AcOH (2 mL, 4 mmol, 2m in Et2O) and water (5 mL) were
added. The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3”10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The residue was pu-
rified by means of flash chromatography.
Deprotection of N-protected a-aminophosphonates with hot HCl(6 m)—
GeneralProcedure E : A mixture of aminophosphonate (1.0 mmol) and
concentrated HCl (4 mL) und water (4 mL) was heated at reflux for 16
to 18 h. After concentration under reduced pressure, the residue was
dried in a vacuum desiccator (KOH) and then purified by means of ion
exchange chromatography (Dowex 50W,H+, 50–100 mesh). Fractions
(TLC: iPrOH/H2O/NH3 6:3:1) containing aminophosphonic acid were
pooled, lyophilised and crystallised from water.
Ce(SO4)2·4H2O (1.0 g) in 10% aqueous H2SO4 (500 mL), followed by
A
heating with a heat gun. Melting points were determined on a Reichert
Thermovar instrument and are uncorrected.
TMEDA, Et3N and pyridine were heated at reflux over powdered CaH2
and toluene was heated at reflux over sodium/benzophenone; they were
then distilled and stored over molecular sieves (4 Š). Et2O was heated at
reflux over LiAlH4 and THF was heated at reflux over potassium under
argon; they were then distilled prior to use. CH2Cl2 was dried by being
passed through aluminium oxide 90 (active, neutral, 0.063–0.200 mm, ac-
tivity I) and stored over molecular sieves (3 Š). TMP was used as sup-
plied.
Deprotection of N-protected a-aminophosphonates with bromotrimethyl-
silane/allyltrimethylsilane—General Procedure F: Allyltrimethylsilane
(0.46 g, 0.64 mL 4.0 mmol) and bromotrimethylsilane (0.77 g, 0.65 mL,
5.0 mmol) were added to
a stirred solution of a-aminophosphonate
(1 mmol) in dry 1,2-C2H4Cl2 (6 mL) at 08C under argon. Then, the mix-
ture was heated for 5 h at 508C (bath temperature). After cooling, vola-
tile components were removed (5 mm Hg). The residue was dissolved in
dry CH2Cl2 (5 mL) and concentrated under reduced pressure three times,
the last time at 0.5 mbar. Methanol (10 mL) and water (5 mL) were
added to the residue and stirred for 30 min. The mixture was concentrat-
ed under reduced pressure. Water was added and removed again under
reduced pressure. After addition of water (20 mL) the mixture was
lyophilised. The crude product was crystallised from water or water/
EtOH.
HPLC control for enantiomeric excess determination of a-aminophos-
phonic acids was performed as reported[15] by using pre-column derivati-
sation with the Sanger reagent to yield DNP derivatives and a chiral ion-
exchange stationary phase based on quinine carbamate (CSP
I in
ref. [15], 150”4 mm i.d.): mobile phase: 80% MeOH/20% 50 mm
NaH2PO4; pHapp 5.6; T=408C; flow rate: 1 mLminÀ1; compound/reten-
tion factor: (R)-(+)-8a/3.49, (S)-(À)-8a/4.81, (R)-(+)-8b/4.00, (S)-(À)-
8b/6.94, (R)-(À)-23/2.88, (S)-(+)-23/3.90, (R)-(+)-38/3.37, (S)-(À)-38/
4.28.
Phosphoryal tion of benzylamines with diethylchol rophosphate—Gener-
alProcedure A : Diethyl chlorophosphate (3.45 g, 2.89 mL, 20 mmol) was
added dropwise to a solution of amine (20 mmol) und triethylamine
(3.04 g, 4.20 mL, 30 mmol) in dry CH2Cl2 (15 mL) at 08C. Stirring was
continued at 208C until the starting material was consumed (TLC, 8 h).
Water (10 mL) and HCl (6 mL, 2m) were added. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (3”10 mL).
The combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by bulb-to-bulb
distillation or flash chromatography.
(R)-(+)- and (S)-(À)-Diethyl N-(1-phenylethyl)phosphoramidate ((R)-
(+)- and (S)-(À)-2a): (R)-(+)-1-Phenylethylamine (0.727 g, 6.0 mmol,
0.77 mL, 96% ee) was converted to (R)-(+)-2a by using General Proce-
dure A. The residue was purified by bulb-to-bulb distillation (1408C,
0.08 mbar) to give phosphoramidate (R)-(+)-2a (1.479 g, 96%) as a col-
ourless oil; [a]2D0 =+40.9 (c=2.37, acetone). Similarly, (S)-(À)-1-phenyl-
G
2a (4.35 g, 85%); [a]2D0 =À43.1 (c=1.61, acetone). 1H NMR (400.1 MHz,
CDCl3): d=1.07 (dt, J=0.8, 7.1 Hz, 3H), 1.28 (dt, J=0.5, 7.1 Hz, 3H),
1.44 (dd, J=0.5, 6.8 Hz, 3H), 3.22 (brt, J=8.8 Hz), 3.69 (m, 1H), 3.90
(m, 1H), 4.02 (m, 2H), 4.28 (dquint, J=6.8, 7.1 Hz, 1H), 7.20 ppm (m,
5H); 13C NMR (100.6 MHz, CDCl3): d=15.8 (d, J=6.9 Hz), 16.1 (d, J=
6.9 Hz), 25.2 (d, J=6.1 Hz), 51.4, 62.0 (d, J=4.6 Hz), 62.2 (d, J=5.4 Hz),
125.8 (2C), 127.0, 128.4 (2C), 145.1 ppm (d, J=4.6 Hz); IR (Si): n˜ =3212,
Phosphorylation of benzyl amines with diisopropyl bromophosphate—
GeneralProcedure B : A solution of bromine (18.0 mL, 18.0 mmol, 1m in
dry CH2Cl2) was added dropwise to a solution of triisopropyl phosphite
(3.75 g, 4.44 mL, 18.0 mmol) in dry CH2Cl2 (10 mL) under argon at
À508C. The mixture was stirred for 30 min at 08C, re-cooled to À508C
and benzyl amine (15 mmol) and Et3N (3.04 g, 4.18 mL, 30 mmol) were
added. After stirring the mixture at 208C until the starting material was
consumed (TLC, several hours), HCl (12 mL, 2m) und water (20 mL)
were added. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3”10 mL). The combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by means of flash chromatography.
2978, 2904, 1457, 1232, 1031, 966 cmÀ1 31P NMR (162 MHz, CDCl3): d=
;
8.7 ppm; elemental analysis calcd (%) for C12H20NO3P (257.3): C 56.02,
H 7.84, N 5.44; found: C 56.19, H 7.37, N 5.06.
(R)-(+)-Tetraethyl N-(1-phenylethyl)bis(phosphoramidate) ((R)-(+)-3):
Phosphoramidate (R)-(+)-2a (1.30 g, 5.0 mmol) was phosphorylated at
the nitrogen atom (flash chromatography: CH2Cl2/EtOAc 1:8, Rf =0.28)
to give (R)-(+)-3 (0.94 g, 47%) as a colourless oil by using General Pro-
cedure B.[12] The analytical sample was additionally purified by using
HPLC (Superspher Si 60: 4 mm; 237 mm”32 mm i.d.; 80 mLminÀ1; hex-
anes/EtOAc 3:7; 2a: tR =26.7 min; 3: tR =32 min); [a]2D0 =+8.8 (c=1.06,
acetone). 1H NMR (250.1 MHz, CDCl3): d=1.20 (t, J=7.1 Hz, 6H), 1.27
(t, J=7.1 Hz, 6H), 1.81 (d, J=7.1 Hz, 3H), 5.12 (tq, J=7.1, 19.9 Hz,
1H), 7.26 (m, 3H), 7.55 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=
15.8 (d, J=3.7 Hz), 15.88 (d, J=4.1 Hz, 2C), 15.93 (d, J=4.1 Hz), 19.2,
56.5, 62.85 (d, J=2.6 Hz), 62.89 (d, J=2.6 Hz), 63.1 (d, J=2.6 Hz), 63.2
(d, J=2.6 Hz), 127.0, 127.6 (2C), 128.0 (2C), 141.7 ppm; 31P NMR
(162 MHz, CDCl3): d=4.9 ppm; IR (Si): n˜ =3491, 2983, 2934, 2909, 1497,
1478, 1449, 1392, 1370, 1260, 1210, 1166, 1028, 982 cmÀ1; elemental analy-
sis calcd (%) for C16H29NO6P2 (393.3): C 48.86, H 7.43, N 3.56; found: C
48.92, H 7.44, N 3.43.
Preparation of N-Boc-protected phosphoramidates from phosphorami-
dates by using sBuLi/Boc2O—GeneralProcedure C : sBuLi (5.14 mL,
7.2 mmol, 1.4m in cyclohexane) was added to a stirred solution of phos-
phoramidate (6 mmol) in dry Et2O or THF (10 mL) under argon at
À788C. After 15 min di-t-butyl dicarbonate (1.48 g, 6.6 mmol, Boc2O) dis-
solved in dry Et2O (5 mL) was added. The mixture was allowed to warm
up in the cooling bath and was stirred until the starting material was con-
sumed (18 h). After addition of AcOH (3 mL, 2m in Et2O) and water
(10 mL), the organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3”10 mL). The combined organic layers were
washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
means of flash chromatography.
