A convenient method for the synthesis of N-protected 1-aminoalkylphosphonate mixed monothioesters and dithioesters

Article abstract of DOI:10.1081/SCC-100104060

A series of N-protected 1-aminoalkylphosphonate mixed monothioesters and dithioesters were synthesized using one-pot reactions of benzyl carbamate, aldehydes and alkoxyphosphine dichlorides or alkylthiophosphine dichloride, followed by alcoholysis with thiol or alcohols in the presence of triethylamine.

Full text of DOI:10.1081/SCC-100104060

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A CONVENIENT METHOD
FOR THE SYNTHESIS
OF N-PROTECTED 1-
AMINOALKYLPHOSPHONATE
MIXED MONOTHIOESTERS AND
DITHIOESTERS
Jiaxi Xu a & Ming Wei a
a College of Chemistry and Molecular Engineering,
Peking University , Beijing, 100871, China
Published online: 02 Aug 2010.
To cite this article: Jiaxi Xu & Ming Wei (2001) A CONVENIENT METHOD FOR THE
SYNTHESIS OF N-PROTECTED 1-AMINOALKYLPHOSPHONATE MIXED MONOTHIOESTERS
AND DITHIOESTERS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:10, 1489-1497, DOI: 10.1081/
SCC-100104060
To link to this article: http://dx.doi.org/10.1081/SCC-100104060
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SYNTHETIC COMMUNICATIONS, 31(10), 1489–1497(2001)
A CONVENIENT METHOD FOR
THE SYNTHESIS OF N-PROTECTED
1-AMINOALKYLPHOSPHONATE MIXED
MONOTHIOESTERS AND DITHIOESTERS
Jiaxi Xu* and Ming Wei
College of Chemistry and Molecular Engineering,
Peking University, Beijing 100871, China
ABSTRACT
A series of N-protected 1-aminoalkylphosphonate mixed
monothioesters and dithioesters were synthesized using one-
pot reactions of benzyl carbamate, aldehydes and alkoxypho-
sphine dichlorides or alkylthiophosphine dichloride, followed
by alcoholysis with thiol or alcohols in the presence of triethy-
lamine.
Recent developments in the design of transition state analogues
for enzymatic reactions have led to the synthesis of phosphonopeptides
containing phosphonamidate bonds used as inhibitors for a variety of
enzymes,1–3 and as haptens for catalytic antibodies with esterase activity.4
1-Aminoalkylphosphonate esters are also recognized as effective transition-
state analogue inhibitors for numerous enzymes, including a number of pro-
teases and esterases.1–3,5–7 They have been widely used as nonhydrolyzable
analogues of phosphonates to inhibit dinucleoside triphosphate hydrolase,8
*Corresponding author.
1489
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1490
XU AND WEI
phosphatidyltransferase,9 and squalene synthetase.10 In addition, phospho-
nate esters have also been used as haptens for the production of catalytic
antibodies possessing esterase activity.11–15 Thus, it is very important to
develop convenient synthetic methodology allowing the ready synthesis of a
numberofphosphonates,especiallyunsymmetricphosphonatemixeddiesters.
Up to now synthesis of symmetric 1-amino-alkylphosphonates has
been widely studied.16–24 The most common method for the synthesis of
unsymmetric phosphonate mixed diesters is through the phosphonochlori-
dates and alcohols.4,25,26 Alternatively condensation of phosphonic mono-
acids with alcohols is an important method, which involves Karenewsky’s
phosphonous acid coupling method,27 or by use of coupling reagents
DCC,28 trichloroacetonitrile,29 BOP (or PyBOP),30,31 or Campbell’s
extended and modified Mitsunobu condensation method.32,33 The third
method is that phosphonodichlorides were successively alcoholized with
different alcohols in proper order using tetrazole as a catalyst.34 In all of
the above methods, it is necessary to synthesize, at first, phosphonic acids,
phosphonate monoacids, or symmetric phosphonate diesters.23,24
RESULTS AND DISCUSSION
We report a convenient method to synthesize N-protected 1-amino-
alkylphosphonate unsymmetric monothioesters and dithioesters using in situ
one-pot reactions of benzyl carbamate, an aldehyde and an alkoxy-
phosphine dichloride or alkylthiophosphine dichloride, followed by reac-
tions with a thiol or alcohols in the presence of triethylamine in anhydrous
benzene as a solvent. It is not necessary to synthesize phosphonic acids, their
monoacids, or their symmetric diesters. These reactions yielded unsym-
metric phosphonate mixed monothioesters or dithioesters 3 in satisfactory
yields under simple and mild conditions, and gave corresponding monoacids
4 simultaneously as the main byproducts.
To improve yields of products 3, the reaction conditions have been
optimized by changing various solvents and reaction time. However, it is not

