Recent advances in phosphorus-carbon bond formation: Synthesis of H-phosphinic acid derivatives from hypophosphorous compounds

Article abstract of DOI:10.1016/j.jorganchem.2004.10.005

This account summarizes the research conducted in our laboratory over the past five years. New methodologies were devised for the formation of P-C bonds with a focus on the reactions of hypophosphorous acid derivatives. Three types of reactions have been developed: palladium-catalyzed cross-coupling, room-temperature radical addition, and palladium-catalyzed addition. Our results are summarized in each of these areas and include some of our most recent data. (1) Our palladium-catalyzed cross-coupling has been extended to the direct coupling of alkyl phosphinates with a variety of aryl, heteroaryl, and even alkenyl electrophiles. (2) The addition of sodium hypophosphite under radical conditions is extended from alkenes to alkynes. (3) The catalytic addition of hypophosphorous compounds using palladium catalysts (hydrophosphinylation) is also discussed.

Full text of DOI:10.1016/j.jorganchem.2004.10.005

Journal of Organometallic Chemistry 690 (2005) 2388–2406
www.elsevier.com/locate/jorganchem
Recent advances in phosphorus–carbon bond formation: synthesis
of H-phosphinic acid derivatives from hypophosphorous compounds
*
Jean-Luc Montchamp
Department of Chemistry, Texas Christian University, P.O. Box 298860, Fort Worth, TX 76129, USA
Received 24 June 2004; accepted 6 October 2004
Available online 11 November 2004
Abstract
This account summarizes the research conducted in our laboratory over the past five years. New methodologies were devised for
the formation of P–C bonds with a focus on the reactions of hypophosphorous acid derivatives. Three types of reactions have been
developed: palladium-catalyzed cross-coupling, room-temperature radical addition, and palladium-catalyzed addition. Our results
are summarized in each of these areas and include some of our most recent data. (1) Our palladium-catalyzed cross-coupling has
been extended to the direct coupling of alkyl phosphinates with a variety of aryl, heteroaryl, and even alkenyl electrophiles. (2)
The addition of sodium hypophosphite under radical conditions is extended from alkenes to alkynes. (3) The catalytic addition
of hypophosphorous compounds using palladium catalysts (hydrophosphinylation) is also discussed.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Organophosphorus compounds; H-phosphinic acids; Organic synthesis; Hydrophosphinylation; Palladium cross-coupling
1. Introduction
Phosphorus–carbon bond formation remains an active and important research area, as new reactions are continu-
ously being developed for the preparation of organophosphorus compounds such as phosphines, phosphonates, and
phosphine oxides. Our laboratory has focused on H–phosphinic acid derivatives R1P(O)(OR)H, a less developed class
of compounds. H-phosphinates are potentially versatile intermediates (Scheme 1) for the synthesis of a variety of
organophosphorus compounds, including phosphonates and phosphinates, as well as primary phosphines, secondary
phosphine oxides, and dichlorophosphines, to name a few [1].
The most commonly employed methods to prepare H–phosphinates are summarized in Scheme 2. Each of these
methods suffers from limitations in scope. The use of (TMSO)2PH is inconvenient and often requires a large excess
of the reagent to avoid formation of symmetrically disubstituted phosphinates [2]. Decomposition and disproportiona-
tion also complicate handling and isolation. Only the most reactive alkyl halides produce a reasonable yield of product
[2]. The radical reaction originally introduced by Nifantꢀev et al. [3] and subsequently developed by Karanewsky et al. [4]
suffers from the strongly acidic medium, thus limiting the substrates that can be employed. Hydrolysis or alcoholysis of
dichlorophosphines is limited by the availability of the starting materials. The reaction of a Grignard reagent (and other
organometallics) with (RO)2PCl [5,4] implies stability of the precursor toward Grignard formation. Gallagher devel-
Abbreviations: AHP, anilinium hypophosphite; Dba, dibenzylideneacetone; Dppf, 1,10-bis(diphenylphosphino)ferrocene; Dppp, 1,3-bis(diph-
enylphosphino)propane; Nixantphos, 4,5-bis(diphenylphosphino)phenoxazine; Xantphos, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
*
Tel.: +1 817 257 6201; fax: +1 817 257 5851.