(S)-(À)-Diethyl 1-(diethoxyphosphinylamino)-1-phenylethylphosphonate
((S)-(À)-6): Phosphoramidate (R)-(+)-3 (0.39 g, 1 mmol) was rearranged
Phosphoramidate–a-aminophosphonate rearrangement of N-Boc-pro-
tected phosphoramidates with sBuLi/TMEDA—GeneralProcedure D :
TMEDA (0.17 g, 0.23 mL, 1.5 mmol) and sBuLi (1.1 mL, 1.5 mmol, 1.4m
by using General Procedure
D (Et2O, 3.5 h; flash chromatography:
CH2Cl2/EtOAc 1:8, Rf =0.08) to give phosphonate (S)-(À)-6 (0.288 g,
Chem. Eur. J. 2008, 14, 8603 – 8614
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8609

F. Hammerschmidt et al.
73%) as
a
colourless oil. [a]2D0 =À24.6 (c=0.57, acetone); 1H NMR
mental analysis calcd (%) for C17H28NO5P (357.4): C 57.13, H 7.90, N
3.92; found: C 56.91, H 7.74, N 4.14.
(250.1 MHz, CDCl3): d=1.00 (dt, J=0.9, 7.1 Hz, 3H), 1.12 (dt, J=0.5,
7.1 Hz, 3H), 1.20 (dt, J=0.5, 7.1 Hz, 6H), 1.27 (dt, J=0.9, 7.1 Hz, 3H),
1.94 (d, J=17.1 Hz, 3H), 3.67 (m, 2H), 3.98 (m, 7H), 7.29 (m, 3H),
7.58 ppm (m, 2H); 13C NMR (62.9 MHz, CDCl3): d=15.7 (d, J=7.4 Hz),
15.9 (d, J=7.8 Hz), 16.1 (d, J=6.0 Hz), 16.2 (d, J=5.5 Hz), 20.0 (dd, J=
1.8, 5.5 Hz), 56.7 (d, J=155.3 Hz), 62.1 (d, J=5.5 Hz), 62.3 (d, J=
5.5 Hz), 63.2 (d, J=7.4 Hz), 63.4 (d, J=7.4 Hz), 127.0 (d, J=5.1 Hz, 2C),
127.4 (d, J=2.7 Hz), 127.8 (d, J=2.3 Hz, 2C), 140.7 ppm; 31P NMR
(162 MHz, CDCl3): d=26.1 (d, J=46.6 Hz), 7.0 ppm (d, J=46.6 Hz); IR
(Si): n˜ =3480, 3240, 2982, 1444, 1393, 1243, 1164, 1029, 970 cmÀ1; elemen-
tal analysis calcd (%) for C16H29NO6P2 (393.3): C 48.86, H 7.43, N 3.56;
found: C 48.83, H 7.22, N 3.39.
Deblocking of (R)-(+)-13a and derivatisation of (R)-(+)-14a with (S)-
MTPACl: Phosphonate (R)-(+)-13a (0.11 g, 0.30 mmol) was dissolved in
dry CH2Cl2 (1 mL). After addition of CF3CO2H (1 mL) the mixture was
stirred for 3 h at 208C (TLC: CH2Cl2/MeOH 10:1) and then concentrated
under reduced pressure. CH2Cl2 (10 mL), water (3 mL) and concentrated
ammonia (5 drops) were added. The organic phase was separated and the
aqueous phase was extracted with CH2Cl2 (10 mL). The combined organ-
ic layers were washed with water (3 mL), dried (Na2SO4) and concentrat-
ed under reduced pressure. Flash chromatography (CH2Cl2/MeOH 15:1,
TLC: 10:1, Rf =0.72) gave aminophosphonate (R)-(+)-14a (65 mg, 84%)
as
a
colourless oil. [a]2D0 =+26.4 (c=1.23, dry ethanol); 1H NMR
(250.1 MHz, CDCl3): d=1.12 (dt, J=0.5, 6.9 Hz, 3H), 1.23 (dt, J=0.5,
6.9 Hz, 3H), 1.69 (d, J=15.8 Hz, 3H), 1.88 (brs, 2H), 3.85 (m, 4H), 7.30
(m, 3H), 7.61 ppm (m, 2H); 31P NMR (162 MHz, CDCl3): d=29.10 ppm;
Deblocking of (S)-(À)-diethyl 1-(diethoxyphosphinylamino)-1-phenyl-
ethylphosphonate ((S)-(À)-6): The phosphonate (250 mg, 0.64 mmol) was
deblocked by using General Procedure E (ion-exchange chromatogra-
phy: water as eluent; TLC: iPrOH/H2O/NH3 6:3:1, Rf =0.62) to give ami-
nophosphonic acid (S)-(À)-8a (0.091 g, 71%, 50% ee). [a]2D0 =À24.6 (c=
0.94, 1m NaOH).
IR (Si): n˜ =3455, 2986, 1682, 1556, 1447, 1207, 1140, 1025 cmÀ1
.
A mixture of aminophosphonate (R)-(+)-14a (26 mg, 0.10 mol), (S)-
MTPACl (63 mg, 0.25 mmol), dry CH2Cl2 (0.5 mL), and dry pyridine
(1 mL) was stirred for 16 h at 208C. Water (a few drops) were added and
the mixture was concentrated under reduced pressure. CH2Cl2 (10 mL)
and HCl (5 mL, 2m) were added. The organic layer was separated,
washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
means of flash chromatography (hexanes/EtOAc 1:5, Rf =0.70) to give
the (R)-Mosher amide of (R)-(+)-14a (40 mg, 85%, 96% ee) as a colour-
(S)-(À)- and (R)-(+)-Diethyl N-(t-butoxycarbonyl)-N-(1-phenylethyl)-
phosphoramidate ((S)-(À)- and (R)-(+)-10a): Compounds 10a were pre-
pared by using General Procedure C. The crude products were purified
by means of flash chromatography (hexanes/EtOAc 1:2, Rf =0.61) to give
colourless oils. Phosphoramidate (S)-(À)-2a (1.54 g, 6.0 mmol) gave (S)-
(À)-10a (1.75 g, 82%); [a]2D0 =À10.3 (c=0.81, acetone). Similarly, diethyl
N-(1-phenylethyl)phosphoramidate ((R)-(+)-2a) (0.50 g, 1.9 mmol) gave
phosphoramidate (R)-(+)-10a (0.65 g, 96%); [a]2D0 =+10.1 (c=2.51, ace-
tone). 1H NMR (400.1 MHz, CDCl3): d=1.29 (s, 9H), 1.29 (dt, J=1.0,
7.1 Hz, 3H), 1.32 (dt, J=1.0, 7.1 Hz, 3H), 1.76 (d, J=6.8 Hz, 3H), 4.09
(m, 4H), 5.42 (dq, J=6.8, 13.9 Hz, 1H), 7.19 (m, 1H), 7.28 (m, 2H),
7.39 ppm (m, 2H); 13C NMR (100.6 MHz, CDCl3): d=16.1 (d, J=
6.9 Hz), 16.2 (d, J=6.9 Hz), 18.2, 27.9 (3C), 54.8 (d, J=3.1 Hz), 63.2 (d,
J=6.1 Hz), 63.7 (d, J=6.1 Hz), 82.2, 126.6, 126.8 (2C), 127.9 (2C), 142.3
(d, J=3.6 Hz), 153.2 ppm (d, J=6.9 Hz); 31P NMR (162 MHz, CDCl3):
d=17.5 ppm; IR (Si): n˜ =2980, 1721, 1292, 1162, 1028 cmÀ1; elemental
analysis calcd (%) for C17H28NO5P (357.4): C 57.13, H 7.90, N 3.92;
found: C 56.93, H 7.62, N 3.84.
1
less oil. H NMR (250.1 MHz, CDCl3): d=1.11 (t, J=7.1 Hz; CH3, minor
diastereomer), 1.15 (t, J=7.1 Hz; CH3, major), 1.17 (t, J=7.1 Hz; CH3,
major), 1.21 (J=7.1 Hz; CH3, minor), 2.06 (d, J=16.2 Hz; CH3, 98%),
2.13 (d, J=16.2 Hz; CH3, 2%), 3.45 (q, J=1.6 Hz; OCH3, 98%), 3.57 (q,
J=1.6 Hz; OCH3, 2%), 3.69–4.00 (m, 4H), 7.21–7.58 (m, 10H), 7.86 ppm
(brd, J=10.7 Hz, 1H; NH, major); 31P NMR (162 MHz, CDCl3): d=
24.96 (minor diastereomer), 24.98 ppm (major).
(R)-(+)- and (S)-(À)-1-Amino-1-phenylethylphosphonic acid ((R)-(+)-
and (S)-(À)-8a) as monohydrates: Phosphonate (R)-(+)-13a (0.13 g,
0.37 mmol) was deprotected according to General Procedure E (Dowex
50W,H+; TLC: iPrOH/H2O/NH3 6:3:1, Rf =0.37; eluent: at first water,
then aqueous AcOH (10%)) to yield aminophosphonic acid (R)-(+)-8a
(0.05 g, 67%) as colourless crystals: m.p. 221–2238C (H2O); [a]2D0 =+43.6
(c=0.81, 1m NaOH); ee of crude product: 97% (ee of crude product of
rearrangement at À308C: 98%). Phosphonate (R)-(+)-13a (0.31 g,
0.85 mmol, from rearrangement at 08C) gave aminophosphonic acid (R)-
(+)-8a (0.11 g, 56%) according to General Procedure F and crystallisa-
tion from water: ee of crude product: 98%; [a]2D0 =+49.5 (c=0.48, 1m
NaOH). Phosphonate (S)-(À)-13a (0.454 g, 1.27 mmol) yielded amino-
phosphonic acid (S)-(À)-8a (0.21 g, 74%) according to General Proce-
dure F and crystallisation from water; m.p. 222–2238C (ref. [26]: 2358C
for monohydrate of racemate); ee of crude product: 92% (prepared from
(R)-1-phenylethylamine ((R)-(+)-1a, 96% ee)); [a]2D0 =À50.2 (c=0.45,
(R)-(+)- and (S)-(À)-Diethyl1-( t-butoxycarbonylamino)-1-phenylethyl-
phosphonate ((R)-(+)- and (S)-(À)-13a): Phosphoramidate (S)-(À)-10a
(0.73 g, 2 mmol) was rearranged in dry THF at À788C in 1 h according to
General Procedure D. Flash chromatography (EtOAc/hexanes 1:1, Rf =
0.28) furnished phosphonate (R)-(+)-13a (0.58 g, 80%) as a colourless
oil; [a]2D0 =+2.9 (c=1.50, acetone). Analogously, (S)-(À)-10a (0.357 g,
1 mmol) was transformed in dry Et2O at À788C (3 h) into phosphonate
(R)-(+)-13a (0.26 g, 65%). (R)-(+)-13a (0.26 g, 76%) was furnished
from (S)-(À)-10a (0.357 g, 1 mmol) in dry Et2O at À788C in 45 min.