MONO- AND DITHIOESTERS
1491
Table 1. Synthesis of N-Protected 1-Aminoalkylphosphonate Mixed Monothio-
esters 3 and Monoacids 4
Entry
R1
R2
Yield of 3 (%)
Yield of 4 (%)
a
b
c
d
e
f
MeO
EtO
PhO
PhS
PhS
PhS
PhS
i-PrS
i-PrS
i-PrS
MeO
EtO
43
40
38
44
39
21
36
26
21
27
26
25
35
22
i-PrO
i-PrS
g
possible to avoid producing monoacids 4, because both phosphonochlori-
date 6 and phosphonic anhydride 7 were observed as reaction intermediates
as mentioned previously.35 The phosphonochloridates 6 reacted with
alcohols or thiol to yield phosphonate mixed esters 3. However, the phos-
phonic anhydrides 7 reacted with alcohols or thiol to yield phosphonates 3
and phosphonic monoacids 4 simultaneously. This explained why reactions
yielded both phosphonates 3 and phosphonic monoacids 4 simultaneously.
Although the yields of phosphonates 3 are not especially high, it is really
a convenient method for synthesis of phosphonate mixed monothioester
or dithioesters.
From the reaction scheme, we know that the two alkyl groups of
the phosphonate mixed diesters could be introduced from different
starting materials, alkoxyphosphine/alkylthiophosphine dichlorides or thiol/
alcohols in the alcoholysis step. According to our experimental results, we
found that phenol and thiophenol were introduced more favorably from
phenoxyphosphine dichloride or phenylthiophosphine dichloride than they
were in the phenolysis or thiophenolysis step, due to weak nucleophilicities.
For the entry a, a symmetric dithioester of phosphonic acid 5a
was obtained in 6% yield. To elucidate the formation procedure of
the symmetric dithioester 5a, both dimethyl 1-(N-carboxybenzylamino)
phenylmethyl-phosphonate and isopropylthio methyl 1-(N-carboxybenzyla-
mino)phenyl-methylphosphonate 3a were carried out ester exchange

1492
XU AND WEI
reactions with isopropylthiol. However, no ester exchange reaction was
found in these reactions. Thus, the symmetric dithioester was presumed to
yield through a pentacoordinated phosphorus intermediate when methyl
1-(N-benzyloxycarbonylamino)phenyl-methylphosphonic chloride reacted
with isopropylthiol. This intermediate can not only eliminate a Cl to yield
the unsymmetric mixed diester 3a, but also eliminate MeO group to
produce isopropylthio 1-(N-benzyloxycarbonylamino) phenyl-methylphos-
phonic chloride. It can further react with isopropylthiol again to give the
symmetric dithioester 5a through another pentacoordinated phosphorus
intermediate.
1
All products were characterized by H NMR, 31P NMR, MS spectro-
1
metries and elemental analyses. In most cases, in the H NMR spectra,
the alkoxyl and/or alkylthio groups of compounds 3 appeared at different

