Formation of 1-hydroxymethylene-1,1-bisphosphinates through the addition of a silylated phosphonite on various trivalent derivatives

Article abstract of DOI:10.1021/acs.joc.0c01182

An easily handled one-pot synthetic procedure was previously developed for the synthesis of bisphosphinates starting from acyl chlorides. Herein, other trivalent derivatives as acid anhydrides and activated esters were tested to form various bisphosphinates. This modulation of the reactivity can be controlled according to the nature of the acid derivative for the use of sensitive and functionalized substrates.

Full text of DOI:10.1021/acs.joc.0c01182

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Article
Formation of 1-Hydroxymethylene-1,1-Bisphosphinates through the
Addition of a Silylated Phosphonite on various Trivalent Derivatives
Jade Dussart-Gautheret, Julia Deschamp, Maelle Monteil, Olivier
Gager, Thibaut Legigan, Evelyne Migianu-Griffoni, and Marc Lecouvey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01182 • Publication Date (Web): 29 Jun 2020
Downloaded from pubs.acs.org on July 2, 2020
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Formation of 1-Hydroxymethylene-1,1-Bisphosphinates through
the Addition of a Silylated Phosphonite on various Trivalent
Derivatives
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Jade Dussart-Gautheret, Julia Deschamp*, Maelle Monteil, Olivier Gager, Thibaut Legigan, Evelyne
Migianu-Griffoni, and Marc Lecouvey*
Université Sorbonne Paris Nord, CSPBAT, CNRS, UMR 7244, F-93017 Bobigny Cedex, France
ABSTRACT: An easily handled one-pot synthetic procedure was previously developed for the
synthesis of bisphosphinates starting from acyl chlorides. Herein, other trivalent derivatives as acid
anhydrides and activated esters were tested in order to form various bisphosphinates. This modulation
of the reactivity can be controlled according to the nature of the acid derivative for the use of sensitive
and functionalized substrates.
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INTRODUCTION
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1-Hydroxymethylene-1,1-bisphosphonates (HMBPs) are phosphorylated molecules which occupy a
prominent place in clinic.1 Indeed, bisphosphonates are well known for their clinical use on bone
diseases and also for their antitumor potential activity.2 HMBPs have high affinity for hydroxyapatite,3
which is the main mineral found in bones, and they can chelate several metal ions, such as Mg(+II),
Ca(+II), and Fe(+II). HMBPs which are easily taken up by the bone tissue,4 are usually used as inhibitors
of bone resorption, and more precisely in osteoporosis, solid tumor bone metastases and myeloma bone
disease.5 These compounds also exhibit interesting antitumor effects on soft tissue primary tumor
models (breast, prostate…).5,6 However, their uses are limited by their unfavorable pharmacokinetics
and biodistribution. In fact, bisphosphonates hardly pass the biological membranes due to their negative
charges at physiological pH. Furthermore, their high hydrophilic nature causes a weak plasma half-life.
Moreover, because of their strong chelating properties, the biodistribution of bisphosphonates is
exclusively limited on bone tissue. These parameters therefore make them particularly difficult to
impregnate soft tissues and thus target soft tumors.7
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In this context, several strategies were developed to improve their cell uptake.8 One of them consists in
the replacement of the phosphonic acid group by a phosphinic acid moiety. This function should
represent a good compromise in terms of hydrophobicity by decreasing both acidity and ionicity at
physiological pH and chelating properties.
For the past years, our laboratory have developed efficient methodologies allowing the access to various
1-hydroxymethylene-1,1-bisphosphonates (HMBPs)9 and more recently to easily purified
1-hydroxymethylene-1,1-bis(H-phosphinates) (HMBPi)10 in short reaction times, and in rather good to
excellent yields. In both cases, HMBPs and HMBPi are synthesized starting from an acyl chloride
respectively in the presence of a commercially available silylated phosphite or a pre-formed silylated
phosphonite (Scheme 1).11
Scheme 1
Synthesis of HMBPs and HMBPi starting from acyl chloride and respectively in the presence of P(OTMS)3 or HP(OTMS)2.
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For our latest study, the synthesis of HMBPi required to manage properly the formation of BTSP 2
starting from hypophosphorous acid 1 in the presence of N,O-bis(trimethylsilyl)acetamide (BSA) as
silylating agent. Indeed, although numerous reports described the use of BTSP, its synthesis was usually
performed in the excess of silylating agent and hence appears inconvenient.12,13 Thanks to a careful
NMR monitoring, the reaction was successfully achieved after 40 minutes by mixing only 2 equivalents
of BSA and 1 equivalent of hypophosphorous acid 1 to in situ generate bis(trimethylsilyl)phosphonite
BTSP 2. After several optimizations in terms of temperature, concentrations, and reagent additions, the
subsequent addition of 1 equivalent of BTSP 2 to 0.5 equivalent of acyl chloride 3 finally led to the
corresponding HMBPi. Therefore, these more eco-compatible conditions were retained to enlarge the
scope of the reaction. Several bisphosphinates 4 have been synthesized starting from alkyl or
(hetero)aromatic acyl chlorides 3 in good yields after only 25 min (Scheme 2).10,11
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Scheme 2
Scope of the reaction between hypophosphorous acid
1
and various acyl chlorides 3a-z in the presence of BSA.
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The preparation of biorelevant analogues of HMBP was also considered in bisphosphinate series such
as alendrinate 5a and neridrinate 5b, analogues of HMBP alendronate and neridronate (Scheme 2).
Under our optimal conditions, the reaction was conducted between the azido acyl chlorides 3 and BTSP
2 to afford the expected HMBPi in excellent yields (80% and 96%) after methanolysis and basic
treatment. Afterward, the bisphosphinates 5a-b were treated with Dowex H+ resin to form the
corresponding bisphosphinic acids. The catalytic hydrogenation of the azido function was subsequently
carried out in the presence of palladium on activated charcoal to finally give the targeted bisphosphinates
5a-b in excellent yields (80% and quantitative).
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During this study, we tried at best to manage the high reactivity of acyl chlorides. Unfortunately, starting
from some electro-withdrawing substituted aromatic acyl chlorides, the formation of a side product was
also observed in various amounts (beyond 10%). Theses by-products have been identified as
phosphinylphosphonate isomers I (depicted in scheme 2) and resulted from a transposition during the
reaction. Regarding our experiments and also those reported in the literature, we have proposed a
postulated mechanism for HMBPi syntheses including alternative routes towards the formation of the
phosphinylphosphinate isomer I (Scheme 3).10
Scheme 3
postulated mechanism for the formations of HMBPi 4 or 7 and phosphinylphosphonate isomer A.
In most of the cases, the first attack of BTSP 2 onto the trivalent electrophile could generate a silylated
-ketophosphinate II which could undergo a second attack of BTSP 2 to form a tetravalent phosphonium
III. After an intramolecular transilylation of III, the resulting silylated HMBPi IV finally furnishes the
expected HMBPi 4 after methanolysis and pH adjustment. However, two side pathways could also occur
especially in the presence of aromatic acyl chlorides 3 bearing electro-withdrawing substituents. In this
cases, we have considered the silylated -ketophosphinate 10 could move towards a stabilized benzylic
carbanion V. His formation could be explained either by the second attack of BTSP 2 onto the carbonyl
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oxygen atom of II or by the opening of VI obtained by intramolecular cyclization of III. The
intermediate V could then give the silylated phosphinylphosphinate VII and finally the isomer I after
methanolysis and pH adjustment. In view of our latest works, the use of less reactive trivalent substrates
could consequently be a good alternative to limit the formation of isomer I and hence enabled us to
access to sensitive or more functionalized HMBPi.
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In bisphosphonate series, our laboratory has already reported an efficient Sila Arbuzov reaction starting
from acid anhydrides and silylated phosphites.14 In this context, the reaction between silylated
phosphonite BTSP 2 and other trivalent electrophiles was investigated in order to smoothly form
1-hydroxymethylene-1,1-bis(H-phosphinate) scaffold which has not been reported yet as much as we
know. Herein we described our detailed study for the synthesis of substituted and functionalized HMBPi.
RESULTS ANS DISCUSSION
Reaction on acid anhydride substrates. At the outset of this study, the reaction was conducted with
hypophosphorous acid 1 and acetic anhydride 6a in the presence of N,O-bis(trimethylsilyl)acetamide
(BSA) in tetrahydrofuran at 0 °C. The results are presented in the table 1 below in comparison with the
yields obtained with the acyl chlorides as starting reagents (Table 1, entries 1, 3 versus 2, 4).
