Synthesis of new α or γ-functionalized hydroxymethylphosphinic acid derivatives

Article abstract of DOI:10.1016/j.tet.2003.11.045

The syntheses of new γ-ethoxycarbonyl- and α-amino-alkyl hydroxymethylphosphinic acid derivatives are described. These compounds were conveniently prepared by Michael addition or Kabachnik-Fields reaction of an original precursor, ethyl benzyloxymethyl hydrogenophosphinate, respectively to α,β-unsaturated esters using a basic activation or to imines. Selective deprotection of the alcohol function was achieved by hydrogenolysis on Pd/C, whereas lithium bromide was used to selectively cleave the phosphinate ester group. Acidic hydrolysis readily gave the free hydroxymethylphosphinic acids.

Full text of DOI:10.1016/j.tet.2003.11.045

Tetrahedron 60 (2004) 877–884
Synthesis of new a or g-functionalized hydroxymethylphosphinic
acid derivatives
*
Henri-Jean Cristau, Agnes Herve and David Virieux
*
`
´
´
Laboratoire de Chimie Organique, UMR 5076, Ecole Nationale Superieure de Chimie de Montpellier 8, Rue de l’Ecole Normale,
34296 Montpellier cedex 5, France
Received 14 July 2003; revised 1 October 2003; accepted 18 November 2003
Abstract—The syntheses of new g-ethoxycarbonyl- and a-amino-alkyl hydroxymethylphosphinic acid derivatives are described. These
compounds were conveniently prepared by Michael addition or Kabachnik–Fields reaction of an original precursor, ethyl benzyloxymethyl
hydrogenophosphinate, respectively to a,b-unsaturated esters using a basic activation or to imines. Selective deprotection of the alcohol
function was achieved by hydrogenolysis on Pd/C, whereas lithium bromide was used to selectively cleave the phosphinate ester group.
Acidic hydrolysis readily gave the free hydroxymethylphosphinic acids.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of a general precursor which could react with
various functional electrophiles.8 Herein, we describe the
synthesis of compounds 1–2, using a common precursor,
phosphinate 4b which is consequently added to a,b-
unsaturated esters or to imines (Scheme 1).
The phosphonic group [–P(O)(OH)2] belongs to a wide
range of biologically active compounds.1–4 But, its high
ionic character limits the transmembranar transport and
consequently some phosphonic acids derivatives show a
very low bioavailability.5 Searching for new biologically
active phosphorus compounds, we investigated the possi-
bility to use the hydroxymethylphosphinic group
[–P(O)(OH)(CH2OH)] as a substitute for the phosphonic
one. This substitution should modify the physical and
chemical properties of the substrates,6 particularly their
ionic character, and consequently improve their biological
activity. To evaluate the potential of such replacement, we
decided to synthesize new functionalized phosphinic acids
of structure 1 and 2, which can be considered as analogs of
valuable inhibitors of various proteases,7 the phosphinic
pseudo-dipeptides 3.
Scheme 1.
2. Results and discussion
2.1. Synthesis of hydroxymethylphosphinic acid 4a
We first chose to prepare hydroxymethylphosphinic acid 4a,
as common precursor of the target compounds. Dihydro-
genophosphinic acid, H3PO2 5 and formaldehyde were
selected as starting material.9 Reactions were performed in
various conditions using acidic activation (see Section 4).
Unfortunately, reaction mixtures were generally composed
by the unreacted H3PO2 5, the targeted hydroxymethyl-
phosphinic acid 4a and often with the di-addition product,
bis(hydroxymethyl)phosphinic acid 6 as a consequence of
the lack of selectivity of the reaction (Scheme 2).9b
Currently, in the syntheses of hydroxymethylphosphinic
derivatives, the hydroxymethyl group is introduced in the
last step. There are only few publications dealing with the
Keywords: Phosphinic acid; Kabachnik–Fields reaction; Ester group.
*
Corresponding authors. Tel.: þ33-4-67-14-43-14; fax: þ33-4-67-14-43-
In the best conditions, the use of 50% aqueous H3PO2 5 with
19; e-mail address: virieux@cit.enscm.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.045

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H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
8 led to a 4b/10 ratio of 96:4, thus allowing the purification
by a two-step extraction procedure. Compound 4b was
isolated in 65% yield.
2.4. Synthesis of ethyl benzyloxymethylphosphinate 12
Scheme 2.
As a final step for the preparation of compound 12, the
esterification of acid 4b was first accomplished with triethyl
orthoformate. Indeed, trialkyl orthoformates have been
extensively used to form phosphonates and phosphinates
from the corresponding acids.13 Esterification of 4b was
performed in refluxing chloroform. Thus, reaction of 4b
with 1 equiv. of triethyl orthoformate afforded after 48 h,
the ester 12, isolated in 70% yield after purification by
extraction (Scheme 4).
an excess (1.5 equiv.) of paraformadehyde in the presence
of hydrochloric acid (1.5 equiv.) in refluxing ethanol, after
12 h, afforded the mono-adduct 4a in 76% yield with only
starting H3PO2 5 as side-product. Unfortunately, all
attempts to separate 4a from 5 either by selective
precipitation or by separation after chemical modification
failed.
2.2. Synthesis of ethyl benzyloxymethylphosphinate 12
as precursor
Then, we turned to the synthesis of another precursor: ethyl
benzyloxymethylphosphinate 12, in which the acidic
function is protected by an ester group and the hydroxy-
methyl substituent is protected as benzyloxymethyl group,
allowing an easier purification step and avoiding retro-
formylation reaction which can occur in basic media.10
Scheme 4.
The use of an excess of triethyl orthoformate did not
improve the yield of compound 12 but lead to the formation
of a major by-product exhibiting a 31P signal at d
38.37 ppm. This compound was identified by its 31P, H,
Preparation of compound 12 was achieved in two steps:
synthesis of benzyloxymethylphosphinic acid 4b, followed
by its esterification.