E-mail address: j.montchamp@tcu.edu.
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.10.005

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2389
O
P
OR
R1
R2
O
P
OR
OR
R1
P
R1
OR2
OR2
O
OR
O
R1
P
Cl
Cl
OR
R1
P
H
R1
P
Cl
S
P
H
R1
P
OR
OH
R1
H
O
P
R2
R1
H
Scheme 1. Transformations of H-phosphinates.
oped the alkylation of i-PrOP(O)H2, using sodium isopropoxide and an alkyl halide, but this reaction has rarely been
used [6]. Finally, the Ciba–Geigy reagent [7] solves a number of these limitations, but relies on a protection–deprotection
strategy, and the acidic cleavage of the acetal is not always compatible with functionalized compounds.
In connection with various projects requiring the synthesis of functionalized H-phosphinates, we became aware of
the relative lack of convenient and general methods to access these intermediates. A program was thus initiated to de-
velop novel methods for P–C bond formation based on hypophosphorous compounds ROP(O)H2 as the starting mate-
rials. Progress toward this objective is outlined below.
2. Results and discussion
2.1. Preparation of alkyl phosphinates ROP(O)H2
O
O
R"xSi(OR')4-x
OH
H
OR'
H
R P
R P
ð1Þ
ð2Þ
toluene (or CH3CN)
reflux, 24 h
80-100 %
O
H
MO P
H
O
R'xSi(OR)4-x
H
H
M = H, PhNH3, NH4
RO P
solvent, heat
~ 2 h
R = Me, Et, Bu, Allyl, Ph, Bn, i-Pr
85-100 %
An important component of the methodologies we have developed, is the discovery of a novel preparation of alkyl
phosphinates from hypophosphorous acid and its salts. Initially, we reported the selective esterification of H-phosphi-
nic acids in the presence of dialkyl phosphinic acids using alkoxysilanes (Eq. (1)) [8]. This reaction is useful when a
particular method gives a mixture of these two products which are otherwise difficult to separate, and it is also more
convenient than most alternatives (CH2N2, or DCC/alcohol). We found that similar conditions can be applied to este-
rify hypophosphorous acid (and some salts) to provide alkyl phosphinates in high yield and in a variety of solvents
(Eq. (2)) [9]. In addition, the alkyl phosphinates (which are used in situ) displayed unusual thermal stability, with only
10–20% decomposition at 85 °C for more than 20 h [9]. In fact, stock solutions of EtOP(O)H2 in CH3CN, THF, or
toluene, were found to be stable at room temperature under nitrogen for over a month (less than 10% decomposition).
Alkyl phosphinates for which the corresponding alkoxysilane is not commercially available can be prepared by
transesterification of PhOP(O)H2, or by a slightly modified Stawinski approach [10], using anilinium hypophosphite
(AHP), PivCl, pyridine, and an alcohol (Eqs. (3) and (4), respectively). Finally, reaction of concentrated H3PO2 in
CH3CN with diphenyldiazomethane cleanly gives the corresponding benzhydryl phosphinate (Ph2CHOP(O)H2)
[11]. The reaction of H3PO2 with diazoalkane was the first reported method to prepare alkyl phosphinates, but it is
not commonly employed [12].

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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
O
O
activated RX
1. Boyd & Regan
OH
H
OH
R
and/or
R P
OH
R P
TMS2NH, heat
or
TMSO
TMSO
RCHO
EWG
anh. H3PO2
P H
R
PO2H2
Me3SiCl, i-Pr2NEt
BTSP
(pyrophoric)
EWG
PO2H2
2. Nifant'ev
R
R
H3PO2
PO2H2
H+, peroxide
heat
3. From dichlorophosphines
O
1) R'OH
R PCl2
OR'
H
R P
2) H2O, H+
4. From organometallics
O
1) (R'O)2PCl
R M
OR'
H
R P
2) H2O, H+
1) solvent switch
2) i-PrONa, THF
5. Gallagher
O
P
O
P
O
R
R
H
R
H
H
i-PrOH
i-PrO
and/or
i-PrO
anh. H3PO2
i-PrO
P
3) RX
C6H6, reflux
Dean-Stark
6. Ciba-Geigy
O
O
O
P
EtO
EtO
1)
P-C bond formation
OEt
R
R'C(OEt)3
anh. H3PO2
OH
H
OEt
H
or
H P
R P
R' = H, CH3
2) H+
R'
Scheme 2. Methods for the preparation of H-phosphinates.
