Rearrangement of S-(2-aminoethyl) thiophosphates to N-(2-mercaptoethyl)- phosphoramidates

Article abstract of DOI:10.1002/ejoc.200700646

A novel rearrangement of S-(2-aminoethyl) thiophosphates to N-(2-mercaptoethyl)phosphoramidates was discovered and developed. The reaction proceeds smoothly at room temperature under basic conditions and the resulting thiol could subsequently be alkylated. The reaction mechanism is investigated by electron structure calculations using density functional theory at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels. The calculations indicate that the reaction proceeds in a two step process when two explicit solvent molecules are included. In the presence of water the rearrangement reaction proceeds in competition with hydrolysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700646

FULL PAPER
DOI: 10.1002/ejoc.200700646
Rearrangement of S-(2-Aminoethyl) Thiophosphates to N-(2-Mercaptoethyl)-
phosphoramidates
Menglin Chen,[a] Alice Maetzke,[a] Svend J. Knak Jensen,[a] and Kurt V. Gothelf*[a]
Keywords: Rearrangement / Thiophosphate / Phosphoramidate / Density functional theory / Hydrolysis
A novel rearrangement of S-(2-aminoethyl) thiophosphates
to N-(2-mercaptoethyl)phosphoramidates was discovered
and developed. The reaction proceeds smoothly at room tem-
perature under basic conditions and the resulting thiol could
subsequently be alkylated. The reaction mechanism is inves-
tigated by electron structure calculations using density func-
tional theory at the B3LYP/6-31G(d) and B3LYP/6-
311+G(d,p) levels. The calculations indicate that the reaction
proceeds in a two step process when two explicit solvent
molecules are included. In the presence of water the re-
arrangement reaction proceeds in competition with hydroly-
sis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Our interest in oligonucleotide conjugation has inspired
us to explore new chemical transformations that potentially
can be applied for DNA functionalization. Phosphorus
chemistry offers a great opportunity to introduce site-spe-
cific modification at the backbone of oligodeoxynucleotides
without interfering with the Watson–Crick hydrogen bond-
ing. Thiophosphates are excellent and soft nucleophiles
which have been extensively utilized for site-specific conju-
gation by aliphatic nucleophilic substitution[1] or by conju-
gate addition.[2] The main drawback of this approach is the
sensitivity of thiophosphoric acid triesters towards hydroly-
sis (Scheme 1, a). We speculated that the lability of the P–S
bond may be applied for introducing other functionalities
at phosphorus by an intramolecular substitution reaction.
Here our studies on the formation and rearrangement of S-
(2-aminoethyl) thiophosphoric acid triesters 1 into the
stable N-(2-mercaptoethyl)phosphoramidates 2 are pre-
sented (Scheme 1, b).
First, we have studied previously reported related substi-
tution reactions at carbon. The rearrangement of O-ethyl
S-(2-hydroxyethyl) thiocarbonate to O-ethyl O-(2-mercap-
toethyl) carbonate which decomposes to give ethylene sul-
fide, ethanol and carbon dioxide has been described
(Scheme 2, a).[3] It is proposed that the rearrangement pro-
ceeds via the 1,3-oxathiolane intermediate. The similar S,N
rearrangement has been developed in protein synthesis and
plays an important role in native chemical ligation[4,5] (see
part b of Scheme 2).
Scheme 1. a) Alkylation of a thiophosphate and subsequent hydrol-
ysis. b) Proposed rearrangement reaction leading to a stable N-(2-
mercaptoethyl)phosphoramidate 2.
The rearrangements of S-(3-hydroxyalkyl) and S-(2-hy-
droxyalkyl) thiophosphates to 3-mercaptoalkyl and 2-mer-
captoalkyl phosphoric acid triesters have also been re-
ported.[6–8] It was claimed that the rearrangement proceeds
via five- or six-membered cyclic intermediates respectively,
where a six-membered cyclic intermediate forms upon heat-
ing at 120–180 °C.[6] The five-membered cyclic intermediate
is formed faster but its formation is followed by fast decom-
position to generate phosphate and ethylene sulfide
(Scheme 2, c).[8] The relation between the rearrangement
rate and the structure of the thiophosphates has been sys-
tematically studied.[9–13] It turned out that the rearrange-
ment differs depending on the R groups. The dialkyl tri-
esters (R = alkyl) generally give the thiol products; the bulk-
ier R is, the slower is the rearrangement.[8,9] Cyclic alkyl R
groups further facilitate the rearrangement.[10] The diaryl
triesters (R = Ar) often stop at the cyclic intermediate due
to the steric hindrance and since phenols (or derivatives)
are good leaving groups.[11,12] Rearrangements of dimeth-
[a] Centre for DNA Nanotechnology at iNANO and Department
of Chemistry, University of Aarhus,
8000 Aarhus C, Denmark
Fax: +45-8619-6199
E-mail: kvg@chem.au.dk
5826
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Rearrangement of S-(2-Aminoethyl) Thiophosphates
Scheme 2. a) Rearrangement of O-ethyl S-(2-hydroxyethyl) thiocar-
bonate. b) Native chemical ligation of protein. c) Rearrangement
of S-(3-hydroxyalkyl) or S-(2-hydroxyalkyl) thiophosphates, R =
alkyl or aryl group.
ylamido-O-phenyl-thiophosphoric acid have also been re-
ported.[13]
Based on the reports described above we have investi-
gated the rearrangement leading to the corresponding P–N
analogs and in the following we demonstrate that in some
cases the reaction shown in Scheme 1 (b) proceeds
smoothly. Furthermore, density functional theory provided
the theoretical calculations for the mechanism of the reac-
tion.