After 1 h, (S)-(À)-10a (0.357 g, 1 mmol) yielded 0.139 g (39%) (R)-(+)-
13a in dry Et2O at À308C, but after 10 min, also at À308C, 0.26 g (73%)
of product were obtained; [a]2D0 =+3.4 (c=0.83, acetone). (S)-(À)-10a
(0.71 g, 2 mmol) gave (R)-(+)-13a (0.42 g, 59%) in dry Et2O at 08C in
3 min; [a]2D0 =+2.4 (c=2.31, acetone). Phosphoramidate (R)-(+)-10a
(0.50 g, 1.4 mmol) was rearranged by means of General Procedure D in
dry Et2O at À788C in 45 min to aminophosphonate (S)-(À)-13a (0.39 g,
79%); [a]2D0 =À2.9 (c=1.52, acetone). 1H NMR (400.1 MHz, CDCl3): d=
1.15 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.31 (brs, 9H), 2.02 (d,
J=16.2 Hz, 3H), 3.69 (m, 1H), 3.86 (m, 3H), 5.61 (brs, 1H), 7.22 (m,
1H), 7.30 (m, 2H), 7.45 ppm (m, 2H); 31P NMR (162 MHz, CDCl3): d=
25.9 ppm; 1H NMR (400.1 MHz, C6D5CD3, 350 K): d=0.90 (t, J=7.1 Hz,
3H), 0.95 (t, J=7.1 Hz, 3H), 1.28 (s, 9H), 2.14 (dd, J=1.5, 15.9 Hz, 3H),
3.53 (m, 1H), 3.72 (m, 3H), 5.75 (brd, J=10.6 Hz, 1H), one Har over-
lapped with signals of [D8]toluene, 7.13 (m, 2H), 7.57 ppm (m, 2H);
13C NMR (100.6 MHz, C6D5CD3, 350 K, 137.5): d=16.2 (d, J=6.1 Hz),
16.2 (d, J=5.4 Hz), 21.7 (d, J=4.6 Hz), 28.4 (3C), 58.5 (d, J=147.6 Hz),
63.1 (d, J=6.9 Hz), 63.1 (d, J=6.9 Hz), 79.3, 127.1 (d, J=3.1 Hz), 127.7
(d, J=4.6 Hz, 2C), 127.9 (d, J=3.1 Hz, 2C), 141.0 (d, J=4.6 Hz),
154.4 ppm; 31P NMR (162 MHz, C6D5CD3, 350 K): d=26.2 ppm; IR (Si):
n˜ =3401, 2979, 2930, 1734, 1495, 1250, 1165, 1047, 1023, 965 cmÀ1; ele-
1
1m NaOH). H NMR (400.1 MHz, D2O/NaOD, HDO=4.67): d=1.62 (d,
J=12.1 Hz, 3H), 7.23 (m, 1H), 7.32 (m, 2H), 7.43 ppm (m, 2H);
13C NMR (100.6 MHz, D2O/NaOD): d=24.1, 57.7 (d, J=130.0 Hz), 126.4
(d, J=3.1 Hz, 2C), 126.9 (d, J=1.5 Hz), 128.4 (d, J=1.5 Hz, 2C),
142.9 ppm; 31P NMR (162 MHz, D2O/NaOD): d=8.1 ppm; IR (ATR):
n˜ =3113, 2929, 1614, 1538, 1500, 1446, 1380, 1177, 1056, 1028, 924 cmÀ1
;
elemental analysis calcd (%) for C8H14NO3P·H2O (219.2): C 43.84, H
6.44, N 6.39; found: C 43.56, H 5.83, N 5.86.
(Æ)- and (S)-(À)-Diethyl N-[1-(1-naphthyl)ethyl]phosphoramidate ((Æ)-
and (S)-(À)-2b): 1-(1-Naphthyl)ethylamine ((Æ)-1b) (1.00 g, 5.84 mmol)
was phosphorylated by using General Procedure A. Flash chromatogra-
phy (EtOAc, Rf =0.25) gave phosphoramidate (Æ)-2b (1.59 g, 89%) as
colourless crystals; m.p. 82–838C (hexanes). Similarly, 1-(1-naphthyl)-
A
midate (S)-(À)-2b (0.83 g, 90%); m.p. 85–888C (hexanes); [a]2D0 =À16.9
(c=0.80, acetone). 1H NMR (400.1 MHz, CDCl3): d=1.03 (t, J=7.1 Hz,
3H), 1.24 (t, J=7.1 Hz, 3H), 1.28 (t, J=7.1 Hz, 6H), 1.62 (d, J=6.8 Hz,
3H), 3.19 (brs, 1H), 3.74 (m, 1H), 3.93 (m, 1H), 4.05 (m, 2H), 5.16 (sext,
J=6.8 Hz, 1H), 7.50 (m, 4H), 7.75 (d, J=8.1 Hz, 1H), 7.85 (dd, J=1.3,
8610
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8603 – 8614

a-Aminobenzylphosphonic Acids via a-Aminobenzyllithiums
FULL PAPER
8.1 Hz, 1H), 8.14 ppm (d, J=8.6 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3): d=15.9 (d, J=7.7 Hz), 16.2 (d, J=6.9 Hz), 24.9 (d, J=4.6 Hz),
47.4, 62.3 (d, J=5.4 Hz), 62.4 (d, J=5.4 Hz), 122.3, 123.0, 125.4, 125.6,
126.1, 127.8, 128.9, 130.3, 133.9, 140.8 ppm (d, J=5.4 Hz); 31P NMR
(162 MHz, CDCl3): d=18.1 ppm; IR (Si, racemate): n˜ =3215, 2979, 1232,
1031, 967 cmÀ1; elemental analysis calcd (%) for C16H22NO3P (307.3): C
62.53, H 7.22, N 4.56; found for (Æ)-2b: C 62.70, H 7.29, N 4.54.
5.36; elemental analysis calcd (%) for C12H14NO3P·H2O (269.2): C 53.53,
H 5.99, N 5.20; found for (R)-(+)-8b: C 53.50, H 5.95, N 5.18.
(Æ)-1-Azidoindan ((Æ)-15) by Mitsunobu reaction: HN3 (5.60 mmol,
7.30 mL, 0.77m in toluene, HN3) was added to a stirred solution of triphe-
nylphosphane (1.26 g, 4.80 mmol) and (Æ)-1-indanol (0.537 g, 4 mmol) in
dry THF (5 mL) at 08C under argon; this was followed immediately by
addition of DIAD (0.97 g, 0.95 mL, 4.80 mmol). The mixture was stirred
for 18 h at 208C. After the addition of MeOH (5 drops) it was concen-
trated under reduced pressure and heated with hexanes. After cooling,
the mother liquor was removed, concentrated under reduced pressure
and purified by means of flash chromatography (hexanes/CH2Cl2 2:1,
Rf =0.48) to give (Æ)-1-azidoindan ((Æ)-15) (0.56 g, 88%) as a colourless
liquid.
(Æ)- and (S)-(+)-Diethyl N-(t-butoxycarbonyl)-N-[1-(1-naphthyl)ethyl]-
phosphoramidate ((Æ)- and (S)-(+)-10b): Diethyl N-[1-(1-naphthyl)-
ethyl]phosphoramidate ((Æ)-2b) (1.54 g, 5 mmol) was converted by using
General Procedure C (THF, flash chromatography: hexanes/EtOAc 2:1,
Rf =0.32) to phosphoramidate (Æ)-10b (1.96 g, 96%) as colourless crys-
tals; m.p. 718C (hexanes). Similarly, diethyl N-[1-(1-naphthyl)ethyl]phos-
phoramidate ((S)-(À)-2b) (0.73 g, 2.36 mmol) was converted to phos-
Preparation of (R)-(+)-1-azidoindan ((R)-(+)-15) by use of diphenyl-
phoramidate (S)-(+)-10b (0.91 g, 95%); m.p. 63–648C (hexanes); [a]D20
=
phosphorylazide/DBU
:
DBU (0.93 g, 0.92 mL, 6.12 mmol) and
1
(PhO)2P(O)N3 (1.68 g, 1.31 mL, 6.10 mmol) were added to a stirred solu-
tion of (S)-(+)-1-indanol (0.68 g, 5.10 mmol, >98% ee) in dry toluene
(8 mL) at 08C under argon. After stirring for 2 h at 08C and 5 h at 208C,
water (10 mL) and 5% HCl (10 mL) were added. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2 (2”15 mL).
The combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by means of flash chro-
matography (hexanes/CH2Cl2 5:1, Rf =0.77) to give (R)-(+)-15 (0.57 g,
70%, 94.1% ee) as a colourless liquid. [a]2D0 =+29.3 (c=1.61, hexane)
(ref. [22]: [a]2D0 =+25.3 (c=1.10, hexane)).