Table 1 Reaction between acetyl chloride 3a or acetic anhydride 6a and hypophosphorous acid 1 in the presence of N,O-
bis(trimethylsilyl)acetamide (BSA)a
entry
trivalent derivative 3a or 6a
methodb
timec
yield 4a (%)d
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2
3
4
3a
A
A
B
B
18 h
-
6a
3a
45 min
20 min
5 min
84
91
90
6a
aReagents and conditions: 1 (10 mmol), BSA (20 mmol), 3a or 6a (5 mmol), THF, Ar, 0 °C. bFor details see experimental section. c The reaction completion was
monitored by 31P{1H} and 31P NMR; the indicated time includes the time of addition. dIsolated yield of HMBPi 4a.
First of all, the silylated phosphonite 2 was generated in situ in 40 minutes in anhydrous THF at 0 °C as
previously mentioned. BTSP 2 was then added to a solution of acetic anhydride 6a diluted in anhydrous
THF at 0 °C (Table 1, entry 2: method A) Surprisingly, we found that the reaction was already complete
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after only 45 minutes at 0 °C and the expected bisphosphinate 4a was obtained in an excellent yield of
84%. Conversely, the same reaction with acetyl chloride 3a did not proceed. Indeed, after methanolysis,
only the hypophosphorous acid, phosphorous acid and methyl ester were recovered (Table 1, entries 1
7
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9
versus 2).
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Thereafter, the influence of reagent additions was studied to easily handle the reaction (Table 1, entries
3-4 versus 1-2; method B). This time, the solution of acetic anhydride 6a in THF was added dropwise
to the silylated phosphonite BTSP 2 at 0 °C (method B). The reaction was successful in shorter reaction
time as only 5 min (acetic anhydride addition) were only necessary to reach a complete conversion. In
this case, the reaction appears to be less exothermic in the presence of acid anhydride 6a than acetyl
chloride 3a which enables faster reagent addition (Table 1, entries 4 versus 3). The methanolysis step
finally leads to the bisphosphinate disodium salt 4a in an excellent yield of 90% after pH adjustment
and purification by simple washes (Table 1, entry 4: method B).
Scope of the reaction. Under the previous optimized conditions, the scope of the reaction was studied
on various aliphatic and cyclic acid anhydrides 6 (Table 2).
Reaction on acyclic acid anhydrides. The reaction performed between a bulkier isobutyric anhydride
6b and the bis(trimethylsilyl)phosphonite 2 was finished after only 9 minutes to afford H-HMBPi 4b in
a very good yield of 86% (Table 2, entry 4). Thereafter, these conditions were tested on benzoic
anhydride 6f (table 2, entry 6). The expected compound 4f was isolated in an excellent yield of 92 %
after only 10 minutes. In both cases, the acid anhydrides 6b and 6f were added faster to the phosphonite
solution because of the lower exothermicity observed compared to what was found in the presence of
acyl chlorides 3b and 3f. Thus, the reaction completions were faster reached in the presence of acid
anhydrides than acyl chlorides (Table 2, entries 2, 4 versus 1, 3). Moreover, the expected compound 4f
was isolated in a yield of 92% instead of 87% (Table 2, entries 6 versus 5).
Reaction on cyclic anhydrides. Afterwards, the reactivity of cyclic anhydride reagents was investigated
such as succinic and glutaric anhydride. This approach should enable the access to functionalized
HMBPi 7a-b bearing a carboxylate on its side chain which could subsequently undergo a peptidic
coupling for instance, or other post-functionalization step. In this cases, the
bis(trimethylsilyl)phosphonite 2 and the cyclic anhydrides were mixed at 0 °C and then, the mixture was
stirred at room temperature respectively for 6h and 4h in order to totally achieve the reaction. After the
methanolysis step and the pH adjustment, the functionalized HMBPi 7a,b were isolated in similar yields
(89 and 86%). These reactions required longer reaction times. Moreover, it was noted that a considerable
quantity of a five-membered ring HMBPi lactone was also formed during this reaction in the presence
of succinic anhydride. However, the mixture of cyclized and linear HMBPi was stirred in an aqueous
solution of NaOH and this treatment was sufficient to give the desired compound 7a in the indicated
yield of 89%. The lactonization was never observed starting from glutaric anhydride.
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Table 2 Reaction between acyl chloride 3 or acid anhydride 6 and hypophosphorous acid 1 in the presence of BSAa
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entry
1
trivalent derivative 3 or 6
temp
0 °C
Timeb
HMBPi 4 or 7
Yieldc (%)
91
20 min
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3
4
5
6
0 °C
0 °C
0 °C
0 °C
0 °C
5 min
20 min
9 min
90
95
86
87
92
20 min
10 min
7
8
0 °C to rt
0 °C to rt
6h
4h
89
86
aReaction conditions: 1 (10 mmol), BSA (20 mmol), 3 (5 mmol), THF, Ar. Concentrations were adjusted depending on addition method
and temperature in order to obtain sufficient solution volumes to allow the reaction occurring. For details see experimental section. b The
reaction completion was monitored by 31P{1H} and 31P NMR; the indicated time includes the time of addition. Isolated yield of HMBPi
c
4a,b,f or 7a,b.
Reaction on activated esters. Another study was then considered and the objective was to evaluate the
reactivity of other trivalent substrates such as esters. Indeed, the reaction between BTSP 2 and esters
should be easier to control due to their lesser reactivity. However no reaction occurred when an aliphatic
or aromatic esters with electron-donating groups were chosen. As a result, we opted for the use of
activated esters 8-9 with electron-withdrawing groups which would be more reactive than conventional
esters but less than acyl chlorides or anhydrides (Table 3).
The syntheses of activated esters as NHS esters 8 and pentafluorophenyl (PFP) esters 9 were firstly
performed under standard conditions and the corresponding esters were obtained in excellent yields (see
the experimental section for details).15
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Table 3 Reaction between activated esters 8 and 9 and hypophosphorous acid 1 in the presence of N,O-bis(trimethylsilyl)acetamide (BSA)a
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entry
electrophile
X
temp
0°C
Timec
20 min
18h
HMBPi 4
Isomer I (%)d
Yielde (%)
1
2
3
3a: X = Cl
-
-
-
-
-
-
91
90
95
86
87
93
8a: X = NHSb
9a: X = OC6F5
0°C to rt
0°C to rt
0°C
5h
20 min
18h
4
3d: X = Cl
0°C to rt
0°C to rt
5
8d: X = NHS
9d: X = OC6F5
3f: X = Cl
5h
6
7
0°C
20 min
18h
-
-
87
85
84
95
80
86
67
61
60
74
71
77
88
58
61
85
91
86
67
93
94
37
30
48
8
8f: X = NHSb
0°C to rt
0°C to rt
0°C
b
9
9f: X = OC6F5
3i: X = Cl
5h
-
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11
12
13
14
15
16
17
18
19
20
21
22
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24
25
26
27
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29
30
20 min
18h
-
8i: X = NHSb
9i: X = OC6F5
3g: X = Cl
0°C to rt
0°C to rt
0°C
-
5h
-
20 min
18h
32
23
-
8g: X = NHSb
9g: X = OC6F5
3n: X = Cl
0°C to rt
0°C to rt
0°C
5h
20 min
4h
-
8n: X = NHSb
9n: X = OC6F5
3m: X = Cl
0°C to rt
0°C to rt
0°C
-
4h
-
20 min
6h30
6h30
20 min
5h
-
8m: X = NHSb
9m: X = OC6F5
3r: X = Cl
0°C to rt
0°C to rt
0°C
-
b
-
-
8r: X = NHSb
9r: X = OC6F5
3p: X = Cl
0°C to rt
0°C to rt
0°C
-
4h
-
20 min
5h
16
3
5
52
16
16
8p: X = NHSb
9p: X = OC6F5
3o: X = Cl
0°C to rt
0°C to rt
0°C
4h
20 min
4h
8o: X = NHSb
9o: X = OC6F5
0°C to rt
0°C to rt
4h
aReaction conditions: 1 (10 mmol), BSA (20 mmol), 8-9 (5 mmol), THF, Ar. b The concentrations were adjusted in order to solubilize the various activated esters.
cThe reaction completions were monitored by 31P{1H} and 31P NMR; the indicated time includes the time of addition. dNMR ratio in crude mixture. eIsolated
yields of HMBPi 4a-o.