MONO- AND DITHIOESTERS
1493
chemical shifts, which correspond to the two pairs of diastereoisomers, and
were split into doublets by phosphorus atom. In EI-MS spectra, it is a
special property of phosphonate that in most cases compounds 3 show
MHþ peaks in electron impact ionization condition.
In summary, a novel and convenient method for synthesis of
N-protected 1-aminoalkylphosphonate mixed monothioester and dithio-
esters has been developed using in situ one-pot reactions of benzyl carba-
mate, an aldehyde, and alkoxyphosphine dichlorides or alkylthiophosphine
dichloride, followed with a thiol or alcohols in the presence of triethylamine.
The reaction procedure was traced by 31P NMR analysis and a mechanism
was proposed.
EXPERIMENTAL
Melting points were obtained on a Yanaco melting point apparatus
and were uncorrected. Elemental analyses were carried out on an Elementar
Vario EL analyzer. The 1H NMR spectra were recorded on a Varian
mercury 200 spectrometer at 200 MHz with TMS as an internal standard
in CDCl3. 31P NMR spectra were obtained on a Varian mercury 200 at
81 MHz and the chemical shifts values are referenced to 85% H3PO4 with
negative shifts upfield. Mass spectra were recorded on a VG ZAB-HS mass
spectrometer.
Phenylthiophosphine dichloride were synthesized.36 All remaining
chemicals were purchased from Beijing Chemical Co. Benzene was refluxed
over sodium and distilled prior to use. Triethylamine was also refluxed over
sodium hydroxide and distilled prior to use.
General Procedure
Alkoxyphosphine dichloride or alkylthiophosphine dichloride 1
(3 mmol) was slowly added dropwise to a stirred mixture of benzyl carba-
mate (0.45 g, 3 mmol) and benzaldehyde (0.32 g, 3 mmol) in anhydrous
benzene (15 mL) at room temperature. After stirring the reaction mixture
for 6 h at RT, it was refluxed for 1 h. After cooling, alcohol or thiol 2
(6 mmol) was added dropwise in the ice-water bath. About 10 min later,
triethylamine (0.67g, 6.6 mmol) was added dropwise, and then the reaction
mixture was allowed to stir overnight. After adding ethyl acetate and water
to make the reaction solution clear, the organic phase was separated and
washed with saturated aqueous NaCl solution 3 to 5 times, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The residue was

1494
XU AND WEI
separated on a silica gel column with a mixture of petroleum ether and ethyl
acetate. (4:1) as an eluent to yield phosphonate mixed diester 3. The aqueous
phase was acidified with 10% HCl to precipitate the byproduct monoacid 4.
For the reaction entry a, phosphonate symmetric dithioester 5a was also
obtained in 6% yield.
Isopropylthio methyl 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3a)
Yield: 43%; m.p. 154ꢀ–156ꢀC. 31P NMR (81 MHz, CDCl3) d: 53.01;
1H NMR (200 MHz, CDCl3) d: 1.11 and 1.35(d, J ¼ 6.8 Hz, 6H, CHMe2),
3.21 (m, 1H, SCH), 3.72(d, JPH ¼ 12 Hz, 3H, POMe), 5.05–5.30(m, 3H,
PhCH2O and CHP), 5.79(br, 1H, CONH), 7.28–7.41(m, 10H, ArH);
EI-MS m/z: 394(MHþ). Anal. calc. for C19H24NO4PS: C: 58.00, H: 6.15,
N: 3.56. Found: C: 58.29, H: 6.32, N: 3.64.
Ethyl isopropylthio 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3b)
Yield: 40%; m.p. 135ꢀ–137ꢀC. 31P NMR (81 MHz, CDCl3) d: 51.15;
1H NMR (200 MHz, CDCl3) d: 1.11 and 1.35(d, J ¼ 6.8Hz, 6H, CHMe2),
l.17–1.30(dt, 3H, Me), 3.19(m, 1H, SCH), 4.00–4.14(m, 4H, POCH2),
5.04–5.27(m, 3H, PhCH2O and CHP), 5.86(br, 1H, CONH), 7.27–7.45
(m, 10H, ArH); EI-MS m/z: 408(MH)þ. Anal calc. for C20H26NO4PS:
C: 58.95, H: 6.43, N: 3.44. Found: C: 58.79, H: 6.19, N: 3.20.
Isopropylthio phenyl 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3c)
Yield: 38%; m.p. 138ꢀ–140ꢀC. 31P NMR (81 MHz, CDCl3) d: 50.07;
1H NMR (200 MHz, CDCl3) d: 1.08 and 1.19 (d, J ¼ 6.8 Hz, 6H, CHMe2),
3.21(m, 1H, SCH), 5.10–5.17(m, 2H, PhCH2O), 5.39–5.50(m, 1H, CHP),
6.12(br, 1H, CONH), 7.02–7.50(m, 15H, ArH); EI-MS m/z: 455(Mþ).
Anal. calc. for C24H26NO4PS: C: 63.28, H: 5.75, N: 3.07. Found: C:
63.41, H: 5.48, N: 3.17.
Methyl phenylthio 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3d)
Yie1d: 44%; m.p. 131ꢀ–133ꢀC. 31P NMR (81 MHz, CDCl3) d: 50.34;
1H NMR (200 MHz, CDCl3) d: 3.64(d, JPH ¼ 12 Hz, 3H, POMe), 5.08 and