+16.1 (c=1.12, acetone). H NMR (400.1 MHz, CDCl3): d=0.94 (dt, J=
0.5, 7.1 Hz, 3H), 1.26 (dt, J=1.0, 7.1 Hz, 3H), 1.40 (s, 9H), 1.95 (d, J=
7.1 Hz, 3H), 3.38 (m, 1H), 3.57 (m, 1H), 4.00 (m, 1H), 4.10 (m, 1H),
6.14 (dq, J=7.1, 17.7 Hz, 1H), 7.45 (m, 3H), 7.76 (brt, J=7.8 Hz, 2H),
7.82 (dd, J=1.5, 7.8 Hz, 1H), 8.18 ppm (d, J=8.4 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): d=15.7 (d, J=7.6 Hz), 16.1 (d, J=6.9 Hz), 19.1,
28.0 (3C), 52.1 (d, J=3.1 Hz), 62.5 (d, J=5.4 Hz), 63.2 (d, J=6.1 Hz),
82.3, 123.9, 124.8, 125.1, 125.9, 127.2, 128.1, 128.7, 131.8, 133.6, 136.1 (d,
J=2.3 Hz), 153.8 ppm (d, J=5.4 Hz); 31P NMR (162 MHz, CDCl3): d=
2.2 ppm; IR (Si, racemate): n˜ =2980, 1708, 1298, 1163, 1027, 978 cmÀ1; el-
emental analysis calcd (%) for C21H30NO5P (407.4): C 61.90, H 7.42, N
3.44; found for (Æ)-10b: C 62.12, H 7.36, N 3.43.
(Æ)- and (R)-(À)-Diethyl1-( t-butoxycarbonylamino)-1-(1-naphthyl)ethyl-
phosphonate ((Æ)- and (R)-(À)-13b): Phosphoramidate (Æ)-10b (1.10 g,
2.70 mmol) was transformed (General Procedure D, flash chromatogra-
phy: hexanes/EtOAc 1:1, Rf =0.28) into phosphonate (Æ)-13b (0.83 g,
75%) as colourless crystals; m.p. 76–788C (hexanes). Similarly, phosphor-
amidate (S)-(+)-10b (0.66 g, 1.61 mmol) gave aminophosphonate (R)-
(À)-13b (0.49 g, 75%); [a]D20 =À68.3 (c=1.06, acetone). 1H NMR
(400.1 MHz, C6D5CD3, 353 K): d=0.77 (t, J=7.1 Hz, 3H), 0.92 (t, J=
7.1 Hz, 3H), 1.09 (brs, 9H), 2.27 (d, J=14.9 Hz, 3H), 3.51 (m, 1H), 3.66
(m, 2H), 3.81 (m, 1H), 5.78 (brd, J=9.9 Hz, 1H), 7.21 (m, 2H), 7.33
(ddd, J=1.5, 6.8, 8.6 Hz, 1H), 7.53 (brd, J=8.1 Hz, 1H), 7.60 (d, J=
8.1 Hz, 1H), 7.65 (dd, J=3.0, 7.6 Hz, 1H), 9.07 ppm (d, J=8.8 Hz, 1H);
13C NMR (100.6 MHz, C6D5CD3, 353 K): d=16.2 (d, J=5.4 Hz), 16.4 (d,
J=5.4 Hz), 25.7 (brs), 28.3 (3C), 30.4 (d, J=148.4 Hz), 63.1 (d, J=
6.9 Hz), 63.2 (d, J=6.1 Hz), 79.3, 125.0, 127.2 (d, J=6.1 Hz), 128.0, 129.3,
133.0 (d, J=4.6 Hz), 135.4, 137.1 (d, J=4.6 Hz), 154.1 ppm (d, J=
15.3 Hz); 31P NMR (162 MHz, C6D5CD3, 353 K): d=26.1 ppm; IR (Si,
racemate): n˜ =3436, 3271, 2979, 1697, 1367, 1248, 1165, 1048, 1165, 1048,
1025 cmÀ1; elemental analysis calcd (%) for C21H30NO5P (407.4): C 61.90,
H 7.42, N 3.44; found for (Æ)-13b: C 61.94, H 7.43, N 3.22.
(Æ)- and (R)-(+)-1-Amino-1-(1-naphthyl)ethylphosphonic acid ((Æ)- and
(R)-(+)-8b)) as hemihydrate and monohydrate, respectively: Phospho-
nate (Æ)-13b (0.33 g, 0.81 mmol) was converted (General Procedure E,
Dowex 50W,H+, H2O; TLC: iPrOH/H2O/NH3 6:3:1, Rf =0.32) to 1-ami-
nophosphonic acid (Æ)-8b (0.03 g, 14%) as brownish crystals. Phospho-
nate (Æ)-13b (0.15 g, 0.38 mmol) was also converted (General Procedure
F) to aminophosphonic acid (Æ)-8b·0.5H2O (0.09 g, 90%) as colourless
crystals; m.p. 205–2088C (water, low solubility even in hot water). Ami-
nophosphonate (R)-(À)-13b (0.30 g, 0.74 mmol) analogously gave amino-
phosphonic acid (R)-(+)-8b·H2O (0.11 g, 53%); m.p. 2128C (water);
[a]2D0 =+101.1 (c=0.44, 1m NaOH) (ee of crude product: 99%, R config-
uration). 1H NMR (400.1 MHz, D2O/NaOD, d=4.67): d=1.74 (d, J=
12.4 Hz, 3H), 7.41 (m, 3H), 7.62 (dd, J=0.5, 6.3 Hz, 1H), 7.72 (d, J=
8.1 Hz, 1H), 7.83 (m, 1H), 8.89 ppm (m, 1H); 13C NMR (100.6 MHz,
D2O/NaOD): d=27.3, 58.2 (d, J=130.8 Hz), 124.8, 125.5, 125.5 (d, J=
6.1 Hz), 125.7 (d, J=2.3 Hz), 127.7, 129.1, 130.4, 131.7 (d, J=3.1 Hz),
134.8 (d, J=1.5 Hz), 142.6 ppm; 31P NMR (162 MHz, D2O): d=
22.2 ppm; IR (ATR, racemate): n˜ =3049, 1615, 1515, 1445, 1390, 1138,
1108, 913 cmÀ1; elemental analysis calcd (%) for C12H14NO3P·0.5H2O
(260.2): C 55.39, H 5.81, N 5.38; found for (Æ)-8b: C 55.35, H 5.1, N
(Æ)-Diethyl N-(1-indanyl)phosphoramidate ((Æ)-19a) from amine: 1-In-
danamine ((Æ)-18) (0.240 g, 1.80 mmol) was converted (General Proce-
dure A, flash chromatography: EtOAc, Rf =0.40) to phosphoramidate
(Æ)-19a (0.29 g, 59%) as colourless crystals. M.p. 658C (hexanes).
(Æ)-Diethyl N-(1-indanyl)phosphoramidate ((Æ)-19a) from azide:
A
stirred solution of triethyl phosphite (0.997 g, 1.03 mL, 6 mmol) and 1-
azidoindan ((Æ)-15) (5 mmol) in dry toluene (10 mL) was heated for 4 h
at 508C. The cooled mixture was diluted with THF and water (5 mL
each) and concentrated under reduced pressure. Flash chromatography
(EtOAc/hexanes 1:2, Rf =0.39) of the crude product gave phosphorami-
date (Æ)-19a (1.32 g, 98%). M.p. 658C (hexanes); 1H NMR (400.1 MHz,
CDCl3): d=1.34 (dt, J=0.8, 7.1 Hz, 3H), 1.35 (dt, J=0.8, 7.1 Hz, 3H),
1.77 (m, 1H), 2.55 (ddt, J=2.8, 7.6, 12.6 Hz, 1H), 2.76 (m, 1H), 2.78 (t,
J=10.9 Hz, 1H), 2.91 (ddd J=2.8, 8.6, 15.7 Hz, 1H), 4.11 (m, 4H), 4.65
(m, 1H), 7.20 (m, 3H), 7.39 ppm (m, 1H); 13C NMR (100.6 MHz,
CDCl3): d=16.2 (d, J=6.9 Hz), 16.3 (d, J=6.9 Hz), 29.8, 36.7 (d, J=
2.3 Hz), 57.0, 62.4 (d, J=6.1 Hz), 62.4 (d, J=6.1 Hz), 123.9, 124.7, 126 6,
127.7, 142.7, 144.5 ppm; 31P NMR (162 MHz, CDCl3): d=9.4 ppm; IR
(Si): n˜ =3207, 2980, 1459, 1232, 1058, 1032, 999 cmÀ1; elemental analysis
calcd (%) for C13H20NO3P (269.3): C 57.98, H 7.49, N 5.20; found: C
57.93, H 7.44, N 5.14.
(Æ)-Diethyl N-(t-butoxycarbonyl)-N-(1-indanyl)phosphoramidate ((Æ)-
17a): Reaction of phosphoramidate (Æ)-19a (1.06 g, 3.94 mmol) gave
(General Procedure C; flash chromatography: EtOAc/hexanes 1:1, Rf =
0.51) phosphoramidate (Æ)-17a (1.32 g, 91%) as
a colourless oil.