Results and Discussion
The thiophosphates 6a and 6b were chosen for the for-
mation of the central adducts S-2-aminoethyl thiophos-
phates 1a and 1b. It immediately turned out that 1 instantly
undergoes rearrangement at room temperature. Hence, pro-
tected derivatives 1a·HBr, 7a and 1b·HBr, 7b of 1a and 1b,
respectively, were prepared by two different methods in or-
der to study the rearrangement. In Method A 2-(Fmoc-
amino)ethanol (4a) was chosen as the starting material.
Upon iodination using DDQ/PPh3/Bu4NI,[14] 2-(Fmoc-
amino)ethyl iodide (5a) was formed in 83% yield. The
methyl derivative 6b was prepared by thioylation of di-
methyl phosphite.[15] Alkylations of thiophosphates 6a and
Scheme 3. Development of the rearrangement. a) Preparation of
Fmoc-protected starting materials. b) Preparation of starting mate-
rials protected as ammonium bromides. c) Demonstration of the
rearrangement reaction. d) Preparation and rearrangements of
three methylated derivatives.
Rearrangement of 1a·HBr, 1b·HBr or 7a, 7b to N-(2-mer-
6b with 5a were performed at 50 °C for 3 h to obtain O,OЈ- captoethyl)phosphoramidates 2a or 2b was carried out by
diethyl S-[2-(Fmoc-amino)ethyl] thiophosphates 7a and 7b treating 1a·HBr, 1b·HBr or 7a, 7b with tBuOK in dry
in almost quantitive conversions (Scheme 3, a). In Method DMSO at room temperature. We have primarily used
B alkylation of thiophosphate (6a, 6b) with 2-bromoethyl- tBuOK as the base since it is non-nucleophilic and substitu-
amine hydrogen bromide (8) at 50 °C for 24 h gave 1a·HBr, tion at phosphorus is avoided. It was also demonstrated
1b·HBr quantitively (Scheme 3, b) For both derivatives that DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) could be
1
1a·HBr and 7a, or 1b·HBr and 7b, base treatment will lead used as the base with similar success. H NMR and 31P
to the formation of 1a and 1b (Scheme 3, c).
NMR spectroscopic data were comparable to the data in
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M. Chen, A. Maetzke, S. J. Knak Jensen, K. V. Gothelf
FULL PAPER
the literature,[16,17] confirming the structure of the expected
Electron structure calculations were made to find a reac-
product. The products 2a and 2b were formed in nearly tion mechanism for the rearrangement reaction of 1b to 2b
quantitive conversions at room temperature at pH12 in and to estimate the involved activation energies.
10 min when 1a·HBr, and 1b·HBr were used, while 7a and
The optimized gas-phase structures of the various spe-
7b led to formation of side products. During work up, oxi- cies, as well as the transition states, were calculated by
dation of the thiol adducts 2a, 2b to the disulfide 3a and 3b quantum chemical geometry optimizations using the soft-
took place. Since the purification procedure is complicated ware package Gaussian 03.[18] The chosen level of theory
because of facile oxidation of thiols to disulfides, only mod- was the B3LYP implementation of the density functional
erate and not optimized yields of compounds 3a and 3b theory (DFT). The calculations used the basis sets 6-31G(d)
were obtained (52 and 41%, respectively). However, captur- and 6-311+G(d,p), where the latter is expected to lead to
ing the thiol by an alkylating agent in situ led to significant the more accurate results. In a few cases the quality of the
higher yields (vide infra).
DFT estimates were checked by single point calculations
To demonstrate the use of the rearrangement for other using the more accurate coupled cluster technique,
detivatives methylated in three different positions, the three CCSD(T). The transition states (TS) were obtained using a
derivatives 4b, 4c and 4d were prepared. Following iodin- synchronous transit-guided Quasi-Newton method[19] and
ation, the iodides, 5b, 5c and 5d were treated with 6a to explicit calculations (IRC) were performed to identify the
produce the corresponding S-alkyl thiophosphates. In all species linked by the transition states. The thermodynamic
three cases the base-induced rearrangement proceeded and properties of the species in water and DMSO solvents were
disulfides 3ab, 3ac and 3ad were obtained in yields of about estimated using the polarized continuum methods
50% (Scheme 3, d).
(PCM)[20,21] with single point calculations on the optimized
The influence of pH on the reaction was studied by 31P structures from the DFT calculations. In this calculation
NMR in [D6]DMSO at different pH values at room tem- the atomic radii were taken from the Universal Force Field
perature. At pH10, 15% rearrangement product was found; (UFF).[22]
at pH11, 60% rearrangement product was obtained, at
Three reaction paths for the rearrangement in Scheme 5
pH12, quantitive conversion was found. The pKa of the were investigated: In the first path (I) the reaction only in-
protonated amine is 10.8, and the pH-dependency showed volved reactant 1b (Figure 1). In the second path (II) two
that the free amine undergoes rearrangement spontane- explicit solvent water molecules were included (Figure 2)
ously. When the reaction of 1a·HBr was performed in water and in the third path, (III), the rearrangement has been
(D2O) 40% of the hydrolysis product diethyl phosphate was investigated as a two-step reaction path via a cyclic interme-
formed along with the expected product 2a (3a).
diate (Figure 3) as suggested in the S,O rearrangement reac-
To optimize the method for functionalization of thio- tions.[6–8] The results for path (III) are also given when a
phosphates and to avoid formation of the disulfide 3a a one single explicit water molecule are included in the calcula-
pot procedure involving the substitution with 8, rearrange- tions.
ment and reaction of the thiol with an electrophile was de-
veloped (Scheme 4). Thiophosphate 6a was subjected to re-
action with 8 followed by increasing the pH to 12 to induce
the rearrangement. After 10 min the thiol reactive electro-
phile benzyl bromide were added to the reaction mixture.