1
13C, IR and mass spectra as ethyl (diethoxymethyl)
phosphinate 13. Its formation can be rationalized by a SN
reaction of the tricoordinated phosphorus atom of com-
pound 12 to the central atom of triethyl orthoformate as
reported by Gallagher et al.13a and Schwabacher et al.13b for
the formation of methyl dimethoxymethylphosphinate in the
esterification reaction of bis(hydrogeno)phosphinic acid
with trimethylorthoformate. Phosphinate 13 could also be
the result of the P-alkylation reaction of acid 4b with triethyl
orthoformate followed by the esterification of
the intermediate acid 14. But no trace of 14 was detected
by 31P NMR analysis (Scheme 5).
2.3. Synthesis of benzyloxymethylphosphinic acid 4b
Phosphinic acid 4b was prepared by a silyl-Arbuzov
reaction using benzyloxymethylchloride 9 and in situ
generated bis(trimethylsilyl)phosphonite 8, formed accord-
ingly to the literature (Scheme 3).11 Unfortunately, besides
the desired phosphinic acid 4b, the symmetric phosphinic
acid 10 was obtained as the result of a double silyl-Arbuzov
reaction of 9 with phosphonite 8.
Scheme 3.
The lack of selectivity may probably be attributed to the
high reactivity of the benzyloxymethyl chloride 9. A similar
observation was pointed out by Coward and Grobelny for the
reaction of the phosphonite 8 with 1 equiv. of N-(bromo-
methyl)phthalimide.12 Dihydrogenophosphinic acid 5
(10%) and hydrogenophosphonic acid 11 (9%) were also
formed as by-products. The latter probably resulted from the
oxidation of 8 known to be a very sensitive and pyrophoric
compound.11 Dilution of the reagent 9 in dry dichloro-
methane and subsequent dropwise addition to the phospho-
nite 8 solution did not improve the yield of 4b with a 4b/10
ratio of 82:18. But, the use of a fourfold excess of compound
Scheme 5.
Kinetic monitoring of the reaction, by 31P NMR was
performed to determine the best conditions for the formation
of phosphinate 12. Concentrations of 4b, 12 and 13 are
plotted versus time in Figure 1. Indeed, after 16 h, the
phosphinate 12 is the only detected product even with an
excess of esterification reagent.
Another attempt to improve the formation of phosphinate
12 using another esterification reagent was successfully

H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
879
presence in the reaction mixture of four unidentified
compounds (31Pd¼44.36, 49.48, 49.85 and 52.91 ppm in
the reaction with 16a and d¼46.60, 48.52, 48.88 and
48.91 ppm in the reaction with 16b) which are difficult to
separate from the desired Michael adducts.
We found that the selectivity of the formation of adducts
depended on the quantity of potassium tertiobutoxide used,
as shown in the reaction of 12 with ethyl methacrylate 16b
(Table 1). The use of 0.20 equiv. of potassium tertio
butoxide afforded phosphinate 17b as a diastereoisomeric
mixture (ed¼18%) in 91% yield. No side-product was
detected in the reaction mixture and after neutralization,
compound 17b was isolated in 69% yield by column
chromatography. However, higher amounts of tBuOK
induce a notable decrease of the yield (Table 1).
Figure 1.
accomplished using tetraethyl orthosilicate 15, recently
employed to esterify phosphinic acids.14 Acid 4b was thus
treated with 1 equiv. of tetraethyl orthosilicate 15 in
refluxing toluene for 12 h to quantitatively afford ester 12,
isolated in 97% yield. (Scheme 6). As reported by
Montchamp,14 simple partioning of the crude product
between acetonitrile and hexane is sufficient to provide
almost pure phosphinate by elimination of the non-polar
silicon derived impurities.
Table 1. Influence of tBuOK amount on the Michael addition of
phosphinate 12 to 16b
tBuOK
(equiv.)
Conversion
(12)
(%)
31P NMR yield
(17b)
(%)
Isolated yield
(17b)
(%)
de
(17b)
(%)
0.20
0.25
0.30
100
100
100
91
79
36
69
20
—
18
11
5
2.6. Aminoalkylation of phosphinate 12 with imines
N-Protected ethyl a-aminoalkyl-benzyloxymethyl-phosphi-
nates 19a–c were prepared by a Kabachnik–Fields reaction
involving the addition of phosphinate 12 to the correspond-
ing aldimines 18a–c or to the 1,3,5-N-benzyl-1,3,5-
hexahydrotriazine 18d. The reaction of phosphinate 12
with 1 equiv. of imines 18a and 18b in refluxing ethanol
afforded the expected phosphinates 19a and 19b, respec-
tively in 81 and 56% yields as an equimolar mixtures of two
diastereoisomers resulting from the chirality of the phos-
phinate group and the a-amino carbon atom (Scheme 8).
Scheme 6. Ethyl benzyloxymethylphosphinate 12 has thus been prepared in
two steps and isolated in 63% overall yield (Schemes 3 and 6).
2.5. Michael addition of phosphinate 12 to
a,b-unsaturated esters
Michael addition of phosphinate 12 to a,b-unsaturated
esters was performed according to a method previously
developed in our laboratory,4 using a catalytic tertio
butoxide activation (Scheme 7). Compound 12 was reacted
with 1 equiv. of ethyl acrylate 16a or ethyl methacrylate 16b
in dry THF in the presence of 0.25 equiv. of potassium
tertiobutoxide to afford the corresponding Michael
products 17a and 17b in 69 and 79% yields, respectively.
Phosphinate 17b was formed as a mixture of two diastereo-
isomers resulting from the two chiral centers. Diastereo-
selectivity is poor, with a 11% diastereoisomeric excess.
Compounds 17a and 17b were purified by column
chromatography on silica gel and isolated, respectively in
26 and 20% yields. These low isolated yields result from the
Scheme 8.
The 31P NMR analysis of the crude reaction mixture showed
the presence of benzyloxymethylphosphinic acid 4b as
side-product (respectively 12% and 29%). A possible
explanation for the formation of the acid 4b is a dealkylation
reaction of ethyl phosphinate 12 by nucleophiles present in
the reaction mixture such as amines.15 Theses amines could
thus react with phosphinate 12 by a nucleophilic attack of
the nitrogen atom on the ethyl ester phosphinic group,
leading to the formation of acid 4b (Scheme 9). This
hypothesis is supported by the fact that, in a control
experiment, the reaction of phosphinate 12 with
Scheme 7.