MONO- AND DITHIOESTERS
1495
5.14(s, 2H, PhCH2O), 5.15–5.32(m, 1H, CHP), 5.95(br, 1H, CONH), 7.20–
7.60(m, 15H, ArH) EI-MS m/z: 428(MHþ). Anal. calc. for C22H22NO4PS:
C: 61.82, H: 5.19, N: 3.28. Found: C: 62.03, H: 5.29, N: 3.45.
Ethyl phenylthio 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3e)
Yield: 39% m.p. 115ꢀ–117ꢀC. 31P NMR (81 MHz, CDCl3) d: 48.57;
1H NMR (200 MHz, CDCl3) d: 1.04 and 1.33(t, J ¼ 7.l Hz, 3H, CH3), 4.02
and 4.22(m, 2H, POCH2), 5.02–5.32(m, 1H, PCH), 5.08 and 5.14(s, 2H,
PhCH2O), 6.01(br, 1H, CONH), 7.20–7.60(m, 15H, ArH); EI-MS m/z:
442(MHþ). Anal. calc. for C23H24NO4PS: C: 62.57, H: 5.48, N: 3.17.
Found: C: 62.82, H: 5.50, N: 3.49.
Isopropyl phenylthio 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonate (3f)
Yield: 21%; m.p. 113ꢀ–115ꢀC. 31P NMR (81 MHz, CDCl3) d: 46.54;
1H NMR (200 MHz, CDCl3) d: 0.86–1.20(d, 6H, 2CH3), 4.68(m, 1H, OCH),
5.07–5.12(s, 2H, PhCH2O), 5.10–5.30(m, 1H, CHP), 5.85(br, 1H, CONH),
7.25–7.70(m, 15H, ArH); FAB-MS m/z: 456(MH)þ. Anal. calc. for
C24H26NO4PS: C: 63.28, H: 5.75, N: 3.07. Found: C: 63.22, H: 5.50, N: 3.29.
Isopropylthio phenylthio l-(N-benzyloxycarbonylamino)phenyl-
methyl-phosphonate (3g)
Yield: 36%; m.p. 111ꢀ–113ꢀC. 31P NMR (81 MHz, CDCl3) d: 64.28;
1H NMR (200 MHz, CDCl3) d: 1.07and 1.20(d, J ¼ 7.0 Hz, 6H, 2CH3),
3.20(m, 1H, SCH), 5.07–5.18(m, 2H, PhCH2O), 5.32–5.42(m, lH, CHP),
5.80 and 5.94(br, 1H, CONH), 7.21–7.58(m, 15H, ArH); EI-MS m/z:
472(MHþ). Anal. calc. for C24H26NO3PS2: C: 61.13, H: 5.56, N: 2.97.
Found: C: 60.89, H: 5.50, N: 3.19.
Phenylthio 1-(N-benzyloxycarbonylamino)phenylmethyl-
phosphonaten (4d)
Yield: 26%; m.p. 187ꢀ–188ꢀC. 31P NMR (81 MHz, CDCl3) d: 21.96;
1H NMR (200 MHz, CDCl3) d: 5.07(s, 2H, PhCH2O), 5.02–5.22(m, 1H,

1496
XU AND WEI
CHP), 6.14(br, 1H, CONH), 7.12–7.56(m, 15H, ArH), 9.98(br, 1H, POH);
EI-MS m/z: 413(Mþ). Anal. calc. for C21H20NO4PS(413.43): C: 61.01,
H: 4.88, N: 3.39. Found: C: 61.23, H: 4.69, N: 3.45.
Diisopropylthio 1-(N-benzyloxycarbonylamino)(4-chlorophenyl)-
methyl-phosphonate (5a)
Yield: 6%; m.p. 150ꢀ–152ꢀC. 31P NMR (81 MHz, CDCl3) d: 66.49;
1H NMR (200 MHz, CDCl3) d: 1.17–l.26 and 1.33–1.41(m, 12H, 2CHMe2),
3.27(m, 2H, 2SCH), 5.10–5.16(m, 2H, PhCH2O), 5.29–5.41(m, 1H, CHP),
5.82(br, 1H, CONH), 7.17–7.45(m, 10H, ArH); EI-MS m/z: 438(MHþ).
Anal. calc. for C21H28NO3PS2: C: 57.64, H: 6.45; N: 3.20. Found: C: 57.61,
H: 6.43, N: 3.47.
ACKNOWLEDGMENTS
This project was supported by NSFC.
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Received in the UK February 24, 2000