O
P
O
H
2 eq. MenOH
solvent, heat
H
H
PhO
MenO P
ð3Þ
ð4Þ
H
100 %
O
O
RO P
O
1.25 eq. Pyr
H
H
+
+
ROH
PhNH O P
3
Cl
RT, N
H
H
2
CH CN
3
1 eq.
1.5 eq.
1.1 eq.
60-90%
0.2 M
2.2. Reactions of alkyl phosphinates with electrophiles
Alkyl phosphinates prepared by the alkoxysilane method react uneventfully with carbonyl compounds and
Michael acceptors (Scheme 3) [9]. Gallagher has reported the only examples of alkylation with alkyl halides
using i-PrOP(O)H2/i-PrONa (Scheme 2, method 5) [6]. The lack of stability of the anions derived from alkyl
phosphinates is well precedented [13], and the use of more hindered isopropyl phosphinate was considered
essential to successful alkylation. We have found that alkyl phosphinates can be alkylated with BuLi at
ꢀ78 °C, or with DBU at room temperature in acceptable yields (Scheme 4) [14]. While preliminary, these re-
sults show promise for the straightforward synthesis of a variety of H-phosphinate esters by alkylation. None-
theless, significant improvements remain to be made, especially in the isolation procedure [15]. At this time, the
DBU-promoted alkylation appears limited to the most reactive alkyl halides, but is very easy to conduct in
practice.

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2391
O
P
HO
Ph
OEt
H
i) OctSi(OEt)3, CH3CN, reflux, 2 h
ii)
H3PO2
PhCHO, i-Pr2NEt, rt, 22 h
NMR: 81%, isolated yield: 52% (1:1)
OHO
P
OEt
H
i) Me2Si(OEt)2, CH3CN, reflux, 2 h
H3PO2
H3PO2
ii)
cyclohexanone, Et3N, reflux, 2 h
NMR: 84%, isolated yield: 31%
O
OEt
i) OctSi(OEt)3, CH3CN, reflux, 2 h
P
H
ii)
CH2=CHCO2Bn
BnO2C
tetramethylguanidine, rt, 3 h
NMR: 92%, isolated yield: 64%
O
P
OBn
H
i) Si(OBn)4, CH3CN, reflux, 2 h
PhNH3OP(O)H2
ii)
CH2=CHCN
NC
i-Pr2NEt, rt, 12 h
NMR: 79%, isolated yield: 60%
Scheme 3. Nucleophilic additions of alkyl phosphinates.
2.3. Palladium-catalyzed cross-coupling of anilinium hypophosphite (AHP) and alkyl phosphinates
Schwabacher and co-workers [16] were first to report the palladium-catalyzed cross-coupling reaction of alkyl phos-
phinates with aryl iodides. Holt and Erb [17] reported one example of cross-coupling between triethylammonium
hypophosphite and a steroid-derived dienyl triflate, but the generality of the reaction was not established. We, in turn,
have investigated the palladium-catalyzed cross-coupling reactions of hypophosphorous compounds with a variety of
electrophiles.
2.3.1. Cross-coupling reactions with AHP
Our initial contribution in this area dealt with the cross-coupling reactions of AHP [18], an easily prepared, relatively
non-hygroscopic salt [19]. A major concern with the cross-coupling reactions of hypophosphorous compounds is the
potential for competing transfer hydrogenation. Indeed, the preparatively useful transfer hydrogenation of alkenes,
alkynes, aldehydes, ketones, and aryl halides is well precedented to take place with hypophosphorous acid or its sodium
and amine salts, under the influence of virtually all transition-metals [20]. This reaction is believed to occur via insertion
1)
2)
BuLi (1 eq.)