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Several aliphatic, aromatic activated esters which were substituted by an electron-donating or an
electron-withdrawing group at the ortho- or para- position were tested. As a general trend, from the
reaction on activated esters permits to form HMBPi in good or even better yields than those obtained
with acyl chlorides. However, the reaction rates appeared slower, as the reaction completions were
observed after 5h for the PFP esters and 18h for the NHS esters. Indeed, after adding the silylated
phosphonite at 0 °C, the temperature was increased at room temperature in order to reach total
conversion. Otherwise, the degradation of the phosphonite occurred faster than the expected reaction.
Furthermore, the reaction between the silylated phosphonite with the activated ester NHS is faster (4h)
in the presence of electron-withdrawing groups at the para- and ortho- positions.
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The first reactions were carried out between the aliphatic activated esters (8a,d; 9a,d) and BTSP 2 under
the optimal conditions B (Table 3, entries 2,3,5,6). In all cases, the corresponding bisphosphinates 4a
and 4d were isolated in excellent yields (4a: 90% and 95%; 4d: 87% and 93%). We even observed better
yields for aliphatic bisphosphinates starting from the PFP esters 9. The reaction was also successful in
the presence of unsubstituted aromatic activated esters 8f and 9f (85% and 84% versus 87% from acyl
chloride 3f) (Table 3, entries 8,9 versus 7).
Various substituted aromatic activated esters 8 and 9 were studied under the optimized conditions
(entries 10-30) and the corresponding bisphosphinates were isolated in moderate to excellent yields
(30% to 94%) (Table 3, entries 10-30). The presence of an alkyl group at the para- position of the
activated esters 8i and 9i provided the expected HMBPi 4i in very good yields (80% and 86%). However
a slight lower yield was observed for 4g, bearing a methyl in ortho- position, compared to those obtained
from acyl chloride (61% and 60% versus 67%) (Table 3, entries 13-15). In this case, we considerable
prevented the formation of the phosphinylphosphonate isomer Ig (23% of isomer for NHS and no isomer
for PFP versus 32% for acyl chloride). Nevertheless, we noted that BTSP 2 and the final product can
unfortunately decompose into silylated phosphorous acid over time due to the slower reaction rate. This
observation explains the yield of 61% starting from PFP ester after 18h, even if no isomer Ig was formed.
In the presence of 4-trifluoromethoxy group at the para- position of the activated esters 8n-9n, the
reaction gives the desired product 4n in the indicated similar yields (71% and 77%), (Table 3, entries
17-18). Moreover, concerning the presence of methoxy group, the corresponding bisphosphinates 4m
were isolated in moderate yields (58% and 61%) while the same product 4m starting from acyl chloride
3m was obtained with an excellent efficiency (86%) (Table 3, entries 19-21). This can be explained by
the presence of the electron-donating group which decreases the reactivity of the trivalent electrophile.
In the presence of para-fluoro- substituent on the activated esters 8r-9r, the reaction also successfully
led to the expected bisphosphinate 4r in excellent yields (91% and 86%), (Table 3, entries 23-24).
Then, we decided to evaluate the reactivity of specific substituted aromatic substrates for which a
significant amount of phosphinylphosphonate isomer I was observed in acyl chloride series. Thus, the
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substitution of an electron-withdrawing group at the ortho- position of the aromatic activated esters
8p-9p afforded the bisphosphinate 4p in an excellent yield (93% and 94% versus 67% starting from acyl
chloride 3p) (Table 3, entries 25-27). A minor quantity of by-product Ip was only detected when the
reaction was carried out on those activated esters 8p and 9p.
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The reaction was also conducted in the presence of the esters 8o and 9o substituted by a highly electro-
withdrawing 4-trifluoromethyl group. HMBPi 4o was obtained in yields of 30% and 47% starting from
8o and 9o respectively. These results are in accordance with those obtained from the corresponding acyl
chloride 3o (37%). These yields are moderate probably due to the high electronegativity of this
substituent (Table 3, entries 28-30). Moreover, starting from 3o, a large amount of the
phosphinylphosphonate isomer Io was detected (52%) as well as the disproportionation of BTSP into
silylated phosphorous acid (11%). In contrast, only 16% of isomer Io was observed starting from 8o and
9o while a significant quantity of silylated phosphorous acid were formed due to their lack of reactivity.
However, the synthesis of HMBPi 4o from 9o remains much better than those obtained from the
corresponding acyl chloride 3o.
In our past study, we have shown the phosphinylphosphinate I could be produced in larger amount when
the silylated -ketophosphinate II was in situ generated in high quantity.10a When the reactions were
performed starting from acyl chlorides, a high exothermicity was indeed observed with fast reaction
rates since a total conversions were reached at the end of acyl chloride additions. In the present study,
the use of activated ester allowed to decrease the reaction rates which formed the silylated -
ketophosphinate II. In those conditions, the side reactions seemed to be limited. However, the
disproportionation of BTSP could also take place if the reaction rate became too slow.
CONCLUSION
In conclusion, we proposed an efficient easily handled methodology which successfully gave various
1-hydroxymethylene-1,1-bis(H-phosphinates) HMBPi. These optimized conditions could be applied
onto various trivalent derivative substrates as acyl chlorides as well as acid anhydrides and activated
esters. Moreover, depending on the nature of the starting materials, we can choose the adequate
electrophile in order to manage the reactivity. For the synthesis of HMBPi starting from acid anhydrides,
the exothermicity of the reaction can be perfectly controlled and no side product was observed.
Furthermore, the use of cyclic acid anhydrides offers the advantage to provide HMBPi bearing a
carboxylic acid on its side chain which could be an anchor for the synthesis of more functionalized
molecules. NHS and PFP esters exhibit also several advantages such as their easy preparation, their
relative stability which permits to preserve and to purify them. So they can be adapted to several types
of substrates. Indeed, the reaction could be implemented on sensitive functionalized substrates which
are incompatible with the preparation of an acyl chloride. Moreover, the formation of side product as
isomer could be limited depending on the nature of the trivalent derivative into consideration.
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This methodology should allow us to access to other biological relevant bisphosphonate analogues.
Their synthesis and biological evaluation will be reported soon.
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EXPERIMENTAL SECTION
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General. Reagents were purchased from common commercial suppliers (Sigma-Aldrich, Alfa Aesar,
Acros Organics) and used as delivered. All solvents were extra-dried grade prior used. N,O-
bis(trimethylsilyl)acetamide (BSA) was purchased from Alfa Aesar (LOT: J24T014). Anhydrous H3PO2
was prepared from commercially aqueous H3PO2 solution (50% w/w) according to the procedure
reported by Montchamp et al.16 Reactions requiring inert conditions were carried out in flame-dried
glassware under an argon atmosphere.
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NMR spectra were recorded at 20 °C on a Bruker Avance-III-400 spectrometer (1H: 400 MHz, 13C:
101 MHz, 31P: 162 MHz, 19F: 377 MHz). Chemical shifts () were given in ppm, the number of protons
(n) for a given resonance was indicated by nH, and coupling constants J in Hz. 1H NMR spectra were
calibrated on non-deuterated solvent residual peak (H2O: 4.79 ppm) while H3PO4 (85% in water) was
used as an external standard for 31P NMR notably for the reaction monitoring. The following
1
abbreviations were used for H, 13C, 31P and 19F NMR spectra to indicate the signal multiplicity: s
(singlet), bs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), dm
(doublet of multiplets), ddm (doublet of doublets of multiplets) and m (multiplet). All 13C NMR spectra
were measured with 1H-decoupling while 31P and 19F NMR spectra were measured with 1H coupling and
1H decoupling. 1H NMR experiments with water presaturation were performed with D1 = 2 s and 128
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scans. The reactions were followed by P and P{1H} NMR experiments (the spectra were recorded
without lock and shims). High-resolution mass spectra (HRMS) were performed on a Bruker maXis
mass spectrometer in negative (ESI-) or positive (ESI+) mode (ESI) by the "Fédération de Recherche"
ICOA/CBM (FR2708) platform. MS analyses were performed using a Q-TOF Impact HD mass
spectrometer equipped with the electrospray (ESI) ion source (Bruker Daltonics). The instrument was
operated in the negative or positive mode with an ESI source on a Q-TOF mass spectrometer with an
accuracy tolerance of 2 ppm. The mass profiles obtained by ESI-MS were analyzed using DataAnalysis
software (Bruker Daltonics). Infrared spectra were recorded on a ThermoFisher scientific Nicolet 380
FT-IR Spectrometer. Smart OMNI-Sampler Germanium ATR Sampling accessory was used. The Smart
OMNI-Sampler utilizes an extremely rugged germanium ATR crystal. The wave numbers were
expressed in cm-1 and comprised between 4000 and 675 cm-1. The samples were analyzed neat. The
following abbreviations were used for IR spectra to indicate the signal intensities: w (weak), m
(medium), s (strong), br (broad). The melting point of HMBPi cannot be measured because the disodium
salts decomposed up to 250 °C.