The reaction was incubated at room temperature for 2 h,
and 76% of the product 9 was isolated.
Scheme 5. Rearrangement of 1b to 2b.
Reaction path I in Figure 1 illustrates a concerted re-
arrangement reaction. The double headed arrows in TSI
indicate the dominant movement of atoms in the rearrange-
ment mode. The attack of the nitrogen lone pair at phos-
phorus and the movement of hydrogen to sulfur proceed in
synchronous motion with an increase in the P–S distance.
The activation energy estimates for this rearrangement are
Scheme 4. One-pot functionalization of thiophosphates.
Whereas the rearrangement reaction of 1a and methyl- in the range of 124 to 133 kJ/mol (Table 1) and ∆HI are in
ated analogs proceed smoothly at room temperature we the range of –25 to –29 kJ/mol in aqueous environment.
were very surprised to find that the 3 carbon analog diethyl We note that the CCSD(T) results are close to the B3LYP
S-(3-aminopropyl) thiophosphate was unwilling to undergo results.
a similar rearrangement. This derivative gave no detectable
The mechanism for the rearrangement in the presence of
amount of the rearrangement product as verified by the ab- two explicit water molecules (Path II) is somewhat different
sence of the corresponding phosphoramidate signal in the as illustrated in Figure 2. It appears that the reaction pro-
31P NMR spectrum. If the reaction was heated only un- ceeds through two transition states and an intervening in-
identified side products were observed.
termediate.
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Rearrangement of S-(2-Aminoethyl) Thiophosphates
Figure 1. Reaction path (I) for the rearrangement reaction of 1b to
2b. The relative energies of the various states displayed are not to
scale.
Figure 3. Reaction path III for the rearrangement of 1b to 2b. The
relative energies of the various states displayed are not to scale.
Table 1. Energy differences for reaction path I illustrated in Fig-
ure 1 calculated at various levels of quantum mechanical approxi-
mations. The data are obtained using the PCM theory to simulate
the aqueous and DMSO environment with the latter results in
brackets.
Level of calculation
B3LYP/6-31G(d)
∆
[kJ/mol]
∆
[kJ/mol] ∆HI [kJ/mol]
I,R
I,F
124.8 (126.5) 149.9 (150.7) –25.1 (–24.2)
B3LYP/6-311+G(d,p) 133.1 (134.8) 159.1 (160.1) –26.0 (–25.1)
CCSD(T)/6-31G(d)
//B3LYP/6-31G(d)
125.1 (127.0) 153.8 (154.7) –28.7 (–27.7)
In III the P–S bond length is longer than the corresponding
one in the reactant complex RII and, likewise, the P–N
bond length is longer than the one in the product complex
PII. Another feature of III is that a hydrogen atom has not
yet been transferred from nitrogen to sulfur, and as a result,
they are positively and negatively charged, respectively. In
the second transition state, TSII,2, the transfer of the hydro-
gen from N to S is mediated in a domino-effect type of
motion (Grotthuss effect)[23] involving a water molecule. We
note that only one of the two explicit water molecules par-
ticipates in the rearrangement mode in TSII,2. The other
one is non-participating, suggesting that additional explicit
Figure 2. Reaction path II for the rearrangement of 1b to 2b. The
relative energies of the various states displayed are not to scale.
The dominant motion in the rearrangement mode in the water molecules will also be non-participating. In Table 2
first transition state, TSII,1, is an asymmetric stretch of the we list the various estimates for the activation energies in-
P–S and P–N bonds. TSII,1 is linked to an intermediate, III. volved in path II.
Table 2. Energy differences for reaction path II illustrated in Figure 2 calculated at various levels of quantum mechanical approximations.
The data are obtained using the PCM theory to simulate the aqueous environment.
Level of calculation
∆
II,F1
[kJ/mol]
∆
II,R1
[kJ/mol]
∆ [kJ/mol]
II,F2
∆III,R2 [kJ/mol]
∆HII [kJ/mol]
B3LYP/6-31G(d)
B3LYP/6-311+G(d,p)
90.9
83.1
55.1
27.7
8.6
11.1
68.0
105.1
–23.6
–38.5
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M. Chen, A. Maetzke, S. J. Knak Jensen, K. V. Gothelf
FULL PAPER
Table 3. Energy differences for reaction path III illustrated in Figure 3 calculated at various levels of quantum mechanical approximations.
The data are obtained using the PCM theory to simulate the aqueous and DMSO environment with the latter results in brackets.