1H NMR (400.1 MHz, CDCl3): d=1.20 (s, 9H), 1.33 (dt, J=0.8, 7.1 Hz,
3H), 1.36 (dt, J=1.0, 7.1 Hz, 3H), 2.33 (m, 1H), 2.47 (m, 1H), 2.84 (m,
1H), 3.03 (ddd, J=2.8, 9.9, 15.9 Hz, 1H), 4.18 (m, 4H), 5.68 (dt, J=8.3,
11.4 Hz, 1H), 7.15 ppm (s, 4H); 13C NMR (100.6 MHz, CDCl3): d=16.1
(d, J=6.8 Hz), 16.3 (d, J=7.6 Hz), 27.7 (3C), 30.3, 30.7 (d, J=1.5 Hz),
62.2 (d, J=3.8 Hz), 63.4 (d, J=6.1 Hz), 63.8 (d, J=5.4 Hz), 82.0, 122.5,
124.7, 126.2, 127.0, 142.2, 143.3 (d, J=3.8 Hz), 153.0 ppm (d, J=7.7 Hz);
31P NMR (162 MHz, CDCl3): d=4.3 ppm; IR (Si): n˜ =2980, 1718, 1457,
1394, 1368, 1295, 1160, 1028, 979 cmÀ1; elemental analysis calcd (%) for
C18H28NO5P (369.4): C 58.53, H 7.64, N 3.79; found: C 58.29, H 7.68, N
3.84.
(Æ)-Diethyl1-( t-butoxycarbonylamino)-1-indanylphosphonate ((Æ)-22a):
Phosphoramidate (Æ)-17a (0.37 g, 1.0 mmol) was rearranged (General
Procedure D; sBuLi/TMEDA, THF; flash chromatography: EtOAc/hex-
anes 1:1, Rf =0.35) to give phosphonate (Æ)-22a (0.20 g, 54%) as colour-
less crystals. M.p. 100–1018C (hexanes); 1H NMR (400.1 MHz, C6D5CD3,
353 K): d=0.84 (t, J=7.1 Hz, 3H), 1.04 (t, J=7.1 Hz, 3H), 1.27 (s, 9H),
2.78–3.01 (m, 4H), 3.56 (m, 1H), 3.75 (m, 1H), 3.88 (m, 2H), 5.52 (brd,
Chem. Eur. J. 2008, 14, 8603 – 8614
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8611

F. Hammerschmidt et al.
J=6.6 Hz, 1H), 7.01 (m, 3H), 7.46 ppm (m, 1H); 13C NMR (100.6 MHz,
C6D5CD3, 353 K): d=16.3 (d, J=5.4 Hz), 16.5 (d, J=4.6 Hz), 28.5 (3C),
31.2 (d, J=1.5 Hz), 34.2, 53.5 (d, J=186.6 Hz), 62.8 (d, J=7.7 Hz), 63.2
(d, J=6.9 Hz), 79.4, 124.9 (d, J=2.3 Hz), 125.3 (d, J=3.1 Hz), 126.6 (d,
J=2.3 Hz), 128.5 (d, J=3.1 Hz), 141.9 (d, J=3.8 Hz), 145.2 (d, J=
6.9 Hz), 153.5 ppm; 31P NMR (162 MHz, C6D5CD3, 353 K): d=25.8 ppm;
IR (Si): n˜ =3271, 2979, 2930, 1718, 1490, 1457, 1391, 1367, 1249, 1163,
7.7 Hz), 79.4, 124.4 (d, J=1.5 Hz), 124.5, 126.0 (d, J=3.1 Hz), 128.0 (d,
J=2.3 Hz), 140.1, 144.1 (d, J=6.9 Hz), 154.0 ppm (d, J=13.8 Hz);
31P NMR (162 MHz, CDCl3): d=24.0 ppm; IR (Si): n˜ =3443, 3071, 2978,
2932, 1718, 1701, 1491, 1457, 1386, 1367, 1248, 1172, 1142, 1106, 1058,
1042, 985 cmÀ1; elemental analysis calcd (%) for C20H32NO5P (397.5): C
60.44, H 8.12, N 3.52; found: C 60.42, H 8.15, N 3.26.
(Æ)-Diethyl1-amino-1-indanypl hosphonate (( Æ)-24) by means of carbox-
ylation: sBuLi (1.1 mL, 1.54 mmol, 1.4m, in cyclohexane) was added to a
stirred solution of N-(1-indanyl)phosphoramidate (Æ)-19a (0.27 g,
1.0 mmol) in dry Et2O (4 mL) at À788C under argon. A few minutes
later, the argon was replaced by CO2 (in a balloon). After 10 min, the
volatiles were removed at À308C under reduced pressure (5 mm) and
the flask was flushed three times with argon and then filled with it. Dry
Et2O (4 mL) was added to the residue. The mixture was cooled to À788C
and dry TMEDA (0.29 g, 0.38 mL, 2.5 mmol) and sBuLi (1.79 mL,
2.51 mmol, 1.4m, in cyclohexane) were added. After stirring for 1 h at
À788C, ethanol (5 mL) was added. The mixture was concentrated under
reduced pressure. The residue was treated with water (10 mL) and ex-
tracted with CH2Cl2 (3”12 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The residue was pu-
rified by means of flash chromatography (CH2Cl2/EtOH 15:1, Rf =0.64)
to give 1-amino-1-indanylphosphonate (Æ)-25 (0.07 g, 26%) as a colour-
less oil. 1H NMR (400.1 MHz, CDCl3): d=1.12 (t, J=7.1 Hz, 3H), 1.28
(t, J=7.1 Hz, 3H), 1.87 (brs, 2H), 1.97 (ddt, J=9.1, 13.4, 21.2 Hz, 1H),
2.79 (dddd, J=4.0, 7.3, 13.4, 14.7 Hz, 1H), 2.99 (m, 2H), 3.78 (m, 1H),
3.95 (m, 1H), 4.08 (m, 2H), 7.21 (m, 3H), 7.45 ppm (m, 1H); 13C NMR
(100.6 MHz, CDCl3): d=16.3 (d, J=5.4 Hz), 16.5 (d, J=6.1 Hz), 30.4 (d,
J=2.3 Hz), 38.4 (d, J=3.1 Hz), 62.5 (d, J=7.6 Hz), 63.0 (d, J=6.9 Hz),
124.7 (d, J=3.1 Hz), 124.7 (d, J=3.1 Hz), 126.7 (d, J=3.1 Hz), 128.4 (d,
J=2.3 Hz), 144.1, 144.2 ppm, PC (n.d.); 31P NMR (162 MHz, CDCl3): d=
28.7 ppm; IR (Si): n˜ =3368, 2980, 1235, 1025, 963 cmÀ1; elemental analysis
calcd (%) for C13H20NO3P (269.3): C 57.98, H 7.49, N 5.20; found: C
57.76, H 7.19, N 5.13.
1062, 1024, 966 cmÀ1
; elemental analysis calcd (%) for C18H28NO5P
(369.4): C 58.53, H 7.64, N 3.79; found: C 58.27, H 7.61, N 3.80.
(R)-(+)-Diisopropyl N-(1-indanyl)phosphoramidate ((R)-(+)-19b): (R)-
(+)-1-Azidoindan ((R)-(+)-15) (0.88 g, 5.5 mmol) and triisopropyl phos-
phite were transformed (flash chromatography: EtOAc/hexanes 1:1; Rf =
0.55) according to the procedure used for the preparation of (Æ)-diethyl
N-(1-indanyl)phosphoramidate from the azide to phosphoramidate (R)-
(+)-19b (1.51 g, 93%) as colourless crystals. M.p. 46–518C (hexanes);
[a]2D0 =+51.3 (c=0.94, hexanes); 1H NMR (400.1 MHz, CDCl3): d=1.34
(d, J=6.3 Hz, 3H), 1.35 (d, J=6.3 Hz, 9H), 1.76 (m, 1H), 2.56 (ddt, J=
2.6, 7.6, 12.6 Hz, 1H), 2.70 (brt, J=10.6 Hz, 1H), 2.76 (m, 1H), 2.90
(ddd, J=2.6, 8.6, 15.9 Hz, 1H), 4.67 (m, 3H), 7.21 (m, 3H), 7.43 ppm (m,
1H); 13C NMR (100.6 MHz, CDCl3): d=23.9 (d, J=5.3 Hz), 23.9 (d, J=
4.6 Hz), 24.0 (d, J=4.6 Hz), 24.0 (d, J=4.6 Hz), 29.9, 36.8 (d, J=3.8 Hz),
57.1, 70.9 (d, J=6.1 Hz), 70.9 (d, J=6.1 Hz), 124.0, 124.6, 126.6, 127.7,
142.8, 144.8 ppm (d, J=7.7 Hz); 31P NMR (162 MHz, CDCl3): d=
7.6 ppm; IR (Si): n˜ =3210, 2977, 2935, 1460, 1385, 1232, 1109, 1017,
986 cmÀ1; elemental analysis calcd (%) for C15H24NO3P (297.3): C 60.59,
H 8.14, N 4.71; found: C 60.55, H 7.93, N 4.70.
(R)-(+)-Diisopropyl
N-(t-butoxycarbonyl)-N-(1-indanyl)phosphorami-
date ((R)-(+)-17b): Phosphoramidate (R)-(+)-19b (1.19 g, 4.0 mmol)
was transformed in dry THF according to General Procedure C (flash
chromatography: hexanes/EtOAc 2:1, Rf =0.48) into phosphoramidate
(R)-(+)-17b (1.18 g, 74%) as a colourless oil. [a]2D0 =+8.1 (c=2.40, hex-
anes).