Thin Layer Chromatography were performed on commercial silica plates (silica-coated aluminum plates
of MERK 5179, 250 mesh) with fluorescent indicator 60 PF254, 0.25 mm thick and UV revealed at 254
nm and a basic solution of KMnO4.
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Synthesis of activated esters 8 and 9.
To a solution of carboxylic acid (8.00 mmol, 1.00 equiv.) and NHS or pentafluorophenol (12.0 mmol,
1.50 equiv.) in anhydrous CH2Cl2 (32.0 mL) at 0 °C were added EDC (12.0 mmol, 1.50 equiv.) and
DMAP (16.0 mmol, 2.00 equiv.). The mixture was stirred for 16h at room temperature. The organic
layer was successively washed twice with an aqueous solution of HCl 1 M and a saturated aqueous
solution of NaHCO3. The combined organic layers were dried over MgSO4 and concentrated in vacuo
to form a pure product. The activated esters were synthesized according the reported procedure and were
used directly for the synthesis of bisphosphinates 4 without any further purification.
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2,5-dioxopyrrolidin-1-yl acetate 8a. White solid (1.26 g, 100% yield). 1H NMR (CDCl3, 400 MHz) 
2.91 – 2.75 (m, 4H), 2.34 (s, 3H). 13C{1H} NMR (CDCl3,101 MHz)  169.2 (2C), 165.6, 25.6 (2C),
17.6. These data are in agreement with those previously reported.17
2,5-dioxopyrrolidin-1-yl hexanoate 8d. White solid (1.69 g, 99% yield). 1H NMR (CDCl3, 400 MHz)
 2.88 – 2.76 (m, 4H), 2.58 (t, 2H, J = 7.5 Hz), 1.79 – 1.69 (m, 2H), 1.43 – 1.29 (m, 4H), 0.90 (t, 3H, J
= 7.2 Hz). 13C{1H} NMR (CDCl3,101 MHz)  169.3 (2C), 168.8, 31.0 (2C), 25.7 (2C), 24.4, 22.3, 14.0.
MS (ESI+) m/z: 214.10 [M+H]+. HRMS (ESI+) m/z: [M+H]+ Calcd. for [C10H16NO4]: 214.1074, found:
214.1072.
2,5-dioxopyrrolidin-1-yl benzoate 8f. White solid (1.73 g, 100% yield). 1H NMR (CDCl3, 400 MHz)
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 8.18 – 8.11 (m, 2H), 7.71 – 7.65 (m, 1H), 7.55 – 7.48 (m, 2H), 3.01 – 2.83 (m, 4H). C{1H} NMR
(CDCl3,101 MHz)  169.3 (2C), 161.9, 135.0, 130.6 (2C), 128.9 (2C), 125.1, 25.7 (2C). These data are
in agreement with those previously reported.18
2,5-Dioxopyrrolidin-1-yl 4-methylbenzoate 8i. White solid (1.81 g, 97% yield). 1H NMR (CDCl3, 400
MHz)  8.02 (d, 2H, J = 8.3 Hz), 7.31 (d, 2H, J = 8.0 Hz), 2.99 – 2.84 (m, 4H), 2.45 (s, 3H). 13C{1H}
NMR (CDCl3,101 MHz)  169.4 (2C), 161.9, 146.1, 130.6 (2C), 129.6 (2C), 122.3, 25.6 (2C), 21.9.
These data are in agreement with those previously reported.18
1
2,5-Dioxopyrrolidin-1-yl 2-methylbenzoate 8g. White solid (1.86 g, 100% yield). H NMR (CDCl3,
400 MHz)  8.12 (dd, 1H, J = 8.3 Hz, J = 1.4 Hz), 7.58 – 7.47 (m, 1H), 7.36 – 7.29 (m, 2H), 2.90 – 2.76
(m, 4H), 2.62 (s, 3H). 13C{1H} NMR (CDCl3,101 MHz)  169.4 (2C), 162.1, 142.1, 134.0, 132.0, 131.4,
126.1, 124.3, 25.7 (2C), 21.6. MS (ESI+) m/z: 234.07 [M+H]+. HRMS (ESI+) m/z: [M+H]+ Calcd. for
[C12H12NO4]: 234.0761, found: 234.0760.
2,5-dioxopyrrolidin-1-yl 4-methoxybenzoate 8m. White solid (1.91 g, 96% yield). 1H NMR (CDCl3,
400 MHz)  8.13 – 8.05 (m, 2H), 7.01 – 6.93 (m, 2H), 3.93 – 3.85 (m, 4H), 2.89 (s, 3H). 13C{1H} NMR
(CDCl3,101 MHz)  169.5 (2C), 164.9, 161.5, 132.9 (2C), 117.1, 114.2 (2C), 55.6, 25.7 (2C). These
data are in agreement with those previously reported.19
2,5-dioxopyrrolidin-1-yl 4-(trifluoromethoxy)benzoate 8n. White solid (2.38 g, 98% yield). 19F{1H}
NMR (CDCl3, 377 MHz)  -57.6 (s). 19F NMR (CDCl3, 377 MHz)  -57.6 (bs). 1H NMR (CDCl3, 400
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MHz)  8.20 (d, 2H, J = 8.8 Hz), 7.35 (d, 2H, J = 8.5 Hz), 3.00 – 2.85 (m, 4H). 13C{1H} NMR (CDCl3,101
MHz)  169.0 (2C), 160.8, 154.0 (d, 1C, J = 1.5 Hz), 132.8 (2C), 123.5, 120.6 (2C), 120.2 (q, 1C, J =
259.6 Hz), 25.7 (2C). MS (ESI+) m/z: 304.04 [M+H]+. HRMS (ESI+) m/z: [M+H]+ Calcd. for
[C12H9F3NO5]: 304.0427, found: 304.0427.
2,5-dioxopyrrolidin-1-yl 4-fluorobenzoate 8r. White solid (1.88 g, 99% yield).19F{1H} NMR (CDCl3,
377 MHz)  -101.3 (s). 19F NMR (CDCl3, 377 MHz)  -101.2 – -101.4 (m). 1H NMR (CDCl3, 400 MHz)
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 8.21 – 8.13 (m, 2H), 7.24 – 7.16 (m, 2H), 2.99 – 2.84 (m, 4H). C{1H} NMR (CDCl3,101 MHz) 
169.2 (2C), 166.9 (d, 1C, J = 257.8 Hz), 160.9, 133.4 (d, 2C, J = 9.8 Hz), 121.4, 116.3 (d, 2C, J = 22.3
Hz), 25.7 (2C). These data are in agreement with those previously reported.19
2,5-Dioxopyrrolidin-1-yl 2-fluorobenzoate 8p. White solid (1.86 g, 98% yield). 19F{1H} NMR
(CDCl3, 377 MHz)  -105.3 (s). 19F NMR (CDCl3, 377 MHz)  -105.3 – -105.4 (m). 1H NMR (CDCl3,
400 MHz)  8.14 – 8.02 (m, 1H), 7.74 – 7.61 (m, 1H), 7.34 – 7.27 (m, 2H), 3.01 – 2.76 (m, 4H). 13C{1H}
NMR (CDCl3,101 MHz)  169.1 (2C), 162.5 (d, 1C, J = 263.2 Hz), 159.3, 136.8 (d, 1C, J = 9.3 Hz),
132.6, 124.5, 117.4 (d, 1C J= 21.9 Hz), 113.8 (d, 1C, J= 9.3 Hz), 25.6 (2C). These data are in agreement
with those previously reported.20
2,5-dioxopyrrolidin-1-yl 4-(trifluoromethyl)benzoate 8o. White solid (2.23 g, 97% yield). 19F{1H}
NMR (CDCl3, 377 MHz) -63.5 (s). 19F NMR (CDCl3, 377 MHz)  -63.5 (bs). 1H NMR (CDCl3, 400
MHz)  8.27 (d, 2H, J = 8.1 Hz), 7.80 (d, 2H, J = 8.2 Hz), 2.91 – 2.83 (m, 4H). 13C{1H} NMR (CDCl3,101
MHz)  168.9 (2C), 160.9, 136.2 (q, 1C, J= 33.2 Hz), 131.0 (2C), 128.5, 125.9 (q, 2C, J= 3.7 Hz), 123.3
(q, 1C, J = 273.2 Hz), 25.7 (2C). These data are in agreement with those previously reported.20
Pentafluorophenyl acetate 9a. Pale yellow oil (1.81 g, 100% yield). 19F{1H} NMR (CDCl3, 377 MHz)
 -152.8 (dm, 2F, J = 17.3 Hz), -158.1 (t, 1F, J = 21.7 Hz), -162.4 (ddm, 2F, J = 21.8 Hz, 17.3 Hz). 1H
NMR (CDCl3, 400 MHz)  2.40 (s, 1H). 13C{1H} NMR (CDCl3,101 MHz)  166.8, 141.3 (dm, 2C, J =
251.3 Hz), 139.7 (dtt, 1C, J = 252.3 Hz, J = 13.5 Hz, J = 4.1 Hz), 139.7 (dm, 2C, J = 252.1 Hz), 125.3
(tdt, 1C, J = 14.5 Hz, J = 4.3 Hz, J = 2.0 Hz), 19.9. These data are in agreement with those previously
reported. 21
19
Pentafluorophenyl hexanoate 9d. Pale yellow oil (2.26 g, 100% yield). F{1H} NMR (CDCl3, 377
MHz)  -153.1 (dm, 2F, J = 18.7 Hz), -158.4 – -158.8 (m, 1F), -162.7 – 163.0 (m, 2F). 1H NMR (CDCl3,