O
P
o
THF -78 C
BuO
BuOP(O)H
2
H
Br
60% isolated
o
THF -78 C to RT
1) NaOMe (1 eq.)
THF/MeOH
O
MeO
P
MeOP(O)H
2
Oct
H
2) OctBr, RT
NMR: 46 ppm, 84%
1) DBU (1.1 eq.)
O
EtO
P
CH CN
3
EtOP(O)H
2
H
2) BnBr (1.1 eq.), RT
NMR: 35 ppm, 73%
40 % isolated
Scheme 4. Alkylation of alkyl phosphinates.

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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
O
P
O
Pd(0)L
H
H
n
Ar X
H
H
PdL H
P-H insertion
C-X insertion
Ar H
n
MO
Ar
MO P
PdL H
n
O
O
Pd(0)L
MOP(O)H
2
n
H
H
OM
ArPdL X
X
n
Ar PdP
Ar
P
OM
L
n
Scheme 5. Competing palladium insertion pathways.
of the metal into a P–H bond with subsequent formation of a metal hydride which is the catalytically active reducing
agent. In order to achieve the desired P–C bond formation, the metal must instead insert into a C–X bond (Scheme 5).
We expected that the ligands around the metal might control the relative rates of these two competing insertions.
As it turns out, even PPh3 provides good control for cross-coupling over transfer hydrogenation with the more
reactive aryl iodides, since palladium insertion into the Csp2–I bond is facile [18]. However, the most general con-
ditions employ dppp as the ligand [18]. With this ligand and Pd(OAc)2, even substrates deactivated towards oxida-
tive addition (for example bromoanisole) react in high yield. One example of a highly activated chloride was also
reported [18]. However, we have not yet been able to employ unactivated aryl chlorides. With Pd(OAc)2/dppp
(2 mol% or less) as the catalyst, and Et3N as the base, AHP successfully couples with aryl iodides, bromide, triflates,
Table 1
Representative examples of the AHP coupling
Entry
1
Electrophile
H-phosphinate
product
X
31P NMR
yield
Isolated
yield
I
97
81
81
87
–
PO2H2
X
Br
OTf
–
O
2
–
93
74
PO2H2
O
I
3
4
I
Br
91
85
85
–
MeO
Cl
PO2H2
MeO
X
–
95
94
Cl
PO2H2
I
5
6
7
–
–
81
94
66
60
Cl
PO2H2
PO2H2
Ph
Br
Ph
Br
OTf
85
69
75
–
X
PO2H2
Hex
Hex
8
9
–
–
64
17
–
–
Br
PO2H2
Pr
PO2H2
Pr
I
Pr
Pr
OTf
PO2H2
10
–
96
74

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2393
OTf
O
O
i) LDA, THF, -78oC
ii) PhNTf2, -78oC to rt
81%
BOC2O, Et3N
DMF, rt
N
N
N
O
H.HCl
O
90%
OtBu
OtBu
PhNH3.H2PO2
2% Pd(OAc)2, dppp
PO2H2
i) DBU, MeI, TMSCl
ii) conc. HCl
O
P
OH
Me
HN
Et3N, THF, reflux
64%
N
60%
O
TPMPA
OtBu
Scheme 6. AHP cross-coupling in the synthesis of TPMPA.
and with benzylic chlorides. Interestingly, the reaction still takes place to some extent without base, suggesting that
the nucleophile is the P(III) form of the hypophosphorous compound. In addition, the reaction was quite tolerant to
moisture and even to air, so that reagent grade solvents can be employed directly [18]. The reaction was then ex-
tended to include alkenyl electrophiles, particularly bromides and triflates [21]. Here also, dppp was found to be
the ideal ligand, except with Z-substituted alkenyl halides for which dppf was superior. The palladium-catalyzed
cross-coupling reaction of AHP with a variety of electrophiles (Eq. (5)) constitutes a useful P–C bond formation
methodology and affords access to many H-phosphinates, which were previously difficult to obtain. Table 1 shows
a few examples. This reaction was applied to the expeditious synthesis of the selective GABAC receptor antagonist
(1,2,3,6-tetrahydropyridin-4-yl)-methyl phosphinic acid (TPMPA) (Scheme 6) [21]. The cross-coupling of AHP pro-
vides significant advantages over other approaches because the P–H bond of the intermediate H-phosphinate can be
elaborated into a variety of compounds (Scheme 1).