Preparation of (R)-(+)-17b by reaction of (R)-1-azidoindan ((R)-(+)-15)
with triisopropyl phosphite, followed by reaction with Boc2O: A solution
of (R)-(+)-15 (0.35 g, 2.2 mmol) and triisopropyl phosphite (0.50 g,
0.59 mL, 2.4 mmol) in dry toluene (8 mL) was stirred at 508C for 18 h
(TLC: EtOAc) under argon. After cooling, Boc2O (0.52 g, 2.4 mmol) dis-
solved in dry toluene (1 mL) was added; then heating was continued for
72 h at +808C and finally AcOH (2 mL, 2m, in Et2O) was added. The
mixture was concentrated under reduced pressure and dissolved in hex-
anes. The mixture was filtered to remove a small amount of urea derived
from 1-aminoindan and the concentrated mother liquor was purified by
means of flash chromatography (EtOAc/hexanes 1:1, Rf =0.67) to give
(R)-(+)-17b (0.51 g, 58%). 1H NMR (400.1 MHz, CDCl3): d=1.20 (s,
9H), 1.31 (d, J=6.1 Hz, 3H), 1.34 (d, J=6.1 Hz, 3H), 1.37 (d, J=6.1 Hz,
3H), 1.38 (d, J=6.1 Hz, 3H), 2.34 (m, 1H), 2.46 (m, 1H), 2.83 (dt, J=
8.6, 15.9 Hz, 1H), 3.03 (ddd, J=2.8, 9.9, 15.9 Hz, 1H), 4.67 (dsept, J=
6.2, 7.8 Hz, 1H), 4.80 (dsept, J=6.2, 7.8 Hz, 1H), 5.71 (dt, J=8.6,
11.1 Hz, 1H), 7.14 ppm (m, 4H); 13C NMR (100.6 MHz, CDCl3): d=23.5
(d, J=5.4 Hz), 23.8 (d, J=5.4 Hz), 23.8 (d, J=5.4 Hz, 2C), 27.7 (3C),
30.3, 30.7, 62.3 (d, J=3.1 Hz), 72.1 (d, J=6.1 Hz), 72.5 (d, J=6.1 Hz),
81.7, 122.4, 124.6, 126.1, 126.9, 142.2, 143.5, 153.0 ppm (d, J=6.9 Hz);
31P NMR (162 MHz, CDCl3): d=1.9 ppm; IR (Si): n˜ =2980, 2934, 1724,
(Æ)-and (S)-(+)-1-Amino-1-indanylphosphonic acid ((Æ)- and (S)-(+)-
23), the former as monohydrate: Phosphonate (Æ)-22a (0.45 g,
1.21 mmol) was deblocked by using General Procedure F and crystallised
from water to give (Æ)-aminophosphonic acid (Æ)-23·H2O (0.14 g, 55%)
as colourless crystals; m.p. 213–2148C. Diisopropyl 1-(t-butoxycarbonyl-
A
blocked by using General Procedure E and purified by means of ion-ex-
change chromatography (Dowex 50W,H+, H2O; TLC: iPrOH/H2O/NH3
6:3:1, Rf =0.43) to furnish aminophosphonic acid (S)-(+)-23 (0.065 g,
67%) as colourless crystals; m.p. 232–2338C (water/ethanol), [a]D20
+30.5 (c=0.43, water) (ee of crude product: 96%, S configuration).
1H NMR (400.1 MHz, D2O, d=4.67): d=2.19 (dddd, J=7.6, 8.8, 14.0,
23.0 Hz, 1H), 2.74 (dddd, J=4.6, 8.2, 14.0, 21.1 Hz, 1H), 3.03 (m, 2H),
7.30 (m, 3H), 7.49 ppm (brd, J=7.6 Hz, 1H); 13C NMR (100.6 MHz,
D2O): d=32.9 (d, J=2.3 Hz), 36.3, 67.7 (d, J=148.4 Hz), 127.4 (d, J=
1.5 Hz), 128.2, 129.3 (d, J=1.5 Hz), 132.5 (d, J=2.3 Hz), 141.0, 147.6 ppm
(d, J=6.1 Hz); 31P NMR (162 MHz, D2O): d=15.1 ppm; IR (ATR, race-
mate): n˜ =2926, 1630, 1602, 1531, 1479, 1459, 1180, 1141, 1090, 1030,
913 cmÀ1; elemental analysis calcd (%) for C9H12NO3P·H2O (231.2): C
46.76, H 6.10, N 6.06; found for (Æ)-23: C 46.35, H 5.86, N 5.97; elemen-
tal analysis calcd (%) for C9H12NO3P (213.2): C 50.71, H 5.67, N 6.57;
found for (S)-(+)-23: C 50.55, H 5.61, N 6.46.
1293, 1270, 1161, 1001 cmÀ1
; elemental analysis calcd (%) for
C20H32NO5P (397.5): C 60.44, H 8.12, N 3.52; found: C 60.42, H 8.08, N
3.58.
(Æ)-Diethyl N-(1,2,3,4-tetrahydronaphthalen-1-yl)phosphoramidate ((Æ)-
27): 1-Amino-1,2,3,4-tetrahydronaphthalene ((Æ)-26) (0.88 g, 6.0 mmol)
was phosphorylated by using General Procedure A (flash chromatogra-
phy: hexanes/EtOAc 2:1, Rf =0.32) to furnish phosphoramidate (Æ)-27
(1.58 g, 93%) as colourless crystals. M.p. 72–748C (hexanes); 1H NMR
(400.1 MHz, CDCl3): d=1.34 (t, J=7.1 Hz, 6H), 1.78 (m, 2H), 2.07 (m,
1H), 2.74 (m, 3H), 4.11 (m, 4H), 4.34 (m, 1H), 7.05 (m, 1H), 7.15 (m,
2H), 8.74 ppm (m, 1H); 13C NMR: (100.6 MHz, CDCl3): d=16.7 (d, J=
6.9 Hz), 20.2, 29.6, 33.0, 50.5, 62.9 (d, J=5.4 Hz, 2C), 126.5, 127.5, 129.0,
129.4, 137.6, 138.8 ppm (d, J=7.7 Hz); 31P NMR: (162 MHz, CDCl3): d=
9.1 ppm; IR (Si): n˜ =3181, 2981, 2935, 1451, 1235, 1040 cmÀ1; elemental
analysis calcd (%) for C14H22NO3P (283.3): C 59.35, H 7.83, N 4.94;
found: C 59.14, H 7.96, N 4.90.
(S)-(À)-Diisopropyl1-(
t-butoxycarbonylamino)-1-indanylphosphonate
((S)-(À)-22b): Phosphoramidate (R)-(+)-17b (0.40 g, 1.0 mmol) was rear-
ranged in dry THF by using General Procedure D (flash chromatogra-
phy: hexanes/EtOAc 2:1, Rf =0.27) to give phosphonate (S)-(À)-22b
(0.24 g, 60%) as
a
colourless oil. [a]D20 =À1.2 (c=1.30, hexanes);
1H NMR (400.1 MHz, CDCl3): d=0.77 (d, J=6.1 Hz, 3H), 1.16 (d, J=
6.1 Hz, 3H), 1.19 (s, 9H), 1.22 (d, J=6.1 Hz, 3H), 1.25 (d, J=6.1 Hz,
3H), 2.66 (m, 2H), 2.92 (m, 2H), 4.30 (dsept, J=6.1, 6.6 Hz, 1H), 4.56
(dsept, J=6.1, 6.6 Hz, 1H), 5.38 (d, J=8.8 Hz, 1H), 7.11 (m, 3H),
7.31 ppm (m, 1H); 13C NMR (100.6 MHz, CDCl3): d=22.7 (d, J=
6.1 Hz), 23.7 (d, J=5.4 Hz), 23.8 (d, J=3.1 Hz), 24.2 (d, J=2.3 Hz), 27.9
(3C), 30.4 (2C), 65.4 (d, J=157.6 Hz), 71.3 (d, J=7.7 Hz), 72.3 (d, J=
8612
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8603 – 8614

a-Aminobenzylphosphonic Acids via a-Aminobenzyllithiums
FULL PAPER
(Æ)-Diethyl N-(t-butoxycarbonyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-
phosphoramidate ((Æ)-28): Phosphoramidate (Æ)-27 (0.57 g, 2.0 mmol)
was Boc-protected by using General Procedure C (flash chromatography:
EtOAc/hexanes 2:1, Rf =0.71) to give phosphoramidate (Æ)-28 (0.66 g,
86%) as a colourless oil. 1H NMR (400.1 MHz, CDCl3): d=1.20 (s, 9H),
1.34 (dt, J=0.8, 7.1 Hz, 3H), 1.38 (brt, J=7.1 Hz, 3H), 1.73 (ddq, J=3.0,
4.8, 13.4 Hz, 1H), 1.97 (m, 1H), 2.13 (m, 1H), 2.27 (m, 1H), 2.75 (m,
2H), 4.18 (m, 4H), 5.27 (dt, J=6.1, 11.6 Hz, 1H), 7.06 (m, 3H), 7.25 ppm
(m, 1H); 13C NMR: (100.6 MHz, CDCl3): d=16.1 (d, J=6.9 Hz), 16.3 (d,
J=6.9 Hz), 23.0, 27.7 (3C), 29.7, 29.7, 56.9 (d, J=3.1 Hz), 63.4 (d, J=
5.4 Hz), 64.1 (d, J=6.1 Hz), 82.0, 125.5, 125.9, 126.0, 128.7, 137.3,
138.1 ppm (d, J=3.8 Hz), C=O (n.d.); 31P NMR: (162 MHz, CDCl3): d=
frames covering a hemisphere of the reciprocal space. After data integra-
tion, corrections for absorption and l/2 effects were applied. The struc-
ture was solved with direct methods and was then refined on F2 with hy-
drogen atoms in idealised positions by using SHELXTL.[27] CCDC-
668518 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Crystal data for (Æ)-32a: C19H30NO5P; Mr =383.41; monoclinic; space
group P21/c (no. 14); T=100(2) K; a=14.5683(9), b=11.5085(7), c=
48.043(3) Š; b=91.007(1)8; V=8053.6(9) Š3; Z=16; Z’=4; 1calcd
=
1.265 gcmÀ3; m=0.165 mmÀ1; 69485 reflections collected up to qmax =308;
23239 independent reflections (Rint =0.035); 18774 observed reflections
(I>2s(I)); final R indices: R1 =0.065 (I>2s(I)), wR2 =0.155 (all data).