880
H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
corresponding phosphinate 20 in 95% yield. Selective
cleavage of the ester group was achieved by using a two
fold excess of lithium bromide in refluxing acetonitrile for 5
days.19 The corresponding salt 21 was isolated after
concentration in 100% yield. Finally, compound 17b was
totally deprotected by an excess of 35% hydrochloric acid at
80 8C for 3 h, affording the phosphinic acid 22 in 98%
yield.6
Scheme 9.
The same deprotection methodology can be performed on
a-aminoalkylphosphinic acid (Scheme 11). The phosphinic
acid function of 19b was selectively deprotected in the
presence of an excess of sodium hydroxide to afford the
phosphinic acid 23 isolated in quantitative yield (Scheme
11) while total deprotection of both hydroxy and amino
groups was achieved by hydrogenolysis on Pd/C leading to
the phosphinate 24 isolated in 96% yield.
dibenzylamine resulted in the quantitative transformation of
ester 12 into acid 4b.
Consequently, the addition of a slight excess (1.2 equiv.) of
imine 18a afforded the corresponding phosphinate 19a in
96% yield and 4b in only 4%. This result implies that the
addition reaction of phosphinate 12 to the aldimine is faster
than the dealkylation reaction. Phosphinate 19a was then
purified on silica gel by column chromatography and
isolated in 70% yield as a mixture of two diastereoisomers.
Similar results were obtained with imines 18b and 18c
which led to the corresponding phosphinates 19b and 19c
which were isolated after column chromatography in 84 and
69% yields, respectively. Phosphinate 19a constitutes a
precursor of the analog of phosphonoleucine which is
known to inhibit leucine aminopeptidase.16
Then, we applied the reaction to the 1,3,5-N-benzyl-1,3,5-
hexahydrotriazine 18d in order to prepare the analog of
phosphonoglycine (Scheme 9).17 Ethylphosphinate 12 was
first treated with 1 equiv. of the triazine 18d in refluxing
ethanol. In contrast to aldimines 18a–c, total disappearance
of 12 in this case needed 48 h. The resulting phosphinate
19d was formed in 50% yield, but isolated after column
chromatography in only 8% yield. This low yield is due to
the formation in the reaction mixture of four side-products at
d 49.20 and 49.30 ppm (23%) and at d 48.84 and 48.94 ppm
(5%). In the other hand, 4b was formed in only 4% yield.
Unfortunately, these side-products were very difficult to
separate from the targeted phosphinate 19d. Use of a 1.5
excess of triazine 18d increased the yield to 60%, and the
phosphinate 19d was isolated in 33% yield.
Scheme 11.
3. Conclusion
A new versatile and stable precursor for the introduction of
hydroxymethylphosphinic group, ethyl benzyloxymethyl
phosphinate 12, has been synthesized in two steps and
isolated in 65% overall yield. Subsequent reaction with
various electrophiles such as a,b-unsaturated esters in the
presence of catalytic amount of potassium tertiobutoxide
and imines or triazine afforded the corresponding
g-carboxy- or a-aminoalkylphosphinates. Total or selective
deprotections can be performed demonstrating the com-
patibility and the complementarity of the various protecting
groups. The synthetic sequence, described here, affords a
reliable and general access to this particular class of
functionalized phosphinic acids. Using the same precursor,
several aryl or heteroaryl hydroxymethylphosphinic acid
derivatives were prepared by palladium (0) catalyzed
arylation.20
2.7. Total or selective deprotections
Total or selective deprotections have been performed on
compound 17b (Scheme 10). The benzylic group was
removed by hydrogenolysis on Pd/C18 to give the
4. Experimental
4.1. General remarks
All reactions involving air or moisture sensitive reagents or
intermediates were carried out under dry nitrogen in flame-
dried glassware. Reagents and solvents were purified before
use and stored under nitrogen atmosphere. All reactions
were monitored by TLC (Merk, SIL, G/UV254) or 31P NMR.
Merck silica gel (70–200 mm) was used for column
Scheme 10. Conditions and reagents: (i) H2-Pd/C, EtOH, Patm, rt; (ii) LiBr
(2 equiv.), MeCN, reflux, 3 days; (iii) excess 35% HCl, 80 8C, 3 h.

H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
881
chromatography. 1H, 13C and 31P NMR spectra were
recorded on a Bruker Ac 200 (1H at 200.13 MHz, 13C at
50.32 MHz and 31P at 81.01 MHz) and on a Brucker AC 250
spectrometers (1H at 250.13 MHz, 13C at 62.89 MHz and
31P at 101.25 MHz). Chemical shifts are expressed in ppm
and coupling constants in Hz. IR spectra were obtained with
Perkin–Elmer 377 and Nicolet FT-IR 210 spectrometers.
Mass spectra were measured with a Jeol JMS DX-300
spectrometer (positive FAB ionisation and High Resolution
using glycerol-thioglycerol or p-nitrobenzyl alcohol
matrix).
water (3£5 mL). The organic layer was dried over MgSO4
before the solvent was removed under reduced pressure to
afford a colourless oil (4.06 g). This oil was dissolved in
water (100 mL) and extracted with ethyl acetate (3£5 mL).
The aqueous layer was then continuously extracted with
dichloromethane for 5 h. The resulting organic layer was
dried over MgSO4 and the solvent was evaporated under
reduced pressure to afford benzyloxymethyl-phosphinic
acid 4b as a colourless oil in 65% yield (3.63 g,
19.52 mmol).
1
2
31P NMR (CDCl3): 29.40 (dt, JPH¼566.0 Hz, JPH
¼
1
4.2. Hydroxymethylphosphinic acid 4a
7.4 Hz). H NMR (CDCl3): 3.71–3.78 (2dd, ABX system,
dHA¼3.73, dHB¼3.77, JHAHB¼13.4 Hz, JPHA¼2.2 Hz,
2
2
Reactions conditions for the direct synthesis of hydroxy-
methylphosphinic acid 4a using H3PO2 5 or its ammonium
salt and the different forms of formaldehyde are listed in
Table 2. The best result is observed for entry 9 where 4a is
selectively obtained in 76% yield (Table 2).