Level of calculation
∆
III,F1
[kJ/mol]
∆
III,R1
[kJ/mol]
∆
III,F2
[kJ/mol]
∆ [kJ/mol]
III,R2
∆HIII [kJ/mol]
B3LYP/6-31G(d)
B3LYP/6-311+G(d,p)
154.3 (153.9)
158.9 (158.3)
68.4 (68.2)
77.2 (77.6)
5.17 (4.98)
5.89 (6.71)
108.5 (107.6)
108.8 (108.2)
–17.4 (–17.0)
–21.2 (–20.8)
It appears from a comparison of the results listed in vation energy found for path I but still much higher than
Tables 1 and 2 that the inclusion of two water molecules in the one found for path II (83.1 kJ/mol).
the rearrangement reaction reduces the activation energy by
about 50 kJ/mol and changes the energy gain going from two-step reaction path via intermediate 10 where the P–S
reactant to product from ∆HI = –26.0 kJ/mol to ∆HII bond and the P–OH bond are longer than those in the reac-
–38.5 kJ/mol at the B3LYP/6-311+G(d,p) level in aqueous tant and the product complex, respectively. The activation
environment. energy for formation of the intermediate from the reactant
The hydrolysis performed with hydroxide, results in a
=
The experimental results show that the rearrangement re- is 33.4 kJ/mol in aqueous solution and the activation energy
action will proceed smoothly even though no water is added from the intermediate to the product is 22.5 kJ/mol. The
to the solution (pure DMSO). This probably indicates that total energy gain in the reaction is –194.7 kJ/mol. The acti-
the proton transfer could proceed through the primary vation energy of water hydrolysis has been calculated to
amine group on another reactant complex which has not about 206.6 kJ/mol at B3LYP/6-311+G(d,p) in aqueous
yet taken part in the reaction. This has not been investi- solution.
gated theoretically.
The reaction in which one of the methoxy groups at
phosphorus in 1b is replaced by intramolecular substitution
with the amine forming a cyclic product was also investi-
gated. For the reaction with and without explicit water
molecules the reaction paths are similar having an acti-
vation energy of about 172 kJ/mol at the B3LYP/6-
311+G(d,p) level. The ∆H for the cyclization reaction is
approximately zero. The cyclic product for reactions of 1a
was not observed experimentally.
Although, it was found that the activation energy barrier
for the hydrolysis with hydroxide [33.4 kJ/mol at the
B3LYP/6-311+G(d,p) level] is significantly lower than the
rearrangement reaction in the presence of two explicit water
molecules [83.1 kJ/mol at the B3LYP/6-311+G(d,p) level],
the experimentally observed distribution of the rearrange-
ment and hydrolysis products at pH12 in D2O were found
A reaction path for the rearrangement of 1b to 2b involv-
ing a cyclic intermediate similar to what was suggested for
the analogous S,O rearrangement (see Scheme 1, b).[6–8] has
also been investigated. The reaction path is illustrated in
to be 60:40. The explanation is that we are comparing an
Figure 3.
intramolecular reaction with
a bimolecular reaction.
The dominant motion in the first transition state, TSIII,1
,
Furthermore it is obvious that the distribution of products
is strongly pH-dependent. The favored pH represents a bal-
ance where the amine should be non-protonated and the
concentration of hydroxide as low as possible.
in reaction path III is the transfer of one of the protons
from the amine to the double bonded oxygen on phospho-
rus. Simultaneously the shortening of the P–N distance
thereby forming the cyclic intermediate IIII is seen. In the
second transition state, TSIII,2, which connects the cyclic
intermediate to the rearrangement product, the dominant
motion is lengthening of the P–S bond simultaneously with
the transfer of the hydrogen from the hydroxy group on
Conclusions
A new rearrangement of S-(2-aminoethyl) thiophosphate
phosphorus to the negatively charged sulfur atom. The to N-(2-mercaptoalkyl)phosphoramidate has been devel-
major difference between reaction path III in Figure 3 and oped. The reaction proceeds smoothly at room temperature
reaction path I in Figure 1 is that the hydrogen atom does at pH12. Theoretical calculations strongly suggest that the
not transfer directly to the sulfur atom but rather moves to mechanism of the rearrangement involves two steps com-
the double bonded oxygen forming a hydroxy group and bining the reactant to the product via a zwitterionic inter-
thereby a cyclic intermediate. In Table 3 we list the various mediate (path II). Water catalyses the proton transfer. The
estimates for the activation energies pertaining to path III.
resulting thiols 2a and 2b tend to form the corresponding
It appears from Tables 1, 2, and 3 that the activation en- disulfides during purification, but it was demonstrated that
ergy for reaction path III is higher than those for reaction the thiol can be trapped by alkylation with benzyl bromide
path I and II.
in an overall yield of 76% for the alkylation, rearrangement
Inclusion of a single explicit water molecule in the re- and alkylation steps. Further application of the novel reac-
arrangement of 1b to 2b leads to an activation energy of tion for labeling of DNA with the site-specificly generated
129.3 kJ/mol for path III. This is slightly less than the acti- thiol functionality is in progress.
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Eur. J. Org. Chem. 2007, 5826–5833

Rearrangement of S-(2-Aminoethyl) Thiophosphates
47.24, 35.68, 35.20 ppm. MS: calcd. 320.1263 [M + Na]+, found
320.1287 [M + Na]+.
Experimental Section
General Methods: Commercially available starting materials were
used without further purification. Solvents were dried according to
standard procedures. Flash chromatography was performed using
Merck silica gel 60 (230–400 mesh). The liquid-state 1H and 13C
and 31P NMR spectra were recorded at 400, 100 and 100 MHz,
respectively, on a Varian Mercury (9.4 T) spectrometer using
CDCl3 as the solvent unless otherwise stated. The chemical shifts
are reported in ppm with CHCl3 (δ = 7.26 ppm) as the reference
for 1H, with H3PO4 (δ = 0 ppm) as the reference for 31P, and relative
to the central CDCl3 resonance (δ = 77.3 ppm) in the 13C NMR
spectra. Yields refer to isolated and spectroscopically homogeneous
materials. High resolution mass spectra were obtained on an LC-
TOF spectrometer (Micromass).