The structure contains four independent molecules, which are cyclically
linked into two pseudocentrosymmetric pairs by means of pairs of CH-
O-H···O=P hydrogen bonds. The four molecules differ significantly in
conformation (P-N-(CO)-O-tBu for two molecules in a cisoid and for two
molecules in a transoid configuration; variations in the orientation of the
(P)-O-Et groups).
4.6 ppm; IR (Si): n˜ =2980, 2935, 1723, 1394, 1368, 1287, 1160, 1032 cmÀ1
;
elemental analysis calcd (%) for C19H30NO5P (383.4): C 59.52, H 7.89, N
3.65; found: C 59.55, H 7.62, N 3.59.
(Æ)-Diethyl1-( t-butoxycarbonylamino)-(1,2,3,4-tetrahydronaphthalen-1-
yl)phosphonate ((Æ)-30): Phosphoramidate (Æ)-28 (0.24 g, 0.64 mmol)
was rearranged by using General Procedure D (THF, flash chromatogra-
phy: CH2Cl2/EtOAc 3:1, Rf =0.58) to give phosphonate (Æ)-30 (0.09 g,
38%) as a colourless oil. 1H NMR: (400.1 MHz, 353 K, C6D5CD3): d=
0.77 (t, J=7.1 Hz, 3H, CH3), 1.05 (t, J=7.1 Hz, 3H), 1.28 (s, 9H), 1.84
(m, 1H), 2.14 (m, 1H), 2.45 (dddt, J=0.5, 3.5, 6.8, 13.7 Hz), 2.74 (m,
2H), 2.93 (dddd, J=3.8, 11.2, 13.7, 25.5 Hz, 1H), 3.35 (ddq, J=7.1, 8.9,
10.1 Hz, 1H), 3.66 (dquint, J=7.1, 10.1 Hz, 1H), 3.89 (m, 2H), 5.90 (brd,
J=10.1 Hz), 6.88 (m, 1H), 6.96 (m, 2H), 7.79 ppm (dt, J=1.8, 7.6 Hz,
1H); 13C NMR (100.6 MHz, 353 K, C6D5CD3): d=16.2 (d, J=5.4 Hz),
16.5 (d, J=5.4 Hz), 20.8 (d, J=2.3 Hz), 28.5 (3C), 30.1, 31.2 (d, J=
3.1 Hz), 58.3 (d, J=148.4 Hz), 62.9 (d, J=6.9 Hz), 63.3 (d, J=6.9 Hz),
79.4, 126.0 (d, J=3.1 Hz), 127.5 (d, J=3.1 Hz), 128.5 (d, J=3.8 Hz), 129.3
(d, J=2.3 Hz), 136.2 (d, J=5.4 Hz), 139.5 (d, J=6.9 Hz), 154.4 ppm (d,
J=16.1 Hz); 31P NMR :(162 MHz, C6D5CD3, 350 K): d=27.4 ppm; IR
(Si): n˜ =2927, 1730, 1489, 1165, 1050, 1024, 966 cmÀ1; elemental analysis
calcd (%) for C19H30NO5P (383.4): C 59.52, H 7.89, N 3.65; found: C
59.61, H 7.71, N 3.60.
(Æ)- and (R)-(+)-1-Azido-1,2,3,4-tetrahydronaphthalene ((Æ)- and (R)-
(+)-34): (Æ)-a-Tetralol (0.15 g, 1.0 mmol) was prepared in analogy to
(R)-(+)-1-azidoindan (flash chromatography: EtOAc/hexanes 1:19, Rf =
0.80) to give (Æ)-34 (0.16 g, 92%) as a colourless liquid. Similarly, (S)-
(À)-1,2,3,4-tetrahydro-1-naphthol (1.26 g, 8.47 mmol, 99.8% ee, [a]D20
=
À30.9 (c=4.9, CHCl3)) was converted to (R)-(+)-34 (1.32 g, 90%);
[a]2D0 =+45.0 (c=3.67, acetone). 1H NMR (400.1 MHz, CDCl3): d=1.81
(m, 1H), 1.98 (m, 3H), 2.74 (m, 1H), 2.84 (m, 1H), 4.56 (ꢀt, J=4.3 Hz,
1H), 7.13 (m, 1H), 7.22 (m, 2H), 7.28 ppm (m, 2H); 13C NMR
(100.6 MHz, CDCl3): d=19.0, 28.8, 29.1, 59.5, 126.1, 128.1, 129.1, 129.4,
133.7, 137.3 ppm; IR (Si, racemate): n˜ =2940, 2096, 1492, 1455, 1245,
1060, 944 cmÀ1; elemental analysis calcd (%) for C10H11N3 (173.2): C
69.34, H 6.40, N 24.26; found: C 69.40, H 6.33, N 24.45.
(Æ)- and (R)-(+)-Diisopropyl N-(1,2,3,4-tetrahydronaphthalen-1-yl)phos-
phoramidate ((Æ)- and (R)-(+)-35): Compound (Æ)-34 (0.16 g,
0.92 mmol) was reacted with triisopropyl phosphite in analogy to the
preparation of diethyl N-(1-indanyl)phosphoramidate ((Æ)-15) from
azide. The crude product was subjected to flash chromatography (hex-
anes/EtOAc 2:1, Rf =0.42) to yield phosphoramidate (Æ)-35 (0.26 g,
91%) as colourless crystals; m.p. 76–778C (hexanes). Similarly, (R)-(+)-
1-azido-1,2,3,4-tetrahydronaphthalene ((R)-(+)-34) (1.20 g, 6.91 mmol)
Rearrangement of (Æ)-diethyl N-(t-butoxycarbonyl)-N-(1,2,3,4-tetrahy-
dronaphthalen-1-yl)phosphoramidate ((Æ)-28) with LiTMP/TMEDA as
base: nBuLi (2.54 mL, 1.6m in hexane, 4.06 mmol) was added to a stirred
solution of 2,2,6,6-tetramethylpiperidine (0.574 g, 0.69 mL, 4.06 mmol)
and TMEDA (0.472 g, 0.61 mL, 4.06 mmol) in dry Et2O (6 mL) at À208C
under argon. After stirring for 30 min, the solution was cooled to À788C
and (Æ)-28 (0.778 g, 2.03 mmol, dissolved in 5 mL of dry Et2O) was
added. Four hours later, the reaction was quenched with AcOH (5 mL,
2m in Et2O) and water (10 mL). The organic phase was separated and
the aqueous phase was extracted three times with Et2O. The combined
organic layers were washed with water, dried (MgSO4) and concentrated
under reduced pressure. The residue was subjected to flash chromatogra-
phy (hexanes/EtOAc 1:1, Rf =0.30) to give starting material (0.287 g,
37%) and a mixture of hydroxyphosphonamidates (Æ)-32a–d (0.287 g,
37%), from which isomer (Æ)-32a was obtained as colourless crystals by
crystallising twice from hexanes. M.p. 116–1178C.
gave phosphoramidate (R)-(+)-35 (2.14 g, 99%); m.p. 65–688C, [a]D20
=
+41.1 (c=0.95, hexane). 1H NMR (400.1 MHz, CDCl3): d=1.32 (d, J=
6.1 Hz, 6H), 1.33 (d, J=6.1 Hz, 3H), 1.34 (d, J=6.1 Hz, 3H), 1.83 (m,
3H), 2.08 (m, 1H), 2.64 (t, J=10.1 Hz, 1H), 2.75 (m, 2H), 4.34 (ddd, J=
6.3, 9.6, 10.1 Hz), 4.64 (m, 2H), 7.04 (m, 1H), 7.14 (m, 2H), 7.53 ppm (m,
1H); 13C NMR (100.6 MHz, CDCl3): d=19.9, 23.9 (d, J=4.6 Hz), 23.9 (d,
J=5.4 Hz), 24.0 (d, J=5.4 Hz, 2C), 29.2, 32.6 (d, J=1.5 Hz), 50.1, 70.9
(d, J=6.1 Hz), 70.9 (d, J=5.4 Hz), 126.0, 127.0, 128.7, 128.9, 137.2,
138.7 ppm (d, J=8.4 Hz); 31P NMR (162 MHz, CDCl3): d=7.5 ppm; IR
(Si, racemate): n˜ =3201, 2976, 2930, 1458, 1221, 1100, 1020, 993 cmÀ1; ele-
mental analysis calcd (%) for C16H26NO3P (311.4): C 61.72, H 8.42, N
4.50; found: C 61.42, H 8.15, N 4.26.
ACHTREUNG
(400.1 MHz, 353 K, C6D5CD3): d=1.03 (s, 9H), 1.13 (t, J=7.1 Hz, 3H),
1.55 (m, 1H), 1.62 (dd, J=7.1, 18.4 Hz, 3H), 1.77 (m, 1H), 2.14 (m, 1H),
2.24 (m, 1H), 2.47 (m, 1H), 2.68 (m, 1H), 3.97 (m, 1H), 4.07 (m, 1H),
4.13 (t, J=6.6 Hz, 1H), 4.50 (m, 1H), 5.48 (dt, J=7.8, 10.1 Hz, 1H), 6.84
(brd, J=7.5 Hz, 1H), 6.93 (brd, J=7.5 Hz, 1H), 6.99 (brd, J=7.5 Hz,
1H), 7.36 ppm (brd, J=7.5 Hz, 1H); 13C NMR: (100.6 MHz, 353 K,
C6D5CD3): d=16.4 (d, J=6.1 Hz), 18.7, 23.4, 27.9 (3C), 30.3, 30.9, 55.8,
61.9 (d, J=8.4 Hz), 67.6 (d, J=138.44 Hz), 82.6, 126.3, 126.4, 126.5, 129.2,
138.2, 139.0 (d, J=4.6 Hz), 155.6 ppm (d, J=8.4 Hz); 31P NMR
(162 MHz, C6D5CD3, 350 K): d=31.9 ppm; IR (Si): n˜ =3317, 2979, 1707,
1399, 1368, 1282, 1157, 1100, 1029 cmÀ1; elemental analysis calcd (%) for
C19H32NO5P (385.4): C 59.21, H 8.37, N 3.63; found: C 59.49, H 8.08, N
3.63.