2JPHB¼2.2 Hz, 2H, PCH2), 4.62 (s, 2H, PhCH2), 4.92 (bs,
1
3
OH), 7.08 (d, JPH¼566.0 Hz, JHH¼2.2 Hz, 1H, P-H),
7.34–7.39 (m, 5H, Ph). 13C NMR (CDCl3): 66.51 (d,
3
1JPC¼115.4 Hz, PCH2), 75.23 (d, JPC¼11.9 Hz, PhCH2),
128.15 (s, 2CH), 128.22 (s, CH), 128.58 (s, 2CH), 136,70 (s,
C). MS FABþ(NBA) m/z¼187 (17%) [MþH]þ, 91 (100%)
C7H7þ. HRMS calcd for C8H12O3P: 187.0534, found:
187.0531.
4.3. Preparation of ammonium phosphinate 7
Commercially available 50% aqueous phosphinic acid
(40 g, 301 mmol) was slowly added to 25% aqueous
ammonia (46.6 mL, 301 mmol) at 0 8C. The mixture was
allowed to reach room temperature and stirred over a period
of 5 h. Removal of water was achieved under reduced
pressure and followed by rigorous drying over P2O5 under
vacuum to obtain ammonium phosphinate 7 as a white solid
in 93% yield (23.3 g, 280 mmol).
4.3.2. Ethyl benzyloxymethyl-hydrogeno-phosphinate 12
(method 1). Triethyl orthoformate (2.2 mL, 13.20 mmol)
was added to a solution of benzyloxymethylphosphinic acid
4b (2.5 g, 13.20 mmol) in 70 mL of anhydrous chloroform.
The reaction mixture was refluxed for 48 h. The conversion
yield determined by 31P NMR was 77 whereas, 33% of acid
4b remained unchanged. As no evolution has been observed
after additional 3 h of stirring, the reaction mixture was
cooled to room temperature before addition of aqueous
KHCO3/K2CO3 (1 M). The biphasic mixture was stirred at
room temperature for additional 15 min before partition of
the organic and aqueous layers. The organic layer was dried
over MgSO4 before the solvent was removed under reduced
pressure to afford the phosphinate 12 as a colourless oil in
70% yield (2.15 g, 9.30 mmol).
4.3.1. Benzyloxymethyl-hydrogeno-phosphinic acid 4b.
Ammonium phosphinate 7 (10 g, 120.4 mmol) and hexa-
methyldisilazane (25.6 mL, 120.4 mmol) were heated
together under nitrogen at 100–110 8C until all the
ammonia by-product has evolved (ca. 2 h) The mixture
was then cooled to 0 8C before the addition of dry
dichloromethane (100 mL). After 15 min stirring at 0 8C, a
solution of benzyloxymethylchloride (4.17 mL, 30.1 mmol)
in 50 mL of dry dichloromethane was added dropwise over
15 min. The resulting mixture was allowed to warm to room
temperature and stirred for 12 h. Then, 18% HCl (5 mL) was
slowly added and the mixture stirred for additional 15 min.
The mixture was filtered and the solution was extracted with
4.3.3. Ethyl benzyloxymethyl-hydrogeno-phosphinate 12
(method 2). Tetraethyl orthosilicate (1.8 mL, 8.26 mmol)
was added to a solution of benzyloxymethylphosphinic acid
4b (1.5 g, 8.26 mmol) in 15 mL of dry toluene. The reaction
mixture was refluxed for 12 h. At this time, the 31P NMR
Table 2. Synthesis of hydroxymethylphosphinic acid 4a
Entry
Formaldehyde source
Phosphorus reagent
Conditions
Reaction mixture (%)
6
4b
7
1
2
3
4
5
6
7
8
Trioxymethylene (1 equiv.)
Trioxymethylene (1 equiv.)
Trioxymethylene (1 equiv.)
Trioxymethylene (1 equiv.)
37% aq. Formaldehyde (1 equiv.)
37% aq. Formaldehyde (1 equiv.)
37% aq. Formaldehyde (1 equiv.)
Paraformaldehyde (1 equiv.)
Paraformaldehyde (1.5 equiv.)
Paraformaldehyde (1 equiv.)
Gazeous Formaldehyde
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
anh. H3PO2
aq. H3PO2
aq. H3PO2
aq. H3PO2
MeOH, 7d, 20 8C, HCl (1 equiv.)
H2O, 7d, 20 8C, HCl (1 equiv.)
MeOH, 7d, 60 8C, HCl (1 equiv.)
H2O, 7d, 60 8C, HCl (1 equiv.)
100
98
99
31
73
28
66
46
24
6
—
2
1
—
—
66
27
54
34
54
76
77
54
71
83
83
3
MeOH, 2.5 days, 20 8C, NH4Cl (1 equiv.)
H2O, 2.5 days, 20 8C, NH4Cl (1 equiv.)
MeOH, 2.5 days, 60 8C, NH4Cl (1 equiv.)
EtOH, 7 days, 80 8C, HCl (1 equiv.)
EtOH, 7 days, 80 8C, HCl (1.5 equiv.)
H2O, 7 days, 80 8C, HCl (1 equiv.)
EtOH, 7 h, 80 8C, PTSA (2 equiv.)
EtOH, 2 days, 110 8C, HCl (1 equiv.)
EtOH, 2 days, 110 8C, HCl (1.2 equiv.)
EtOH, 2 days, 110 8C, HCl (1.5 equiv.)
—
18
—
—
—
17
—
14
5
9
10
11
12
13
14
46
15
12
5
Paraformaldehyde (1 equiv.)a
Paraformaldehyde (1.2 equiv.)a
Paraformaldehyde (1.5 equiv.)a
12
a
Reactions were performed in a caped thick-wall tube.

882
H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
analysis showed that all the acid 4b had quantitatively been
transformed to the phosphinate 12. The mixture was then
allowed to cool to room temperature and the solvent was
removed under reduced pressure. According to Montchamp
procedure, the oily residue was purified by partition
between CH3CN and hexane. The hexane layer contained
the non-polar silicon-derived by-products, while the polar
phosphinate remained in the CH3CN layer. This latter was
concentrated under reduced pressure to afford phosphinate
12 as a colourless oil in 97% yield (1.72 g, 8.03 mmol).