2-Fmoc-Amino Ethyl Iodide 5a: To a flame-dried flask containing
a mixture of DDQ (0.5448 g, 2.4 mmol) and PPh3 (0.6288 g,
2.4 mmol) in dry CH2Cl2 (30 mL), (nBu)4NI (0.8865 g, 2.4 mmol)
was added at room temperature. 2-(Fmoc-amino)ethanol (4a)
(0.5660 g, 2.0 mmol) was then added to the solution. The yellow
color of the solution immediately changed to deep red. After
20 min, the solvent was evaporated. Column chromatography of
the crude mixture on silica gel using n-pentane/ethyl acetate (9:1)
as eluent gave 5a as white powder (0.54 g, 1.66 mmol) in 83% yield;
1
m.p. 148–150 °C, H NMR (400 MHz, [D6]DMSO): δ = 7.87 (d, J
= 7.2 Hz, 2 H), 7.64 (d, J = 7.2 Hz, 2 H), 7.39 (t, J = 7.2 Hz, 2 H),
7.31 (t, J = 7.2 Hz, 2 H), 5.12 (br. 1 H), 4.31 (d, J = 7.2 Hz, 2 H),
4.20 (t, J = 6.8 Hz, 1 H), 3.29 (q, J = 7.0 Hz, 2 H), 3.17 (t, J =
6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 156.6,
144.5, 141.4, 128.3, 127.8, 125.8, 120.8, 66.11, 47.42, 43.60, 6.92
ppm. MS: calcd. 416.0123 [M + Na]+, found 416.0100 [M + Na]+.
Alcohol 4b: To a stirred solution of Fmoc-Cl (0.35 g, 1.4 mmol)
in Et2O (5 mL) in ice bath, a solution of (Ϯ)-2-amino-1-propanol
(0.11 mL, 1.4 mmol) in Et2O (5 mL) was slowly added. After
20 min, the ice bath was removed and the reaction was continued
at room temperature. After 2 h, the white precipitate was removed
by filtration, and the filtrate was washed with water and dried with
MgSO4. Column chromatography of the crude mixture on silica
gel using n-pentane/ethyl acetate (9:1) as eluent gave 4b as white
Iodides 5b, 5c and 5d: To a flame-dried flask containing a mixture
of DDQ (0.2724 g, 1.2 mmol) and PPh3 (0.3144 g, 1.2 mmol) in dry
CH2Cl2 (15 mL), (nBu)4NI (0.4433 g, 1.2 mmol) was added at room
temperature. 4b (or 4c or 4d) (0.2970 g, 1.0 mmol) was then added
to the solution. The yellow color of the solution immediately
changed to deep red. After 20 min, the solvent was evaporated.
Column chromatography of the crude mixture on silica gel using
n-pentane/ethyl acetate (9:1) as eluent gave the product.
1
powder (0.3860 g, 1.30 mmol) in 93% yield. H NMR (400 MHz,
CDCl3): δ = 7.69 (d, J = 7.2 Hz, 2 H), 7.52 (d, J = 7.2 Hz, 2 H),
7.33 (t, J = 7.2 Hz, 2 H), 7.25 (t, J = 7.2 Hz, 2 H), 5.11 (br., 1 H),
4.36 (d, J = 6.8 Hz, 2 H), 4.14 (t, J = 6.4 Hz, 1 H), 3.84 (m, 1 H),
3.26 (m, 1 H), 2.99 (m, 1 H), 1.11 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 157.6, 144.0, 141.4, 127.9, 127.3,
125.3, 120.1, 67.51, 67.03, 48.28, 47.32, 20.69 ppm. MS: calcd.
320.1263 [M + Na]+, found 320.1271 [M + Na]+.
5b (using 4b): White powder (0.345 g, 0.85 mmol) in 85% yield;
m.p. 118–120 °C, 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J =
7.6 Hz, 2 H), 7.68 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H),
7.31 (t, J = 7.2 Hz, 2 H), 4.32 (d, J = 7.2 Hz, 2 H), 4.19 (dt, J1 =
6.8, J2 = 23 Hz, 1 H), 3.36 (m, 2 H), 3.15 (m, 1 H), 1.76 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.4, 144.0,
141.5, 128.0, 127.3, 125.3, 120.2, 67.07, 50.99, 47.40, 28.48, 25.65
ppm. MS: calcd. 430.0280 [M + Na]+, found 430.0287 [M + Na]+.
Alcohol 4c: To a stirred solution of Fmoc-Cl (0.35 g, 1.4 mmol)
in Et2O (5 mL) in ice bath, a solution of (Ϯ)-1-amino-2-propanol
(0.12 mL, 1.4 mmol) in Et2O (5 mL) was slowly added. After
20 min, the ice bath was removed and the reaction was continued
at room temperature. After 2 h, the white precipitate was removed
by filtration, and the filtrate was washed with water and dried with
MgSO4. Column chromatography of the crude mixture on silica
gel using n-pentane/ethyl acetate (9:1) as eluent gave 4c as white
5c (using 4c): White powder (0.354 g, 0.87 mmol) in 87% yield; m.p.
147–149 °C, 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 7.6 Hz,
2 H), 7.69 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.33 (t,
J = 7.6 Hz, 2 H), 4.33 (d, J = 7.2 Hz, 2 H), 4.26 (m, 2 H), 3.53 (m,
1 H), 3.31 (m, 1 H), 3.24 (m, 1 H), 1.13 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.6, 144.1, 141.6, 128.0, 127.4,
125.4, 120.3, 67.09, 47.53, 46.73, 21.54, 16.96 ppm. MS: calcd.
430.0280 [M + Na]+, found 430.0291 [M + Na]+.