X
R
R
R
3
2
or
R'
R
1
X
1
O
P
O
P
(X = Br, OTf, I)
H
H
OH
H
(X = OTf, I, Br, CH2Cl)
ð5Þ
PhNH O
3
2 mol % Pd(OAc) , 2.2 mol% dppp
2
o
R
1
CH CN, or DMF, or THF; 60-85 C
3
+
(then H )
2.3.2. Direct formation of H-phosphinate esters
More recently, we have focused on the Schwabacher-like cross-coupling of alkyl phosphinates. Schwabacher
showed that aryl iodides can cross-couple successfully with MeOP(O)H2 (prepared from H3PO2/(MeO)3CH)
but the scope was limited by transfer hydrogenation as well as the rapid thermal decomposition of methyl phos-
phinate [16a]. In subsequent work, the use of t-BuOP(O)H2 was also demonstrated [16b]. Since our method to
prepare alkyl phosphinates results in enhanced thermal stability, [9] the prospect of extending the Schwabacher
cross-coupling seemed excellent. The combination of the AHP cross-coupling [18] with our selective esterification
of H-phosphinic acids [8] would provide the same overall transformation. However, this two-step approach pre-
sents some problems: First, the manipulation is complicated by the fact that the intermediate phosphinate salts
must be acidified prior to the esterification to obtain good yields of esters; and second, the esterification step
often requires long reaction times (12–24 h). A single step process has obvious advantages, especially for
substrates (such as nitrogen heterocycles) for which intermediate acidification is problematic, or for highly
water-soluble H-phosphinic acids which cannot be extracted easily. The direct coupling of alkyl phosphinates
provides H-phosphinate esters which can be purified by standard chromatographic techniques, and it minimizes
manipulations and reaction time. We have found that alkyl phosphinates (prepared by the alkoxysilane method)
couple successfully with aryl- and heteroaryl iodides, bromides, triflates, and benzylic chlorides (Eq. (6)) [22]. We
have just extended the process to also include alkenyl halides [23]. Initially, DABCO was employed as the base,
but generally Et3N was found to give similar results. In some cases, the overall reaction may still proceed via
the coupling of a salt followed by in situ esterification [22]. However, the HX which is produced during the
coupling step must be essential to esterification, since the alkoxysilane esterification of pure H-phosphinate salts

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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
From iodides
O
P
Me
O
P
O
P
O
P
H
OBu
H
OBu
H
OBu
H
OBu
Cl
MeO
83%
80%
80%
63%
O
O
P
O
H
OBu
H
OBu
H
OBu
P
P
S
BOCHN
N
82%
64%
36%
From bromides
O
H
P
O
P
O
P
O
P
H
H
H
OBu
OBu
OEt
OBu
N
N
NC
69%
65%
78%
51%
From a triflate
From benzylic chlorides
O
H
O
P
P
O
P
O
H
H
H
OBu
P
OBu
OBu
OBu
N
N
80%
24%
46%
88%
Chart 1. Synthesis of H-phosphinate esters via palladium-catalyzed cross-coupling.
is very inefficient [8]. At least in the case of aryl iodides, the cross-coupling appears to proceed in a single step
(like in the identical Schwabacher reaction [16a]) since some reactions conducted in the absence of a base (and
therefore without the possibility for the formation of a hypophosphite salt) occur in nearly quantitative yields.
The mechanistic subtleties of the one-pot reaction are currently being examined [23].
(RO) SiR' (3 eq.); ArX or HetX (1 eq.)
4-n
n
O
OR
PhNH .OP(O)H
3
2
Ar(Het) P
H
ð6Þ
3 eq.