Further purification can be accomplished using chroma-
tography on silica gel with dichloromeyhane as eluent.
64.92 (d, 1JPC¼110.2 Hz, PCH2O), 75.17 (d, 3JPC¼12.6 Hz,
CH2), 128.05 (CH), 128.,11 (s, CH), 128.51 (s, CH), 136.,67
(s, C), 172.15 (d, JPC¼16.4 Hz, CO). IR (NaCl): 1745
3
(CvO), 1220 (PO); 1100, 1080, 1040 (O–C). MS FABþ
þ
(NBA) m/z¼315 (100%) [MþH]þ, 91 (86%) C7H7
.
4.4.2. Ethyl (2-ethoxycarbonyl-1-propyl)-(benzyloxy-
methyl)-phosphinate 17b. 31P NMR (CDCl3): 48.82
1
(59%) and 49.87(41%). H NMR (CDCl3): 1.04–1.16 (m,
9H, CH3, 2CH3), 1.68–1.71 (m, 1H, CH), 2.14–2.23 (m,
1H, CH), 2.73–2. 75 (m, 1H, H), 3.54–3.59 (m, 2H, CH2),
3.84–4.00 (m, 4H, 2CH2), 4.42–4.45 (m, 2H, CH2), 7.11–
7.28 (5H, CH). 13C NMR (CDCl3): 16.47 (s, CH3), 18,90
(d, 3JPC¼6.0 Hz, CH3), 21.02 (d, 3JPC¼6.0 Hz, CH3), 21.46
1
31P NMR (CDCl3): 32.22 (dquint., JPH¼552.5 Hz,
1
3
3
1
2JPH¼8.7 Hz). H NMR (CDCl3): 1.33 (t, JH–H¼7.1 Hz,
3H CH3), 3.73–3.81 (2 dd, ABX system, dHA¼3.76,
dHB¼3.80, 2JHAHB¼213.8 Hz, 2JPHA¼4.2 Hz, 2JPHB¼10.1
Hz, 2H, PCH2), 4.08–4.19 (m, 2H, POCH2), 4.58 (s, 2H,
(d, JPC¼6.0 Hz, CH3), 32.13 (d, JPC¼93.8 Hz, CH2),
1
2
32.,22 (d, JPC¼93.8 Hz, CH2), 35.93 (d, JPC¼3.3 Hz,
CH), 35.96 (d, 2JPC¼2.7 Hz, CH), 63.11 (s, CH2), 63.,24 (d,
2JPC¼4.9 Hz, CH2), 67.65 (d, JPC¼109.8 Hz, CH2), 67,85
1
1
3
1
3
PhCH2), 7.08 (d, JPH¼552.5 Hz, JHH¼2.3 Hz, 1H, PH),
(d, JPC¼109.4 Hz, CH2), 77.44 (d, JPC¼12.6 Hz, CH2),
7.30–7.34 (m, 5H, Ph). 13C NMR (CDCl3): 16.32 (d, 3JPC
¼
77.48 (d, JPC¼12.6 Hz, CH2), 130.41, 130.47, 130.49,
3
2
6.0 Hz, CH3), 62.83 (d, JPC¼7.0 Hz, POCH2), 65.82
130.86: 6-CH, 139.21, 139.29, 177.63, 177.46 (4C). IR
(NaCl): 1740 (CvO); 1220 (PO); 1100, 1040 (OC). MS
FABþ(NBA) m/z¼329 (100%) [MþH]þ, 91 (93%) C7H7þ.
1
3
(d, JPC¼114.2 Hz, PCH2), 75.28 (d, JPC¼11.9 Hz,
PhCH2), 128.13 (s, 2CH), 128.28 (s, CH), 128.57 (s,
2CH), 136.56 (s, C). IR (NaCl): 1200 (PO); 1125 (COC);
1100, 1050 (POC). MS FABþ(NBA) m/z¼215 (21%)
[MþH]þ; 91 (100%) C7H7þ. HRMS calcd for C10H16O3P:
251.0837, found: 215.0815.
4.5. General procedure for preparation of phosphinates
19a–d
In a typical procedure, a solution of imine or hexahydro-
triazine 18a–d (1.2 equiv., 1 mol L21) in anhydrous ethanol
is added dropwise to a solution of phosphinate 12 (1 equiv.,
0.2 mol L21) in anhydrous ethanol. The mixture is refluxed
under nitrogen until the complete consumption of starting
material 12 (generally in 12 h; excepted for 19d; 48 h were
needed). The reaction mixture is then concentrated and
chromatographied on silica gel (gradient of elution: from
petroleum ether/ethyl acetate, 90:10 to ethyl acetate 100%)
to afford the phosphinate 19a–d.
4.4. General procedure for preparation of phosphinates
17. Synthesis of 17b
A solution of phosphinate 12 (1 g, 4.67 mmol) in 8 mL of
anhydrous THF was added dropwise to precooled (0 8C, ice
bath) suspension of potassium tertiobutoxide (105 mg,
0.93 mmol) in 10 mL of anhydrous THF. The resulting
mixture was stirred at 0 8C for 15 min. After this time, ethyl
methacrylate (0.57 mL, 4.67 mmol) was added dropwise.
The reaction mixture was allowed to warm to room
temperature and stirred under nitrogen for 12 h. At this
time, 31P NMR analysis of the mixture showed that all the
phosphinate 12 had reacted and that phosphinate 17b had
been formed as a mixture of two diastereoisomers in 91%
yield. The reaction mixture was then neutralized by addition
of aqueous HCl (1N)and diluted with 20 mL of water. The
solution was extracted with ethyl acetate (3£30 mL). The
organic layer was first washed with brine and then dried
over MgSO4. Evaporation of the solvent afforded the crude
phosphinate 17b as a yellow oil which was purified by flash
chromatography on silica gel (gradient for elution: from
petroleum ether/ethyl acetate, 80:20 to ethyl acetate 100%)
to afford the pure phosphinate 17b as a mixture of two
diastereoisomers (59:41) in 69% yield (yellow oil, 1.05 mg,
3.22 mmol).