1
powder (0.3891 g, 1.31 mmol) in 94% yield. H NMR (400 MHz,
CDCl3): δ = 7.56 (d, J = 7.2 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H),
7.20 (t, J = 7.2 Hz, 2 H), 7.12 (t, J = 7.8 Hz, 2 H), 4.19 (d, J =
6.8 Hz, 2 H), 4.00 (t, J = 6.4 Hz, 1 H), 3.59 (m, 1 H), 3.34 (m, 2
H), 0.99 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 156.8, 143.8, 141.2, 127.6, 126.9, 124.9, 119.8, 66.45, 65.39,
48.37, 47.01, 16.76 ppm. MS: calcd. 320.1263 [M + Na]+, found
320.1261 [M + Na]+.
5d (using 4d): White powder (0.358 g, 0.88 mmol) in 88% yield;
m.p. 55–57 °C. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J =
7.8 Hz, 2 H), 7.50 (dd, J1 = 7.2, J2 = 15.6 Hz, 2 H), 7.41 (t, J =
7.8 Hz, 2 H), 7.34 (t, J = 7.8 Hz, 2 H), 4.54 (d, J = 6.4 Hz, 2 H),
4.43 (d, J = 6.8 Hz, 2 H), 4.24 (m, 1 H), 3.64 (t, J = 7.8 Hz, 1 H),
3.35 (J = 7.8 Hz, 1 H), 3.25 (J = 6.8 Hz, 1 H), 2.94 (d, J = 32 Hz,
3 H), 2.81 (t, J = 7.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 156.2, 155.8, 144.0, 141.5, 127.9, 127.3, 125.2, 124.8, 120.4,
120.2, 67.65, 67.24, 51.98, 51.64, 47.43, 35.26, 35.01, 1.55, 0.90
ppm. MS: calcd. 430.0280 [M + Na]+, found 430.0290 [M + Na]+.
Alcohol 4d: To a stirred solution of Fmoc-Cl (0.776 g, 3.0 mmol)
in Et2O (15 mL) in ice bath, a solution of 2-(methylamino)ethanol
(0.24 mL, 3.0 mmol) in Et2O (15 mL) was slowly added. After
20 min, the ice bath was removed and the reaction was continued
at room temperature. After 2 h, the white precipitate was removed
by filtration, and the filtrate was washed with water and dried with
MgSO4. Column chromatography of the crude mixture on silica
gel using n-pentane/ethyl acetate (9:1) as eluent gave 4d as white
powder (0.77 g, 2.6 mmol) in 86% yield. 1H NMR (400 MHz,
CDCl3): δ = 7.71 (d, J = 7.2 Hz, 2 H), 7.53 (d, J = 6.4 Hz, 2 H),
7.34 (t, J = 7.8 Hz, 2 H), 7.26 (t, J = 7.2 Hz, 2 H), 4.54 (br., 1 H),
O,OЈ-Dimethyl Thiophosphate, Sodium Salt 6b: To a stirred solu-
tion of diethyl phosphite (0.44 g, 4 mmol) in CH2Cl2 (60 mL),
phenylacetyl disulfide (3.63 g, 12 mmol) and N,N-diisopropylethyl-
amine (DIPEA) (3.3 mL) was added. The reaction mixture turned
to purple in 10 min. After 1 h, the reaction mixture was extracted
4.37 (d, J = 6.8 Hz, 2 H), 4.18 (t, J = 6.4 Hz, 1 H), 3.70 (m, 1 H), with 0.01  NaOH aqueous solution and washed with diethyl ether.
3.39 (m, 2 H), 3.11 (m, 1 H), 2.88 (d, J = 17.2 Hz, 3 H) ppm. 13C The aqueous phase was dried to get 6b as white powder (0.58 g,
NMR (100 MHz, CDCl3): δ = 157.2, 156.4, 143.9, 141.3, 127.7,
127.1, 125.0, 124.9, 120.0, 67.53, 67.27, 60.53, 60.33, 51.61, 50.96,
3.5 mmol) in 89% yield; m.p. 195–197 °C, 1H NMR (400 MHz,
CD3OD): δ = 3.61 (d, J = 12.8 Hz, 6 H) ppm. 13C NMR (100 MHz,
Eur. J. Org. Chem. 2007, 5826–5833
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5831

M. Chen, A. Maetzke, S. J. Knak Jensen, K. V. Gothelf
FULL PAPER
CD3OD): δ = 53.12, 53.06 ppm. 31P NMR (100 MHz, CD3OD): δ
= 59.1 ppm. MS: calcd. 186.9571 [M + Na]+, found 187.0077 [M
+ Na]+.
H), 2.57 (q, J = 7.0 Hz, 2 H), 2.32 (t, J = 6.8 Hz, 2 H), 1.94 (t, J
= 7.0 Hz, 1 H), 1.15 (t, J = 7.0 Hz, 6 H) ppm. 31P NMR (100 MHz,
[D6]DMSO): δ = 9.57 ppm.