400 MHz)  2.66 (t, 2H, J = 7.4 Hz), 1.83 – 1.74 (m, 2H), 1.46 – 1.33 (m, 4H), 0.93 (t, 3H, J = 6.9 Hz).
13C{1H} NMR (CDCl3,101 MHz)  169.9, 141.4 (dm, 2C, J = 250.9 Hz), 139.5 (dtt, 1C, J = 253.9 Hz,
J = 13.3 Hz, J = 3.9 Hz), 138.1 (dm, 2C, J = 254.5 Hz), 125.3 (tdt, 1C, J = 14.2 Hz, J = 4.1 Hz, J = 1.8
Hz), 33.4, 31.2, 24.6, 22.4, 13.9. MS (ESI+) m/z: 283.07 [M+H]+. HRMS (ESI+) m/z: [M+H]+ Calcd.
for [C12H12F5O2]: 283.0752, found: 283.0752.
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Pentafluorophenyl benzoate 9f. Pale yellow solid (2.26 g, 98% yield). 19F{1H} NMR (CDCl3, 377
MHz)  -152.4 (dm, 2F, J = 17.3 Hz), -157.9 (t, 1F, J = 21.7 Hz), -162.3 (ddm, 2F, J = 21.8 Hz, 17.3
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Hz). H NMR (CDCl3, 400 MHz)  8.24 – 8.18 (m, 2H), 7.75 – 7.68 (m, 1H), 7.59 – 7.52 (m, 2H).
13C{1H} NMR (CDCl3,101 MHz)  162.6, 141.3 (dm, 2C, J = 252.3 Hz), 139.4 (dtt, 1C, J = 252.6 Hz,
J = 13.2 Hz, J = 4.1 Hz), 139.2 (dm, 2C, J = 252.8 Hz), 134.8, 130.8 (2C), 128.9 (2C), 125.1 (tdt, 1C, J
= 14.5 Hz, J = 4.3 Hz, J = 2.0 Hz), 19.7. These data are in agreement with those previously reported. 22
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Pentafluorophenyl 4-methylbenzoate 9i. Pale yellow oil (2.39 g, 99% yield). 19F{1H} NMR (CDCl3,
377 MHz)  -152.6 (dm, 2F, J = 17.2 Hz), -158.3 (t, 1F, J = 21.7 Hz), -162.4 – 162.7 (m, 2F). 1H NMR
(CDCl3, 400 MHz)  8.09 (d, 2H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.0 Hz), 2.48 (s, 3H). 13C{1H} NMR
(CDCl3,101 MHz)  162.5, 141.4 (dm, 2C, J = 252.3 Hz), 139.5 (dm, 1C, J = 253.0 Hz), 138.0 (dm, 2C,
J = 254.3 Hz), 130.8 (2C), 129.6 (2C), 125.7 – 125.2 (m, 1C), 145.9, 124.2, 21.8. MS (ESI+) m/z: 303.04
[M+H]+. HRMS (ESI+) m/z: [M+H]+ Calcd. for [C14H8F5O2]: 303.0439, found: 303.0439.
Pentafluorophenyl 2-methylbenzoate 9g. White solid (2.39 g, 99% yield). 19F{1H} NMR (CDCl3, 377
MHz)  -152.5 (dm, 2F, J = 22.1 Hz), -158.4 (t, 1F, J = 21.6 Hz), -162.5 – 162.7 (ddm, 2F, J = 21.6 Hz,
17.3 Hz). 1H NMR (CDCl3, 400 MHz)  8.19 (dd, 1H, J = 8.2 Hz, J = 1.4 Hz), 7.55 (dd, 1H, J = 7.6 Hz,
J = 1.4 Hz), 7.42 – 7.32 (m, 2H), 2.66 (s, 3H). 13C{1H} NMR (CDCl3,101 MHz)  162.8, 142.3, 141.5
(dm, 2C, J = 251.5 Hz), 139.5 (dm, 1C, J = 253.1 Hz), 139.2 (dm, 2C, J = 253.4 Hz), 133.8, 132.2,
131.7, 126.2, 125.6 – 125.2 (m, 1C), 126.0, 21.7. MS (ESI+) m/z: 303.04 [M+H]+. HRMS (ESI+) m/z:
[M+H]+ Calcd. for [C14H8F5O2]: 303.0439, found: 303.0438.
Pentafluorophenyl 4-(trifluoromethoxy)benzoate 9n. White solid (2.95 g, 99% yield). 19F {1H} NMR
(CDCl3, 377 MHz)  -57.6 (s, 3F), -152.4 (dm, 2F, J = 17.3 Hz), -157.4 (t, 1F, J = 21.7 Hz), -162.0 (ddm,
2F, J = 21.2 Hz, J =17.5 Hz). 19F NMR (CDCl3, 377 MHz)  -57.6 (bs), -152.4 (dm, 2F, J = 17.3 Hz), -
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157.4 (t, 1F, J = 21.7 Hz), -162.0 (ddm, 2F, J = 21.2 Hz, J =17.5 Hz). H NMR (CDCl3, 400 MHz) 
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8.27 (d, 2H, J = 8.8 Hz), 7. 38 (d, 2H, J = 8.5 Hz). C{1H}NMR (CDCl3,101 MHz)  161.4, 154.0,
141.4 (dm, 2C, J = 253.8 Hz), 139.7 (dm, 1C, J = 255.5 Hz), 138.0 (dm, 2C, J = 252.2 Hz), 132.9 (2C),
125.5 – 124.9 (m, 1C), 125.2, 120.6 (2C), 120.3 (q, 1C, J = 259.5 Hz). MS (ESI+) m/z: 373.02 [M+H]+.
HRMS (ESI+) m/z: [M+H]+ Calcd. for [C14H5F8O3]: 373.0105, found: 373.0104.
Pentafluorophenyl 4-methoxybenzoate 9m. White solid (2.49 g, 98% yield). 19F{1H} NMR (CDCl3,
377 MHz)  -152.6 (dm, 2F, J = 17.2 Hz), -158.5 (t, 1F, J = 21.7 Hz), -162.7 (ddm, 2F, J = 21.9 Hz, J
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=17.1 Hz). H NMR (CDCl3, 400 MHz)  8.15 (d, 2H, J = 8.7 Hz), 7.01 (d, 2H, J = 8.8 Hz), 3.91 (s,
3H). 13C{1H} NMR (CDCl3,101 MHz)  164.8, 162.3, 141.4 (dm, 2C, J = 255.9 Hz), 139.4 (dm, 1C, J
= 253.0 Hz), 137.9 (dm, 2C, J = 251.6 Hz), 133.0 (2C), 125.8 – 125.3 (m, 1C), 119.1, 114.2 (2C), 55.6.
These data are in agreement with those previously reported.23
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Pentafluorophenyl 4-fluorobenzoate 9r. White solid (2.43 g, 99% yield). 19F{1H} NMR (CDCl3, 377
MHz)  -102.0 (s, 1F), -152.6 (dm, 2F, J = 18.5 Hz), -157.9 (t, 1F, J = 21.6 Hz), -162.3 (ddm, 2F, J =
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20.7 Hz, J =18.3 Hz). H NMR (CDCl3, 400 MHz)  8.29 – 8.19 (m, 2H), 7.23 (t, 2H, J = 8.6 Hz).