4.5.1. Ethyl (N-benzylamino-phenyl-methyl)-benzyloxy-
methyl phosphinate 19a. 31P NMR (CDCl3): 45.42 (s,
1
47%), 46.10 (s, 53%). H NMR (CDCl3): 1.08, 1.31 (2 t,
3JPH¼7.0, 7.0 Hz, 3H, CH3), 3.20 (bs, NH), 3.42–4.21 (m,
7H, CH2, CH2, CH, CH2), 4.45, 4.57 (2s, 2H, PCH2), 7.26–
7.40 (m, 15H, Ph). 13C NMR (CDCl3): 16.40, 16.73
3
3
(2d, JPC¼5.2, 5.6 Hz, CH3), 51.17, 51.31 (2d, JPC¼14.9,
1
16.7 Hz, CH2), 58.43, 59.99 (2d, JPC¼104.2, 100.1 Hz,
CH), 61.70, 62.31 (2d, 2JPC¼7.1, 7.4 Hz, CH2), 63.94, 64.15
1
3
(2d, JPC¼111.3, 111.0 Hz, CH2), 74.92, 75.34 (2d, JPC
¼
15.1, 15.2 Hz, CH2), 127–128,93 (Ph), 135,13, 135,20 (2d,
2JPC¼8.2, 8.6 Hz, C), 136.84, 137.02 (2s, C), 139.30,
139.34 (2s, C). MS FABþ(NBA) m/z¼410 (5%) [MþH]þ,
196 (16%) [(PhCH2N(H)(Ph)CH]þ, 91 (100%) C7H7þ. IR
(NaCl): 1220 (PO), 1110 (POC). HRMS calcd for
C24H29O3: 410.1885, found: 410.1870.
4.4.1. Ethyl (2-ethoxycarbonyl-1-ethyl)-(benzyloxy-
1
methyl)-phosphinate 17a. 31P NMR (CDCl3): 49.88. H
4.5.2. Ethyl 1-(1-N-benzylamino-3-methyl-butyl)-benzyl-
oxy-methyl phosphinate 19b. 31P NMR (CDCl3): 51.29 (s,
52%), 51.56 (s, 48%). 1H NMR (CDCl3): 0.77–0.95 (m, 3H,
CH3), 1.32–1.37 (m, 3H, CH3), 2.00–2.04 (m, 2H, CH2),
3.15 (bs, NH), 3.85–4.15 (m, 8H, 3CH2, 2CH), 5.26–5.30
(m, 2H, CH2), 7.25–7.63 (m, 10H, Ph). 13C NMR (CDCl3):
NMR (CDCl3): 1.20 (t, 3JHH¼6.3, 3H, CH3), 1.27 (t, 3JHH
¼
7.0, 3H, CH3), 1.24–1.30 (m, 1H, CH2), 2.02–2.15 (m, 1H,
CH2), 3.67–3.70 (m, 2H, CH2), 3.91–4.55 (m, 6H, 3CH2),
4.55 (s, 2H, CH2), 7.25–7.33 (m, 5H, CH). 13C NMR
3
(CDCl3): 14.13 (s, CH3), 16.53 (d, JPC¼5.9 Hz, CH3),
1
3
3
3
21.73 (d, JPC¼95.3 Hz, CH2), 26.,32 (d, JPC¼2.6 Hz,
16.66, 16.76 (2d, JPC¼5.6, 5.2 Hz, CH3), 21.47 (d, JPC
¼
2
4
CH2), 60.86 (s, CH2), 60.91 (d, JPC¼4.8 Hz, POCH2),
23.1 Hz, CH), 23.43 (d, JPC¼10.4 Hz, CH3), 24.43, 24.68

H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
883
1
(2d, 4JPC¼11.2, 10.0 Hz, CH3), 37.68, 38.15 (2d, 2JPC¼2.2,
4.1 Hz, CH2), 51.87 (d, 1JPC¼105.7 Hz, 11CH), 52.39, 52.47
(2d, 3JPC¼6.6, 3.7 Hz, CH2), 52.60 (d, 1JPC¼99.4 Hz, CH),
31P NMR (CDCl3): 52.22 (59%), 52.85 (41%). H NMR
(CDCl3): 1.15–1.25 (m, 9H, 3CH3), 1.67–1.89 and 2.15–
2.37 (m, 2H, CH2), 2.80–2.86 (m, 2H, CH), 3.77–3.78 (m,
2H, CH2), 4.01–4.11 (m, 4H, 2CH2), 4.79 (bs, OH). 13C
2
61.16, 61.19 (2d, JPC¼7.4, 7.8 Hz, CH2), 63.49, 64.06
1
3
3
(2d, JPC¼104.2, 100.9 Hz, CH2), 75.25, 75.31 (d, JPC
¼
NMR (CDCl3): 14.02 (s, CH3), 16.47 (d, JPC¼5.6 Hz,
3
12.3, 12.3 Hz, CH2), 127.16, 127.19, 127.22, 127.44,
127.69, 128.00, 128.06, 127.06, 127.08, 128.13, 128.15,
128.19, 128.30, 128.38, 128.45, 128.50 (CHAr), 136.81,
136.85 (2s, C), 140.06, 140.14 (2s, C). MS FABþ(NBA)
m/z¼390 (18%) [MþH]þ, 178 (100%) [(PhCH2N(H))
CH3), 19.02, 19.13 (2d, JPC¼8.9, 9.3 Hz, CH3), 29.15,
1
2
29.20 (2d, JPC¼89.7, 89.9 Hz, CH2), 33.68 (d, JPC
¼
3.3 Hz, CH), 58.65, 59.14 (2d, 1JPC¼106.1, 106.1 Hz, CH2),
60.80 (s, CH2), 61.01, 61.14 (2d, 2JPC¼13.0, 13.0 Hz, CH2),
3
175.38, 175.51 (2d, JPC¼8.9, 8.9 Hz, C). IR (NaCl): 3390
þ
(Me2CHCH2)]CHþ, 91 (100%) C7H7 , 77 (10%) Phþ. IR
(OH); 1730 (CvO); 1210, 1180 (PO); 1030 (OC). MS
FABþ(NBA) m/z¼239 (100%), [MþH]þ; 211 (8%),
[MþH–Et]þ.