(Æ)- and (R)-(À)-Diisopropyl N-(t-butoxycarbonyl)-N-(1,2,3,4-tetrahy-
dronaphthalen-1-yl)phosphoramidate ((Æ)- and (R)-(À)-36): Phosphor-
A
Procedure C (flash chromatography: CH2Cl2/EtOAc 10:1, Rf =0.35) to
give phosphoramidate (Æ)-36 (0.61 g, 93%) as a colourless oil. Analo-
gously, phosphoramidate (R)-(+)-35 (2.03 g, 6.51 mmol) gave Boc-pro-
tected phosphoramidate (R)-(À)-36 (2.43 g, 91%); [a]2D0 =À26.1 (c=1.57,
hexane). 1H NMR (400.1 MHz, CDCl3): d=1.19 (s, 9H), 1.30 (d, J=
6.1 Hz, 3H), 1.34 (d, J=6.1 Hz, 3H), 1.37 (d, J=6.1 Hz, 3H), 1.38 (d, J=
6.1 Hz, 3H), 1.73 (ddq, J=2.8, 4.6, 13.1 Hz, 1H), 1.97 (m, 1H), 2.11 (m,
1H), 2.29 (m, 1H), 2.68 (m, 1H), 2.80 (m, 1H), 4.68 (oct, J=6.1 Hz,
1H), 4.82 (oct, J=6.1 Hz, 1H), 5.29 (dt, J=6.8, 11.2 Hz, 1H), 7.00 (m,
1H), 7.04 (m, 3H), 7.24 ppm (m, 1H); 13C NMR (100.6 MHz, CDCl3):
d=23.0, 23.4 (d, J=5.4 Hz), 23.8 (d, J=5.4 Hz), 23.8 (d, J=3.8 Hz), 23.9
(d, J=4.6 Hz), 27.7 (3C), 29.7 (2C), 56.9 (d, J=3.1 Hz), 72.0 (d, J=
6.1 Hz), 72.7 (d, J=6.9 Hz,), 81.6, 125.4, 125.8, 125.8, 128.7, 137.3, 138.4
Crystalstructure anayl sis : X-ray data of (Æ)-32a were collected at 100 K
on a Bruker Smart APEX CCD area detector diffractometer with graph-
ite-monochromated MoKa radiation, l=0.71073 Š, using 0.38 w-scan
Chem. Eur. J. 2008, 14, 8603 – 8614
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8613

F. Hammerschmidt et al.
(d, J=3.8 Hz), 153.1 ppm; 31P NMR (162 MHz, CDCl3): d=2.2 ppm; IR
(Si, racemate): n˜ =2980, 2935, 1724, 1386, 1368, 1287, 1162, 1071,
1000 cmÀ1; elemental analysis calcd (%) for C21H34NO5P (411.5): C 61.30,
H 8.33, N 3.40; found: C 61.38, H 8.16, N 3.39.
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2267–2276.
(Æ)- and (S)-(À)-Diisopropyl[1-( t-butoxycarbonylamino)-1,2,3,4-tetrahy-
dronaphthalen-1-yl]phosphonate ((Æ)- and (S)-(À)-37): Phosphorami-
date (Æ)-36 (0.29 g, 0.70 mmol) was rearranged (THF; flash chromatog-
raphy: CH2Cl2/EtOAc 3:1, Rf =0.61) by using General Procedure D to
give phosphonate (Æ)-37 (0.17 g, 59%) as a colourless oil. Analogously,
phosphoramidate (R)-(À)-36 (0.82 g, 2.0 mmol) yielded aminophospho-
nate (S)-(À)-37 (0.44 g, 53%); [a]2D0 =À25.9 (c=0.64, hexane). 1H NMR
(400.1 MHz, 353 K, C6D5CD3): d=0.62 (d, J=6.1 Hz, 3H), 1.04 (d, J=
6.3 Hz, 3H), 1.14 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 1.27 (s,
9H), 1.87 (m, 1H), 2.12 (m, 1H), 2.47 (dddt, J=0.5, 3.5, 6.6, 13.6 Hz,
1H), 2.70 (m, 2H), 2.96 (dddd, J=3.8, 11.1, 13.4, 25.4 Hz, 1H), 4.20 (oct,
J=6.1 Hz, 1H), 4.62 (oct, J=6.3 Hz, 1H), 5.95 (brd, J=10.1 Hz, 1H),
6.97 (3H overlapped with signals of C6D5CD3), 7.82 ppm (m, 1H);
13C NMR (100.6 MHz, 353 K, C6D5CD3): d=20.9, 22.9 (d, J=6.1 Hz),
23.9 (d, J=5.4 Hz), 24.2 (d, J=3.1 Hz), 24.5 (d, J=2.3 Hz), 28.6 (3C),
30.2, 31.3 (d, J=4.6 Hz), 58.4 (d, J=149.9 Hz), 71.4 (d, J=7.7 Hz), 72.5
(d, J=7.7 Hz), 79.3, 126.0 (d, J=3.1 Hz), 127.3 (d, J=3.1 Hz), 128.6 (d,
J=4.6 Hz), 129.2 (d, J=3.4 Hz), 136.6 (d, J=4.6 Hz), 139.6 (d, J=
6.9 Hz), 154.5 ppm (d, J=16.8 Hz); 31P NMR (162 MHz, 353 K,
C6D5CD3): d=25.8 ppm; IR (Si, racemate): n˜ =3401, 2978, 2934, 1730,
1488, 1367, 1248, 1167, 1103, 987 cmÀ1; elemental analysis calcd (%) for
C21H34NO5P (411.5): C 61.30, H 8.33, N 3.40; found: C 61.10, H 8.06, N
3.30.
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73, 2559–2562.
(Æ)- and (S)-(À)-(1-Amino-1,2,3,4-tetrahydronaphthalen-1-yl)phosphonic
acid ((Æ)- and (S)-(À)-38), the former as a sesquihydrate: Phosphonate
Æ)-37 (0.96 g, 2.3 mmol) was deblocked by using General Procedure E
and purified by means of ion-exchange chromatography (Dowex 50W,
H+, water; TLC: iPrOH/H2O/NH3 6:3:1, Rf =0.48) to give 1-aminophos-
phonic acid (Æ)-38 (0.40 g, 67%) as colourless crystals; m.p. 2188C
(water). Analogously, aminophosphonate (S)-(À)-37·1.5H20 (0.50 g,
1.21 mmol) was deblocked by using General Procedure F and lyophilised
crude product was crystallised from water (258C)/ethanol (258C to
+48C; seemed to be less soluble in hot water than water of 258C) to
give aminophosphonic acid (S)-(À)-38 (0.11 g, 40%); ee of crude prod-
uct: 97%; m.p. 230–2328C; [a]2D0 =À13.9 (c=0.43, water). 1H NMR
(400.1 MHz, D2O): d=1.75 (m, 1H), 2.02 (m, 2H), 2.43 (m, 1H), 2.77
(m, 2H), 7.22 (m, 3H), 7.64 ppm (dt, J=1.0, 7.6 Hz, 1H); 13C NMR
(100.6 MHz, D2O): d=18.8 (d, J=3.8 Hz), 29.1, 31.4, 56.8 (d, J=
142.3 Hz), 126.7 (d, J=1.5 Hz), 127.7 (d, J=3.1 Hz), 128.9 (d, J=1.5 Hz),
130.3, 132.0 (d, J=2.3 Hz), 139.0 ppm (d, J=5.4 Hz); 31P NMR
(162 MHz, D2O): d=15.8 ppm; IR (ATR, racemate): n˜ =3401, 3198,
2859, 1614, 1525, 1494, 1448, 1182, 1024, 921 cmÀ1; elemental analysis
calcd (%) for C10H14NO3P (227.2): C 52.86, H 6.21, N 6.17; found for (S)-
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reported.
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(À)-38:
C 52.62, H 6.20, N 6.07; elemental analysis calcd (%) for
C10H14NO3P·1.5H2O (254.2): C 47.24, H 6.74, N 5.51; found for (Æ)-38):
C 46.97, H 6.51, N 5.43.
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Acknowledgements
This work was supported by the Fonds zur Fçrderung der wissenschaftli-
chen Forschung (FWF, Austria) (grant no. P 15779-N03). We thank S.
Felsinger and K. Tyll for recording the NMR spectra, Ao. Univ.-Prof. Dr.
M. Lämmerhofer and Mag. S. Schiesel (Department of Analytical
Chemistry and Food Chemistry, University of Vienna) for the determina-
tion of the ee values of the aminophosphonic acids and Ao. Univ.-Prof.
Dr. K. Mereiter (Institute of Chemical Technologies and Analytics,
Vienna University of Technology) for performing X-ray structure
[27]SHELXTL, Version 6.12, Bruker AXS Inc., Madison, WI (USA).
analysis.
[1]a) V. P. Kukhar, H. R. Hudson, Aminophosphonic and Aminophos-
phinic Acids, Wiley, 2000, pp. 33–67; b) P. Kafarski, B. Lejczak,
Received: March 14, 2008
Published online: August 4, 2008
8614
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