13C{1H} NMR (CDCl3,101 MHz)  166.8 (d, 1C, J = 257.4 Hz), 161.6, 141.4 (dm, 2C, J = 251.5 Hz),
139.6 (dm, 1C, J = 253.6 Hz), 138.0 (dm, 2C, J = 252.5 Hz), 133.5 (d, 2C, J = 9.8 Hz), 125.5 – 124.9
(m, 1C), 123.2 (d, 1C, J = 3.0 Hz), 116.3 (d, 2C, J = 22.3 Hz). These data are in agreement with those
previously reported. 24
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Pentafluorophenyl 2-fluorobenzoate 9p. White solid (2.38 g, 97% yield). 19F{1H} NMR (CDCl3, 377
MHz)  -106.5 (s, 1F), -152.3 (dm, 2F, J = 17.0 Hz), -157.8 (t, 1F, J = 21.6 Hz), -162.0 – 162.7 (ddm,
2F, J = 21.8 Hz, J = 16.9 Hz). 19F NMR (CDCl3, 377 MHz)  -106.5 – 106.6 (m), -152.3 (dm, 2F, J =
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17.0 Hz), -157.8 (t, 1F, J = 21.6 Hz), -162.0 – 162.7 (ddm, 2F, J = 21.8 Hz, J = 16.9 Hz). H NMR
(CDCl3, 400 MHz)  8.12 (td, 1H, J = 7.7 Hz, J = 1.8 Hz), 7.73 – 7.64 (m, 1H), 7.32 (dd, 1H, J = 7.8
Hz, J = 1.0 Hz), 7.28 – 7.22 (m, 1H). 13C{1H} NMR (CDCl3,101 MHz)  162.7 (d, 1C, J = 263.9 Hz),
159.9 (d, 1C, J = 4.1 Hz), 141.4 (dm, 2C, J = 251.9 Hz), 139.7 (dm, 1C, J = 253.6 Hz), 137.8 (dm, 2C,
J = 254.8 Hz), 136.5 (d, 1C, J = 9.3 Hz), 132.8, 125.3 – 124.8 (m, 1C), 124.4 (d, 1C, J = 3.9 Hz), 117.5
(d, 1C, J = 21.8 Hz), 115.6 (d, 1C, J = 9.3 Hz). MS (ESI+) m/z: 307.01 [M+H]+. HRMS (ESI+) m/z:
[M+H]+ Calcd. for [C13H5F6O2]: 307.0188, found: 307.0187.
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Pentafluorophenyl 4-(trifluoromethyl)benzoate 9o. White solid (2.74 g, 96% yield). F{1H} NMR
(CDCl3, 377 MHz)  -63.5 (s, 3F), -152.5 (dm, 2F, J = 17.2 Hz), -157.3 (t, 1F, J = 21.6 Hz), -162.0
1
(ddm, 2F, J = 21.6 Hz, J = 17.3 Hz). H NMR (CDCl3, 400 MHz)  8.33 (d, 2H, J = 8.1 Hz), 7.83 (d,
2H, J = 8.2 Hz). 13C{1H} NMR (CDCl3,101 MHz)  161.5, 141.5 (dm, 2C, J = 253.6 Hz), 139.7 (dm,
1C, J = 255.1 Hz), 138.1 (dm, 2C, J = 252.4 Hz), 136.1 (q, 1C, J = 32.8 Hz),131.1 (2C), 130.2, 126.0
(2C), 125.4 – 124.8 (m, 1C), 123.3 (q, 1C, J = 260.5 Hz). These data are in agreement with those
previously reported.22
Synthesis of HMBPi 4a-o, 5a-b and 7a-b.
General procedure for method A. To a dry and argon flushed 100 mL three-necked flask equipped
with a thermometer, an argon inlet and an addition funnel, were successively introduced anhydrous
hypophosphorous acid 1 (660 mg, 10.0 mmol, 2.00 equiv.) and anhydrous tetrahydrofuran (1.00 mL)
under argon atmosphere. N,O-bis(trimethylsilyl)acetamide (BSA) (3.055 g, 20.0 mmol, 4.00 equiv.) was
added dropwise at 0 °C under argon and the mixture was stirred for 40 minutes. The reaction conversion
was monitored by 31P NMR spectroscopy. To another dry and argon flushed 100 mL three-necked flask
equipped with a thermometer, an argon inlet and an addition funnel, were successively introduced acyl
chloride 3 (5.00 mmol, 1.00 equiv.) and anhydrous tetrahydrofuran (2.25 mL for acyl chloride and
1.00 mL for acid anhydride). The bis(trimethylsilyl)phosphonite 2 was added dropwise (at -70 °C for
acyl chloride and 0 °C for acid anhydride). The reaction was monitored by 31P NMR spectroscopy. The
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reaction mixture was quenched with methanol (10.0 mL) at 0 °C and the mixture was stirred for
25 minutes. Then, methanol was evaporated under reduced pressure. The residue was dissolved in water
(2mL) and the pH was adjusted to 7.0 by adding an aqueous solution of sodium hydroxide (0.5 M) and
the solution was lyophilized. The crude residue was washed with methanol (Na2HPO3 removal) and
ethanol (acetamide removal) to give a pure solid 4.
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Optimized experimental procedure for method B. To a dry and argon flushed 100 mL three-necked
flask equipped with a thermometer, an argon inlet and an addition funnel, were successively introduced
anhydrous hypophosphorous acid 1 (660 mg, 10.0 mmol, 2.00 equiv.) and anhydrous tetrahydrofuran
(2.00 mL) under argon atmosphere. N,O-bis(trimethylsilyl)acetamide (BSA) (3.055 g, 20.0 mmol,
4.00 equiv.) was added dropwise at 0 °C under argon and the mixture was stirred for 40 minutes. The
reaction conversion was monitored by 31P NMR spectroscopy. A solution of acyl chloride 3 or acid
anhydride 6 or activated ester 8-9 (5.00 mmol, 1.00 equiv.) in anhydrous tetrahydrofuran (1.00 mL) was
added dropwise at 0 °C. The reaction completion was monitored by 31P NMR spectroscopy.
For acyl chlorides 3 and acid anhydrides 6 the reaction was already completed after addition except for
cyclic acid anhydrides. For cyclic acid anhydrides and activated esters 8-9, the reaction was stirred at
room temperature until reaction completion.
The reaction mixture was quenched with methanol (10.0 mL) at 0 °C and the mixture was stirred for
25 minutes. Then, methanol was evaporated under reduced pressure. The residue was dissolved in water
(2mL) and the pH was adjusted to 7.0 by adding an aqueous solution of sodium hydroxide (0.5 M) and
the solution was lyophilized. The crude residue was washed with methanol (Na2HPO3 removal) and
ethanol (acetamide removal) to give a pure solid 4.
1-Hydroxyethane-1,1-bis(H-phosphinate) disodium salt 4a. White powder (0.99 g, 91%
yield (from acyl chloride 3a), 0.98 g, 90% yield (from acid anhydride 6a), 0.98 g, 90% yield
(from NHS ester 8a), 1.03 g, 95% yield (from pentafluorophenyl ester 9a)). IR (neat, cm-1) =
31
31
3301br, 2375w, 1187s, 1072m, 962m, 742m. P{1H} NMR (D2O, 162 MHz)  25.9 (s). P
NMR (D2O, 162 MHz)  25.9 (dm, P-H, J = 524.8 Hz). 1H NMR (D2O, 400 MHz)  6.84 (dm,
2H, J= 524.8 Hz), 1.31 (t, 3H, J = 15.3 Hz). 13C{1H} NMR (D2O, 101 MHz)  71.4 (t, 1C, J =
96.3 Hz), 14.4. These data are in agreement with those previously reported.13c
1-Hydroxy-2-methylpropane-1,1-bis(H-phosphinate) disodium salt 4b. White powder
(1.17 g, 95% yield (from acyl chloride 3b), 1.06 g, 86% yield (from acid anhydride 7b). IR
(neat, cm-1) 3361br, 2969w, 2371w, 1185s, 1106m, 974m, 755m. 31P{1H} NMR (D2O, 162
MHz)  24.8 (s). 31P NMR (D2O, 162 MHz)  24.8 (dm, P-H, J = 529.6 Hz). 1H NMR (D2O,
400 MHz)  7.02 (dm, 2H, J = 529.6 Hz), 2.39 – 2.22 (m, 1H), 1.11 (d, 6H, J = 6.8 Hz). 13C{1H}
NMR (D2O, 101 MHz)  76.5 (t, 1C, J = 92.8 Hz), 31.1, 17.4 (2C). These data are in agreement
with those previously reported.10
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1-Hydroxyhexane-1,1-bis(H-phosphinate) disodium salt 4d. White powder (1.17 g, 86%
yield (from acyl chloride 3d), 1.18 g, 87% yield (from NHS ester 9d), 1.26 g, 93% yield (from
PFP ester 10e). IR (neat, cm-1) = 3328br, 2956w, 2303w, 1182s, 1105m, 959m, 746w.