(NaCl): 2990, 1240, 1220 (PO), 1110 (POC). HRMS calcd
for C22H33O3NP: 390.2207, found 390.2198.
4.5.3. Ethyl benzyloxymethyl-1-(N-diphenylmethyl-
amino)-1-cyclohexyl-methyl phosphinate 19c. 31P NMR
(CDCl3): 50.72 (s, 49%), 51.42 (s, 51%). 1H NMR (CDCl3):
1.17–1.42 (m, 10H), 1.33–1.40 (2t, 3JHH¼7.1, 7.2 Hz, 3H,
CH3), 2.23 (bs, 1H, CH), 2.89, 2.93 ppm (2 bs, 1H, NH),
3.78–3.82 (m, 2H, CH2), 4.00–4.66 (m, 4H, 2CH2), 5.20,
5.28 (2 bs, 1H, CH), 7.20–7.40 (m, 15H, Ph). 13C NMR
4.5.6. Lithium (2-ethoxycarbonyl-1-propyl)-(benzyloxy-
methyl)-phosphinate 21. Lithium bromide (81 mg,
0.92 mmol) was added to a solution of phosphinate 17b
(150 mg, 0.46 mmol) in 5 mL of CH3CN. The reaction
mixture was refluxed for 5 days and the solvent is
evaporated to quantitatively afford compound 21 (141 mg,
0.46 mmol) as a yellow oil.
3
(CDCl3): 16.66, 16.89 (2d, JPC¼5.2, 5.2 Hz, CH3), 26.18,
26.28, 26.50, 26.67, 26.86, 26.93, 28.11, 28.89, 28.93,
31.37, 31.57, 31.62 (5CH2), 38.39, 38.73 (2d, JPC¼6.3,
31P NMR (D2O): 51.61. 13C NMR (D2O): 13.7 (s, C), 19.05
2
3
1
(d, JPC¼8.1 Hz, CH3), 32.31 (d, JPC¼91.3 Hz, CH2),
1
2
6.7 Hz, CH), 56.81, 57.07 (2d, JPC¼99.5, 91.5 Hz, CH),
34.89 (d, JPC¼23.0 Hz, CH), 62.34 (s, CH2), 68.38 (d,
60.63, 60.78 (2d, 2JPC¼6.1, 6.3 Hz, CH2), 65.05, 65.08 (2d,
1JPC¼109.7 Hz, CH2), 75.13 (d, JPC¼11.5 Hz, CH2),
3
3
1JPC¼101.9, 97.1 Hz, CH2), 65.44, 65.74 (2d, JPC¼8.2,
128.72, 128.93, 129.10 (s, 5CH), 137.57 (s, C), 185.35 (d,
4JPC¼9.8 Hz, C). IR (NaCl): 3300 (OH); 1750 (CvO);
1225 (PO); 1105 (OC).
11.9 Hz, CH), 75.17, 75.26 (2d, 3JPC¼11.9, 12.6 Hz, CH2),
127.16, 127.19, 127.22, 127.44, 127.69, 128.00, 128.06,
128.12, 128.29, 128.34, 128.44, 128.50 (CHAr), 136.81,
136.88 (2s, C), 143.26, 143.49 (2s, C), 143.59, 143.83
(C). MS FABþ(NBA) m/z¼492 (5%) [MþH]þ,þ 278
(33%) [(Ph2CHN(H)) (Cy)]CHþ, 167 (100%) C7H7 . IR
(NaCl): 2950, 2870, 1220 (PO); 1105 (POC). MS HR
(NBA): HRMS calcd for C24H29NO3P: 410.0385, found
410.0368.
4.5.7. (2-Carboxy-1-propyl)-(hydroxymethyl)-phos-
phinic acid 22. Phosphinate 17b (160 mg, 0.49 mmol)
was stirred with 35% aqueous HCl (0.5 mL, 15 equiv.)
at 80 8C for 5 h. Neutralisation with 2N aqueous
NaOH followed by evaporation of the solvent and drying
over P4O10 afforded acid 22 in 98% yield (87 mg,
0.48 mmol).
4.5.4. Ethyl 1-(N-benzylaminomethyl)-benzyloxymethyl
1
1
phosphinate 19d. 31P NMR (CDCl3): 48.40 (s). H NMR
31P NMR (D2O): 40.88. H NMR (D2O): 1.61 (br s, 3H,
3
(CDCl3): 1.34 (t, JHH¼7.0 Hz, 3H, CH3), 2.15 (bs, NH),
CH3), 1.85–2.08 (m, 1H, CH), 2.29–2.48 (m, H, CH),
2.85–3.42 (m, 1H, CH), 4.00 (br s, OH), 10.16 (bs, OH). 13C
3.61–3.67 (dd, 2H, PCH2N), 3.76–3.93 (m, 4H, PCH2,
PhCH2N), 4.07–4,66 (m, 2H, POCH2), 4.61 (s, 2H,
PhCH2O), 7.27–7.37 (m, 10H, 2Ph). 13C NMR (CDCl3):
3
NMR (D2O): 21.21 (d, JPC¼7.4 Hz, CH3), 38.44 (d,
1
JPC¼3.2 Hz, CH), 47.61 (d, JPC¼91.91 Hz, CH2), 48.68
3
1
1
3
16.64 (d, JPC¼5.2 Hz, CH3), 44.32 (d, JPC¼105.7 Hz,
(d, JPC¼94.5 Hz, CH2), 182.33 (d, JPC¼7.8 Hz, C). IR
(NaCl): 3350 (OH); 1710 (CvO); 1225 (PO). MS FABþ
(NBA) m/z¼183 (100%) [MþH]þ.
3
PCH2N), 54.97 (d, JPC¼15.3 Hz, PhCH2N), 63.99 (d,
1JPC¼109.8 Hz, PCH2O), 61.33 (d, JPC¼7.1 Hz, POCH2),
2
3
75.25 (d, JPC¼12.3 Hz, PhCH2O), 127.25 (s, CH), 128.08
(s, CH), 128.15 (s, CH), 128.28 (s, CH), 128.45 (s, CH),
136.87 (s, C), 139.13 (s, C). MS FABþ(NBA) m/z¼
334 (5%) [MþH]þ, 120 (30%) PhCH2N(H)CHþ2 ,91 (100%)
C7H7þ. MS HR (NBA): HRMS calcd for C18H25NO3P:
334.1572, found 334.1563.