Et N (3 eq.); cat. Pd(OAc) ,/dppp
3 2
solvent, heat
R = Bu, Et; X = I, Br, OTf, CH Cl
2
An interesting extension of the direct coupling was made with the use of aminosilicates (Eq. (7)) [22,23]. The
commercially available 3-aminopropyltriethoxysilane serves three distinct purposes: it may act as the base for the pal-
ladium-catalyzed process (to shuttle from Pd(II) to Pd(0)), it provides the esterification reagent, and it simplifies the
work-up since the silicate by-product can be removed by simple aqueous wash.
(RO) SiCH CH CH NH (1.2 eq.)
3
2
2
2
2
O
P
ArX (1 eq.)
OR
PhNH .OP(O)H
Ar
ð7Þ
3
2
H
2 mol% Pd(OAc) ,/dppp
1.2 eq.
2
solvent, heat
R = Me, Et
Some of the H-phosphinate esters synthesized are summarized in Chart 1 (all yields shown are isolated [15]). It
should be noted that many of these compounds have never been prepared before. Thus the initial objective of expand-
ing the scope of the Schwabacher coupling has now been accomplished, and a variety of H-aryl- and H-hetero-
arylphosphinates can be prepared conveniently in a single step. Finally, we have just extended this cross-coupling
reaction to include alkenyl halides, and a full study is currently in progress [23]. A successful example is shown in
Eq. (8).

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2395
Et N (1.2 eq.)
3
O
P
Ph
Ph
OBu
PhNH .OP(O)H
+
(BuO) Si +
3
2
4
Br
2 mol% Pd(OAc) ,/dppp
2
H
ð8Þ
THF, reflux
1.2 eq.
1.2 eq.
1.0 eq.
80% NMR yield
79 % isolated
2.4. Radical reactions of hypophosphorous compounds
The addition of phosphorus-centered radicals to olefins has been known for several decades [24]. As early as 1955,
Williams and Hamilton [25] investigated the use of aqueous H3PO2. Nifantꢀev et al. [3] then significantly developed the
reaction to the point where it has become a major preparative method for H-phosphinic acids. In fact, a slightly mod-
ified version of the Nifantꢀev radical addition is used today in the manufacture of the heart drug Monopril [26]. In spite
of the modern improvements in the reaction conditions [4] (AIBN initiator, refluxing EtOH), the medium is always
strongly acidic and therefore not compatible with functionalized molecules.
Table 2
Scope of the radical hydrophosphinylation
31
Entry
1
Alkene
H-phosphinate product
R@
P NMR yield
Isolated yield
H
Me
90
–
80a
96b
O
H
Hex
RO P
Hex
2
H
89
85
76
87a
O
H
55d
Ph
Me
Bu
65c,e
RO P
Ph
3
4
–
72
71a
Cl
O
H
HO P
Cl
H
96
97
86a
60b
60c
O
H
Me
Bu
P
–
RO
5
6
H
Me
100
100
51a
60d
NHBOC
O
H
H
RO P
NHBOC
H
Me
77
93
49a
40b
O
OPiv
RO P
OPiv
7
8
–
–
100
42a
52c
.
O
NH2 AcOH
H
HO P
NH2
–
O
OAc
H
BuO P
OAc
TfO
80a
59c
O
9
H
Bu
82
62
H
RO P
TfO
a
Method A: (i) NaH2PO2 Æ H2O, alkene, Et3B, air, MeOH, rt, 2 h and (ii) H+.
Method B: (i) conc. H3PO2, (MeO)3CH, 1–2 h and (ii) dioxane, alkene, Et3B, air, rt, 2 h.
b
c
Method C: (i) aq. H3PO2, BuOH, cyclohexane, reflux, Dean–Stark trap, 4–6 h and (ii) alkene, Et3B, air, rt, 2 h.
Method D: (i) conc. H3PO2, (MeO)3SiCH2CH2CH2NH2.TFA, CH3CN, reflux, 2 h and (ii) alkene, Et3B, air, rt, 2 h.