O,OЈ-Diethyl S-[2-(Fmoc-amino)ethyl] Thiophosphate (7a): To a
stirred solution of 6a (0.2080 g, 1.1 mmol) in DMSO (1 mL), was
added 5a (0.3930 g, 1.0 mmol). The reaction mixture was stirred at
50 °C for 3 h. The reaction mixture was extracted 3 times with di-
ethyl ether and washed with brine and water. The combined ex-
tracts were evaporated to dryness to get 7a as brown oil (0.41 g,
0.95 mmol) in 95% yield. 1H NMR (400 MHz, [D6]DMSO): δ =
7.84 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 7.2 Hz, 2 H), 7.37 (t, J =
7.6 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 2 H), 5.86 (br., 1 H), 4.29 (d, J
= 6.8 Hz, 2 H), 4.18 (t, J = 6.4 Hz, 1 H), 4.02 (m, 4 H), 3.22 (t, J
= 7.0 Hz, 2 H), 2.82 (m, 2 H), 1.21 (t, J = 7.2 Hz, 6 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 156.7, 144.5, 141.4, 128.3,
127.7, 125.8, 120.8, 66.1, 63.91, 63.86, 47.35, 41.47, 30.44, 16.58,
16.51 ppm. 31P NMR (100 MHz, [D6]DMSO): δ = 26.4 ppm. MS:
calcd. 458.1166 [M + Na]+, found 458.1177 [M + Na]+, 474.0923
[M + K]+.
The reaction mixture was extracted 3 times with diethyl ether and
washed with brine and water. The combined organic phase was
evaporated to dryness. Column chromatography of the crude mix-
ture on silica gel using n-pentane/ethyl acetate (3:1) to CH2Cl2/
MeOH (9:1) as eluent gave 3a (0.055 g, 0.13 mmol) as brown oil in
1
52% yield. H NMR (400 MHz, CDCl3): δ = 3.96 (m, 8 H), 3.12
(dt, J1 = 7.2, J2 = 11.2 Hz, 4 H), 2.68 (t, J = 6.8 Hz, 4 H), 1.20 (m,
12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.54, 62.48, 40.50,
40.46, 30.47, 16.45, 16.39 ppm. 31P NMR (100 MHz, CDCl3): δ =
9.47 ppm. MS: calcd. 447.0919 [M + Na]+, found 447.0895 [M +
Na]+, 458.1198 [M + K]+.
Disulfides 3ab, 3ac and 3ad: To a stirred solution of 6a (0.104 g,
0.5 mmol) in [D6]DMSO (1 mL), was added 5b (or 5c or 5d)
(0.204 g, 0.5 mmol). The reaction mixture was stirred at 50 °C for
3 h. 31P NMR (δ = 26.7 ppm) showed the reaction is completed in
quantitive conversion. After reaction mixture was cooled down to
room temperature, KOtBu (0.112 g, 1.0 mmol) was added. After
20 min, the reaction was extracted 3 times with diethyl ether and
washed with brine and water. The combined organic phase was
evaporated to dryness. Column chromatography of the crude mix-
ture on silica gel using n-pentane/ethyl acetate (3:1) to CH2Cl2/
MeOH (9:1) as eluent gave the product.
3ab (using 5b): Brown oil (0.057 g, 0.12 mmol) in 50% yield. 1H
NMR (400 MHz, CDCl3): δ = 4.11 (m, 8 H), 3.20 (m, 2 H), 3.05
(m, 2 H), 2.47 (m, 2 H), 1.47 (d, J = 6.4 Hz, 6 H), 1.31 (m, 12 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 63.13, 63.09, 47.61, 43.12,
30.80, 16.42, 16.36 ppm. 31P NMR (100 MHz, CDCl3): δ = 9.77
ppm. MS: calcd. 475.1231 [M + Na]+, found 475.1235 [M + Na]+.
3ac (using 5c): Brown oil (0.059 g, 0.13 mmol) in 52% yield. 1H
NMR (400 MHz, CDCl3): δ = 4.00 (m, 8 H), 3.36 (m, 2 H), 2.97
(m, 2 H), 2.60 (m, 2 H), 1.26 (m, 12 H), 1.16 (d, J = 7.0 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 62.66, 62.63, 47.69, 30.57,
22.39, 16.54, 16.48 ppm. 31P NMR (100 MHz, CDCl3): δ = 9.90
ppm. MS: calcd. 491.0971 [M + K]+, found 491.1008 [M + K]+.
3ad (using 5d): Brown oil (0.055 g, 0.12 mmol) in 48% yield. 1H
NMR (400 MHz, CDCl3): δ = 4.03 (m, 8 H), 3.21 (m, 4 H), 2.68
(d, J = 9.2 Hz, 6 H), 2.63 (t, J = 6.8 Hz, 4 H), 1.30 (m, 12 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 62.49, 62.45, 48.89, 48.77, 47.51,
32.54, 32.42, 16.41, 16.34 ppm. 31P NMR (100 MHz, CDCl3): δ =
9.59 ppm. MS: calcd. 447.0919 [M + Na]+, found 491.0971 [M +
K]+, 491.0998 [M + K]+.
O,OЈ-Dimethyl S-[2-(Fmoc-amino)ethyl] Thiophosphate (7b): To a
stirred solution of 6b (0.180 g, 1.1 mmol) in DMSO (1 mL), was
added 5a (0.3930 g, 1.0 mmol). The reaction mixture was stirred at
50 °C for 3 h. The reaction mixture was extracted 3 times with di-
ethyl ether and washed with brine and water. The combined ex-
tracts were evaporated to dryness to get 7b as brown oil (0.38 g,
0.92 mmol) in 92% yield. 1H NMR (400 MHz, CDCl3): δ = 7.76
(d, J = 8.0 Hz, 2 H), 7.59 (d, J = 7.8 Hz, 2 H), 7.40 (t, J = 7.8 Hz,
2 H), 7.31 (t, J = 7.6 Hz, 2 H), 5.43 (br., 1 H), 4.41 (d, J = 7.2 Hz,
2 H), 4.22 (t, J = 6.8 Hz, 2 H), 3.79 (d, J = 12.4 Hz, 6 H), 3.50 (t,
J = 5.6 Hz, 2 H), 2.99 (dt, J1 = 5.6, J2 = 17.2 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.5, 144.0, 141.5, 127.9, 127.2,
120.1, 66.95, 54.27, 54.21, 47.37, 41.92, 30.67 ppm. 31P NMR
(100 MHz, CDCl3): δ = 29.0 ppm. MS: calcd. 408.1035 [M + H]+,
found 408.1098 [M + H]+.