4.5.8. 1-(1-N-Benzylamino-3-methyl-butyl)-benzyloxy-
methyl phosphinic acid 23. Same procedure as described
for 17b. 31P NMR (D2O): 39.06 (s). 1H NMR (D2O): 1.01–
1.35 (m, 6H, CH3), 1.63–1.97 (m, 2H, CH2), 3.21 (bs, NH),
3.82–4.12 (m, 5H, CH, 2CH2), 4.61 (s, 2H, CH2) 7.26–7.38
(10H, Ph), 8.2 (bs, OH). 13C NMR (D2O): 21.41 (s, CH3),
22.15 (s, CH3), 24.78 (d, 3JPC¼7.1 Hz, CH), 35.53 (s, CH2),
4.5.5. Ethyl (2-ethoxycarbonyl-1-propyl)-(hydroxy-
methyl)-phosphinate 20, hygrogenolysis of 17b. Pd/C
10% (212 mg, 0.20 mmol) was added to a solution of
phosphinate 17b (330 mg, 1 mmol) in 10 mL of absolute
ethanol. The mixture was placed under hydrogen at
atmospheric pressure and room temperature. After con-
sumption of the required volume of nitrogen, the mixture
was filtered on celite and the filtrate was concentrated under
reduced pressure to afford phosphinate 20 as a yellow oil in
95% yield (227 mg, 0.95 mmol).
1
49.76 (d, JPC¼92.6 Hz, CH2), 50.27 (s, CH2), 65.72
1
3
(d, JPC¼118.0 Hz, CH2), 75.48 (d, JPC¼13.4 Hz,
CH2), 128.18, 128.36, 128.47, 129.04, 129.49, 130.89 (s,
CHAr), 130.03 (s, C), 136.35 (s, 19C). MS FABþ(NBA)
3
m/z¼362 (21%) [MþH]þ, 178 (100%) PhCH2N(Me2CH
CH2)CHþ, 91 (100%) C7H7þ, 77 (5%) Phþ. IR (NaCl)
3320 (OH), 1225 (PO), 1105 (POC). MS HR (NBA);
HRMS calcd for C20H28O3NP: 362.1513, found
362.1542.

884
H.-J. Cristau et al. / Tetrahedron 60 (2004) 877–884
Valiant, M. E.; Mellin, T. N.; Busch, R. D. J. Med. Chem.
1988, 31, 1772–1778. (d) Grobelny, D.; Wrondak, E. W.;
Galardy, R. E.; Oroszlan, S. Biochem. Biophys. Res. Commun.
1990, 169, 1111–1116.
4.5.9. Ethyl 1-(1-amino-3-methyl-butyl)-hydroxymethyl
phosphinate 24. A solution of 19 (140 mg, 0,36 mmol,
1 equiv.) in 5 mL of ethanol was added to a solution of
sodium hydroxide (1 N, 3 equiv.). The reaction mixture was
stirred 5 h at room temperature and was neutralized by the
addition of 1 N hydrochloric acid. After filtration and
concentration, 130 mg of a yellowish oil were recovered
(100% yield, 0.36 mmol).
8. (a) Rosenthal, A. F.; Gringauz, A.; Vargas, L. A. J. Chem. Soc.
Chem. Commun. 1976, 384–385. (b) Kapura, A.;
Shermergorn, I. M. J. Gen. Chem. USSR 1989, 59,
1137–1142. (c) Maier, L. Phosphorus Sulfur 1981, 11,
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Boganova, N. V.; Lutsenko, I. F. J. Gen. Chem. USSR 1989,
59, 2133–2134. (e) Froestl, W.; Mickel, S. J.; Hall, R. G.;
Sprecher, G.; von, G.; Strub, D.; et al. J. Med. Chem. 1995, 38,
3297–3312. (f) Reck, F.; Marmor, S.; Fisher, S.; Wuonola,
M. A. Bioorg. Med. Chem. Lett. 2001, 11, 1451–1454.
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(b) Mollier, H.; Vincens, M.; Vidal, M.; Pasqualini, R.; Duet,
M. Bull. Soc. Chim. Fr. 1991, 787–795. (c) Nazarov, Yu. V.;
Muslinkin, A. A. Russ. J. Appl. Chem. 2000, 73, 1043–1047.
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703–706.
31P NMR (CDCl3): 47.94 (s, 51%), 49.30 (s, 49%). 1H NMR
(CDCl3): 0.83–0.91 (m, 6H, 2CH3), 1.23–1.30 (m, 3H,
CH3), 1.29 (bs, NH2), 1.92–1.98 (m, 2H, CH2), 3.29–3.51
(m, 1H, CH) 3.85–4.26 (m, 5H, 2CH2, CH), 5.52 (bs, OH).
3
13C NMR (CDCl3): 16.50 (d, JPC¼4.8 Hz, CH3), 21.09
4
4
(d, JPC¼6.3 Hz, CH3), 23.17 (d, JPC¼3.72 Hz, CH3),
3
2
24.09 ppm (d, JPC¼9.3 Hz, CH), 37.27 (2d, JPC¼1.9,
2.2 Hz, CH2), 45.73, 47.61 (2d, 1JPC¼97.9, 90.8 Hz), 56.61,
1
2
56.99 (d, JPC¼103.8, 101.4 Hz, CH2), 62.18 (d, JPC
¼
117.0 Hz, CH2). MS FABþ(NBA) m/z¼210 (51%)
[MþH]þ, 86 (100%) H2N(Me2CHCH2)CHþ. IR (NaCl)
3310 (OH), 1230 (PO), 1115 (POC). HRMS calcd for
C8H21O3NP 210.1263, found 210,1259.
11. (a) Boyd, A. C.; Regan, Tetrahedron Lett. 1992, 33, 813–816.
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´
20. Cristau, H. J.; Herve, A.; Virieux, D. Synthesis 2003, in press.