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31P{1H} NMR (D2O, 162 MHz)  25.1 (s). P NMR (D2O, 162 MHz)  25.1 (dm, P-H, J =
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525.6 Hz). 1H NMR (D2O, 400 MHz)  6.92 (dm, 2H, J = 525.6 Hz), 1.87 – 1.69 (m, 2H), 1.61
13
–1.43 (m, 2H), 1.38 – 1.18 (m, 4H), 0.93 – 0.75 (m, 3H). C{1H} NMR (D2O, 101 MHz) 
74.2 (t, 1C, J = 94.9 Hz), 32.0, 30.6, 22.2 (t, 1C, J = 6.5 Hz), 21.8, 13.3. These data are in
agreement with those previously reported.10
1-Hydroxy-1-phenylmethane-1,1-bis(H-phosphinate) disodium salt 4f. White powder (1.22
g, 87% yield (from acyl chloride 3f), 1.29 g, 92% yield (from acid anhydride 6f), 1.19 g, 85%
yield (from NHS ester 8f), 1.18 g, 84% yield (from PFP ester 9f)). IR (neat, cm-1) = 3263br,
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2973w, 2317w, 1601w, 1489w, 1446w, 1395w, 1195s, 1119m, 975m, 732m. P{1H} NMR
(D2O, 162 MHz)  24.4 (s). 31P NMR (D2O, 162 MHz)  24.4 (dm, P-H, J = 538.2 Hz). 1H NMR
(D2O, 400 MHz)  7.48 – 7.42 (m, 2H), 7.34 (t, 2H, J = 7.0 Hz), 7.26 – 7.16 (m, 1H), 6.94 (dm,
2H, J = 538.2 Hz). 13C{1H} NMR (D2O, 101 MHz)  136.1, 128.5 (2C), 127.2, 125.4 (2C), 77.4
(t, 1C, J = 91.8 Hz). These data are in agreement with those previously reported.10
1-Hydroxy-1-(4-tolyl)methane-1,1-bis(H-phosphinate) disodium salt 4i. White powder
(1.39 g, 95% yield (from acyl chloride 3i), 1.17 g, 80% yield (from NHS ester 8i), 1.26 g, 86%
yield (from PFP ester 9i)). IR (neat, cm-1)  3236br, 2978w, 2900w, 2310w, 1647w, 1510w,
1335w, 1188s, 1095s, 976m, 753m. 31P{1H} NMR (D2O, 162 MHz)  24.4 (s). 31P NMR (D2O,
1
162 MHz)  24.4 (dm, P-H, J = 537.0 Hz). H NMR (D2O, 400 MHz)  7.42 (dt, 2H, J = 8.1
13
Hz, J = 1.7 Hz), 7.25 (d, 2H, J = 8.1 Hz), 7.02 (dm, 2H, J = 537.0 Hz), 2.31 (s, 3H). C{1H}
NMR (D2O, 101 MHz)  137.0 (t, 1C, J = 2.6 Hz), 132.8, 128.8 (2C), 125.3 (t, 2C, J = 4.4 Hz),
77.0 (t, 1C, J = 92.1 Hz), 20.1. These data are in agreement with those previously reported.10
1-Hydroxy-1-(2-tolyl)methane-1,1-bis(H-phosphinate) disodium salt 4g. White powder
(0.99 g, 67% yield (from acyl chloride 3g), 0.90 g, 61% yield (from NHS ester 8g), 0.89 g, 60%
yield (from PFP ester 9g). IR (neat, cm-1) = 3217br, 2898m, 2901m, 2327w, 1452w, 1394w,
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1178m, 1080s, 975w, 753w. P{1H} NMR (D2O, 162 MHz)  24.7 (s). P NMR (D2O, 162
MHz)  24.7 (dm, P-H, J = 540.7 Hz). 1H NMR (D2O, 400 MHz)  7.65 – 7.58 (m, 1H), 7.28 –
7.14 (m, 3H), 7.12 (dm, 2H, J= 540.7 Hz), 2.56 (s, 3H). 13C{1H} NMR (D2O, 101 MHz)  137.7
– 137.3 (m, 1C), 134.7, 132.7, 127.2, 126.9 (t, 1C, J = 5.3 Hz), 125.4, 80.0 (t, 1C, J = 89.4 Hz),
22.2. These data are in agreement with those previously reported.10
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1-Hydroxy-1-(4-trifluoromethoxyphenyl)methane-1,1-bis(H-phosphinate) disodium salt
4n. White powder (1.35 g, 74% yield (from acyl chloride 3n), 1.30 g, 71% yield (from NHS
ester 8n), 1.40 g, 77% yield (from PFP ester 9n). IR (neat, cm-1)  3258br, 2989w, 2315w,
1610w, 1507w, 1192s, 1118m, 1098m, 1056w, 975w, 742w. 31P{1H} NMR (D2O, 162 MHz)
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 23.8 (s). P NMR (D2O, 162 MHz)  23.8 (dm, P-H, J = 539.3 Hz). F {1H} NMR (D2O,
377 MHz)  -57.8 (s). 19F NMR (D2O, 377 MHz)  -57.8 (bs); 1H NMR (D2O, 400 MHz)  7.59
(dm, 2H, J = 8.6 Hz), 7.33 (d, 2H, J = 8.6 Hz), 7.03 (dm, 2H, J = 539.3 Hz). 13C{1H} NMR (D2O,
101 MHz)  147.9 (d, 1C, J = 1.7 Hz), 135.0, 126.8 (t, 2C, J = 4.3 Hz), 120.7 (2C), 120.3 (q,
1C, J = 256.1 Hz), 77.0 (t, 1C, J = 90.9 Hz). These data are in agreement with those previously
reported.10
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1-Hydroxy-1-(4-methoxyphenyl)methane-1,1-bis(H-phosphinate) disodium salt 4m.
White powder (1.36 g, 88% yield (from acyl chloride 3m), 0.90 g, 58% yield (from NHS ester
8m), 0.94 g, 61% yield (from PFP ester 9m). IR (neat, cm-1)  3247br, 3001w, 2902w, 2313w,
1609w, 1509m, 1467w, 1191s, 1117m, 1034m, 975w, 740w. 31P{1H} NMR (D2O, 162 MHz)
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 24.3 (s). P NMR (D2O, 162 MHz)  24.3 (dm, P-H, J = 535.9 Hz); H NMR (D2O, 400
MHz)  7.52 – 7.43 (m, 2H), 7.01 (dm, 2H, J = 535.9 Hz), 7.01 (d, 2H, J = 8.9 Hz), 3.81 (s,
3H). 13C{1H} NMR (D2O, 101 MHz)  157.8, 128.4, 126.7 (t, 2C, J = 4.5 Hz), 113.8 (2C), 76.7
(t, 1C, J = 92.9 Hz), 55.3. These data are in agreement with those previously reported.10
1-Hydroxy-1-(4-fluorophenyl)methane-1,1-bis(H-phosphinate) disodium salt 4r. White
powder (1.26 g, 85% yield (from acyl chloride 3j), 1.35 g, 91% yield (from NHS ester 8r), 1.27
g, 86% yield (from PFP ester 9r). IR (neat, cm-1)  3224br, 2987m, 2309w, 1606w, 1507m,
1194s, 1090s, 1056s, 975w, 748m. 31P{1H} NMR (D2O, 162 MHz)  24.0 (d, J = 2.6 Hz). 31P
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NMR (D2O, 162 MHz)  24.0 (dm, P-H, J = 537.5 Hz). F {1H} NMR (D2O, 377 MHz)  -
116.7 – -116.8 (m). 19F NMR (D2O, 377 MHz)  -116.6 – -116.8 (m). 1H NMR (D2O, 400 MHz)
 7.59 – 7.50 (m, 2H), 7.20 – 7.12 (m, 2H), 7.04 (dm, 2H, J = 537.5 Hz). 13C{1H} NMR (D2O,
101 MHz)  161.9 (d, 1C, J = 242.5 Hz), 131.8, 127.4 – 127.0 (m, 2C), 115.1 (d, 2C, J = 21.5
Hz), 77.0 (t, 1C, J = 91.6 Hz). These data are in agreement with those previously reported.10
1-Hydroxy-1-(2-fluorophenyl)methane-1,1-bis(H-phosphinate) disodium salt 4p.