O,OЈ-Diethyl S-(2-Aminoethyl) Thiophosphate Hydrogen Bromide
(1a·HBr): To a stirred solution of 6a (0.104 g, 0.5 mmol) in [D6]-
DMSO (1.0 mL), was added 8 (0.104 g, 0.5 mmol) at 50 °C. 31P
NMR showed the reaction is completed in 12 h in quantitive con-
version. After removal of KBr by filtration, 1a·HBr was used with-
out further purification. 1H NMR (400 MHz, [D6]DMSO): δ =
8.22 (br., 3 H), 4.03 (m, 4 H), 3.00 (m, 4 H), 1.20 (t, J = 6.8 Hz, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 64.05, 63.99, 42.55,
42.51, 34.11, 34.08, 16.28, 16.21 ppm. 31P NMR (100 MHz, [D6]-
DMSO): δ = 26.4 ppm. MS: calcd. 214.0667 [M–Br]+, found
214.0678 [M–Br]+.
Disulfide 3b: To a stirred solution of 1b·HBr (0.13 g, 0.5 mmol) in
methanol (1.0 mL), was added KOtBu (0.112 g, 1.0 mmol) at room
temperature. After 20 min, the solvent was evaporated. Column
chromatography of the crude mixture on silica gel using CH2Cl2/
methanol (95:5) as eluent gave 3b as brown oil (0.077 g, 0.21 mmol)
in 41% yield. 1H NMR (400 MHz, CDCl3): δ = 3.73 (d, J =
11.2 Hz, 12 H), 3.25 (m, 4 H), 2.78 (t, J = 6.4 Hz, 4 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 53.45, 53.39, 39.99, 39.96, 29.83
ppm. 31P NMR (100 MHz, CDCl3): δ = 10.7 ppm. MS: calcd.
391.0293 [M + Na]+, found 391.0286 [M + Na]+.
O,OЈ-Dimethyl S-(2-Aminoethyl) Thiophosphate Hydrogen Bromide
(1b·HBr): To a stirred solution of 6b (0.082 g, 0.5 mmol) in [D6]-
DMSO (1.0 mL), was added 8 (0.104 g, 0.5 mmol) at 50 °C. 31P
NMR showed the reaction is completed in 12 h with quantitive
conversion. After removal of KBr by filtration, 1b·HBr was used
without further purification. 1H NMR (400 MHz, CD3OD): δ =
3.81 (d, J = 12.8 Hz, 6 H), 3.26 (t, J = 7.2 Hz, 2 H), 2.95 (dt, J1 =
7.2, J2 = 15.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CD3OD): δ =
54.73, 54.66, 42.44, 28.12, 28.09 ppm. 31P NMR (100 MHz,
CD3OD): δ = 32.5 ppm. MS: calcd. 186.0354 [M – Br]+, found
186.0378 [M – Br]+.
N-[2-(Benzylthio)ethyl]phosphoramidate (9): To a stirred solution of
6a (0.104 g, 0.5 mmol) in methanol (1.0 mL), was added 8 (0.104 g,
0.5 mmol) at 50 °C. After 20 h, the reaction mixture was cooled
down and KOtBu (0.112 g, 1.0 mmol) was added at room tempera-
ture. After 10 min, benzyl bromide (0.17 g, 1.0 mmol) was added.
After 2 h, the solvent was evaporated. Column chromatography of
O,OЈ-Diethyl N-(2-Mercaptoethyl)phosphoramidate (2a) and Disul-
fide 3a: To a stirred solution of 1a·HBr (0.15 g, 0.5 mmol) in [D6]-
DMSO (0.5 mL), was added KOtBu (0.112 g, 1.0 mmol) at room
1
temperature. H NMR and 31P NMR showed the reaction is com-
pleted in 10 min and 2a was obtained with quantitative conversion.
1H NMR (400 MHz, [D6]DMSO): δ = 3.84 (m, 4 H), 2.98 (m, 1 the crude mixture on silica gel using CH2Cl2/methanol (95:5) as
5832
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5826–5833

Rearrangement of S-(2-Aminoethyl) Thiophosphates
1
[12] B. A. Arbuzov, O. N. Nuretdinova, Bull. Acad. Sci. USSR Div.
Chem. Sci. 1983, 32, 613–615.
eluent gave 9 as brown oil (0.115 g, 0.38 mmol) in 76% yield. H
NMR (400 MHz, CDCl3): δ = 7.24 (m, 5 H), 4.15 (s, 2 H), 4.05
(m, 4 H), 3.06 (m, 2 H), 2.44 (t, J = 8.0 Hz, 2 H), 1.30 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 138.1, 129.1, 128.6, 127.8,
62.72, 62.61, 50.10, 45.26, 45.22, 29.37, 29.33, 16.47, 16.40 ppm.
31P NMR (100 MHz, CDCl3): δ = 9.98 ppm. MS: calcd. 304.1136
[M + H]+, found 304.1179 [M + H]+, 327.0620 [M + Na]+.
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This study was funded in part by the Danish National Research
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Scientific Computing, HDW-0107-13-(AU).
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Received: July 13, 2007
Published Online: October 9, 2007
Eur. J. Org. Chem. 2007, 5826–5833
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5833