White powder (1.00 g, 67% yield (from acyl chloride 3p), 1.39 g, 93% yield (from NHS ester
8p), 1.40 g, 94% yield (from PFP ester 9p). IR (neat, cm-1) = 3261br, 3036w, 2325w, 1614w,
1485w, 1447w, 1194s, 1116m, 1089m, 968w, 753w. 31P{1H} NMR (D2O, 162 MHz)  22.0 (d, J =
31
14.9 Hz). P NMR (D2O, 162 MHz)  22.0 (dm, P-H, J = 549.6 Hz). 19F {1H} NMR (D2O, 377
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MHz)  -108.8 (t, J = 15.0 Hz). F NMR (D2O, 377 MHz)  -108.7 – -109.0 (m). H NMR
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(D2O, 400 MHz)  7.65 – 7.51 (m, 1H), 7.41 – 7.29 (m, 1H), 7.29 – 7.19 (m, 1H), 7.17 (dm,
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2H, J = 549.6 Hz), 7.16 – 7.05 (m, 1H). C{1H} NMR (D2O, 101 MHz)  159.1 (dt, 1C, J =
243.9 Hz, J = 3.4 Hz), 129.2 – 129.0 (m, 1C), 128.1 – 127.1 (m, 1C), 124.3, 123.7 (dm, 1C, J =
14.7 Hz), 115.7 (d, 1C, J = 22.6 Hz), 77.4 (td, 1C, J = 87.2 Hz, J = 6.2 Hz). These data are in
agreement with those previously reported.10
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1-Hydroxy-1-(4-(trifluoromethyl)phenyl)methane-1,1-bis(H-phosphinate) disodium salt
4o.
White powder (0.64 g, 37% yield (from acyl chloride 3o), (0.52 g, 30% yield (from NHS ester
8o), 0.83 g, 48% yield (from PFP ester 9o). IR (neat, cm-1) = 3321br, 2983w, 2320w, 1651w,
1611w, 1193s, 1116m, 1069s, 977w, 762m. 31P{1H} NMR (D2O, 162 MHz)  23.6 (s).
31P NMR (D2O, 162 MHz)  23.6 (dm, P-H, J = 540.4 Hz). 19F {1H} NMR (D2O, 377 MHz) 
-61.9 – -62.3 (m). 19F NMR (D2O, 377 MHz)  -61.9 – -62.3 (m); 1H NMR (D2O, 400 MHz) 
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7.74 – 7.67 (m, 4H), 7.07 (dm, 2H, J = 540.4 Hz). C{1H} NMR (D2O, 101 MHz)  140.6,
128.3 (dt, 1C, J = 32.0 Hz, J = 2.8 Hz), 125.8 – 125.7 (m, 2C), 125.2 – 125.0 (m, 2C), 124.4 (q,
1C, J = 271.0 Hz), 77.6 (t, 1C, J = 90.0 Hz). These data are in agreement with those previously
reported.10
1-Hydroxy-1-(5-azidopentyl)methane-1,1-bis(H-phosphinate) disodium salt 5a. White powder
(1.51 g, 96% yield). IR (neat, cm-1): 3328br, 2956w, 2303w, 2121w, 1182s, 1105m, 959m, 746w.
31P{1H} NMR (D2O, 162 MHz)  24.9 (s). 31P NMR (D2O, 162 MHz)  24.9 (dm, P-H, J = 526.4 Hz).
1H NMR (D2O, 400 MHz)  6.93 (dm, 2H, J = 526.4 Hz), 3.32 (t, 2H, J = 6.2 Hz), 1.89 – 1.73 (m, 2H),
1.69 – 1.50 (m, 4H), 1.44 – 1.31 (m, 2H). 13C{1H} NMR (D2O, 101 MHz)  74.1 (t, 1C, J = 94.6 Hz),
51.1, 30.4, 27.7, 26.9, 22.2 (t, 1C, J = 6.5 Hz). MS (ESI-) m/z: 270.04 [M-H]-, 292.02 [M-2H+Na]-,
252.03 [M-H-H2O]-, 227.04 [M-H-N3]-, 204.05 [M-H-H3PO2]- . HRMS (ESI-) m/z: [M-H]- Calcd. for
[C6H14N3O5P2]: 270.0414, found: 270.0415.
1-Hydroxy-1-(5-aminopentyl)methane-1,1-bis(H-phosphinate) disodium salt 5b. White solid (0.06
g, quantitative yield). IR (neat, cm-1): 3318br, 2952w, 2309w, 1204w, 1178s, 1102m, 975m, 739w.
31P{1H} NMR (D2O, 162 MHz)  = 24.8 (s).31P NMR (D2O, 162 MHz)  24.8 (dm, P-H, J = 525.6 Hz).
1H NMR (D2O, 400 MHz)  6.90 (dt, 2H, J = 525.8 Hz, J = 17.8 Hz), 2.95 (t, 2H, J = 7.1 Hz), 1.85 –
1.72 (m, 2H), 1.71 – 1.45 (m, 4H), 1.42 – 1.24 (m, 2H). 13C{1H} NMR (D2O, 101 MHz)  74.0 (t, 1C,
J = 95.2 Hz), 39.2, 30.1, 26.4, 26.2, 22.0. MS (ESI-) m/z: 244.05 [M-H]-. HRMS (ESI-) m/z: [M-H]-
Calcd. for [C6H16NO5P2 ]: 244.0509, found: 244.0513.
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Sodium 4-hydroxy-4,4-bis(H-phosphinyl)butanoate 7a. White powder (1.31 g, 89% yield (from
succinic anhydride)). IR (neat, cm-1): 3320br, 2950w, 2309w, 1725m,1204w, 1178s, 1102m, 975m,
739w. 31P{1H} NMR (D2O, 162 MHz)  25.2 (s). 31P NMR (D2O, 162 MHz)  25.2 (dm, P-H, J = 526.9
Hz). 1H NMR (D2O, 400 MHz 6.90 (dm, 2H, J= 526.9 Hz), 2.54 – 2.42 (m, 2H), 2.14 – 1.93 (m, 2H).
13C{1H} NMR (D2O, 101 MHz)  182.9, 73.4 (t, 1C, J = 95.3 Hz), 31.7 (t, 1C, J = 7.2 Hz), 26.4; MS
(ESI-) m/z: 230.98 [M-H]-, 252.96 [M-2H+Na]-, 212.97 [M-H-H2O]-, 165.00 [M-H-H3PO2]-. HRMS
(ESI-) m/z: [M-H]- Calcd. for [C4H9O7P2]: 230.9831, found: 230.9829.
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Sodium 5-hydroxy-5,5-bis(H-phosphinyl)pentanoate 7b. White powder (1.34 g, 86% yield (from
glutaric anhydride)); IR (neat, cm-1): 3321br, 2951w, 2310w, 1725m, 1205w, 1177s, 1100m, 975m,
740w; 31P{1H} NMR (D2O, 162 MHz)  24.9 (s); 31P NMR (D2O, 162 MHz)  24.9 (dm, PH, J = 526.9
Hz); 1H NMR (D2O, 400 MHz 6.92 (dm, 2H, J = 526.9 Hz), 2.25 – 2.07 (m, 2H), 1.89 – 1.70 (m, 4H);
13C{1H} NMR (D2O, 101 MHz)  183.2, 74.0 (t, 1C, J = 94.9 Hz), 38.1, 30.2, 19.9 (t, 1C, J = 7.1 Hz);
MS (ESI-) m/z: 245.00 [M-H]-, 266.98 [M-2H+Na]-, 179.01 [M-H-H3PO2]-; HRMS (ESI-) m/z: [M-H]-
Calcd. for [C5H11O7P2]: 256.9447, found: 256.9444.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H, 13C{1H}, 31P {1H}, 31P and 19F NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: julia.deschamp@univ-paris13.fr
*E-mail: marc.lecouvey@univ-paris13.fr
ORCID:
Jade Dussart-Gautheret: 0000-0001-7434-3741
Julia Deschamp: 0000-0002-1979-6913
Evelyne Migianu-Griffoni: 0000-0002-4029-9874
Marc Lecouvey: 0000-0001-8218-9203
ACKNOWLEDGMENT
Université Sorbonne Paris Nord, Centre National de la Recherche Scientifique (CNRS), Ministère de
l’Enseignement Supérieur et de la Recherche (MESR) and GDR Phosphore (CNRS) are gratefully
acknowlegded for financial support.
REFERENCES
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