Method E: (i) conc. H3PO2, (BuO)4Si, cyclohexane or CH3CN, reflux, 2 h and (ii) alkene, Et3B, air, rt, 2 h.
d
e

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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
To solve this significant limitation, we have developed a room-temperature radical hydrophosphinylation reaction,
which proceeds under very mild conditions and has a broad scope [27]. Our process is based on the initiation of the
radical reaction through trialkylboranes autooxidation. Alkyl radicals are then sufficiently reactive to form the desired
hypophosphorous radical and to maintain a viable chain reaction at low temperature. In the classical thermal reaction,
multiple additions of the initiator are always required.
2.4.1. Alkenes
Using trialkylboranes (usually a commercial solution of Et3B in hexane or THF) in an open reaction vessel success-
fully initiates the addition of hypophosphorous compounds to alkenes. Hypophosphorous acid, its salts (including
AHP and NaH2PO2), and even alkyl phosphinates can be added to alkenes at room temperature [27]. With alkyl phos-
phinates, a substoichiometric amount of R3B is sufficient to achieve good yields of addition, but the other starting
materials are best used with 0.5–1.0 equivalent of R3B. In our initial work [27], the alkyl phosphinates were prepared
by the orthoformate method [28] (Fitch), or by the Dean–Stark method [29] (Nifantꢀev), and thus were more sensitive
to decomposition, or limited to a small set of solvents. Since then, we found our alkoxysilane method to be superior,
both in terms of convenience and generality (alkyl group, reaction solvent) [9]. The radical-based hydrophosphinyla-
tion [27] has a very broad scope (Table 2) and is conveniently run at room temperature and in an open flask, thus mak-
ing it an experimentally straightforward reaction which can be easily scaled-up. The reactions are usually complete in
less than two hours. Nifantꢀev and Koroteev [30] had studied the reaction of NaH2PO2 under neutral conditions, but
this required multiple addition of a peroxide initiator in an autoclave, at high temperature.
For the first time, we have been able to prepare H-phosphinates in high yields from both acid- and base-sensitive
alkenes (enol ethers, enol esters, and BOC-protected amines) [27]. Alkyl phosphinates are themselves sensitive to mois-
ture and air, but the conditions we employ are sufficiently mild, and the reaction times sufficiently short, for decom-
position to not be a major problem. Even alkyl chlorides, which would normally be reduced above ambient
temperature, are well-tolerated, however, bromides are reduced under our conditions. A feature of the reaction is
its very high selectivity for the formation of H-phosphinates: even when excess alkene is employed, the disubstituted
phosphinates are minor products. This indicates the much higher reactivity toward radical formation of the phosph-
inylidene group (P(O)H) in hypophosphorous compounds over H-phosphinates. The only type of H-phosphinate ester
which reacted in preparatively useful yield was PhP(O)(OR)H, but this has not been investigated thoroughly. The ther-
mal radical reaction of H-phosphinate esters is also well known and has often been used to prepare disubstituted phos-
phinate esters.
A limitation of our radical hydrophosphinylation is the apparent electrophilicity of the P-centered radicals, so that
polar electron-poor alkenes (such as Michael acceptors), and other substrates which give stabilized radicals (such as
styrene) are mediocre substrates. In the case of allyltributyltin, we demonstrated a recycling stratagem which employed
cyclohexyl bromide as a shuttle to improve chain propagation [27]. With Michael acceptors, the addition of ROP(O)H2
can be conducted under basic conditions (Scheme 3), so the radical reaction is unnecessary.
With our new alkoxysilane methodology for the preparation of alkyl phosphinates, thermal decomposition is min-
imal even over an extended period of time [9]. Thus, more classical reaction conditions using AIBN could be contem-
plated. Although we have not yet conducted a full study of these conditions, the use of AIBN in refluxing CH3CN gives
satisfactory results, as shown in Eq. (9) [31].
EtO
OEt
Si
(2 eq.)
1)
2)
O
P
CH3CN, reflux, 2 h
EtO
conc. H3PO2
NHBOC
80% isolated
ð9Þ
H
NHBOC
AIBN, reflux
We have also studied the reactivity of 1,1-difluoroolefins to see if the corresponding a,a-difluorophosphinates could
be prepared and serve as phosphate analogs. Unfortunately, although P–C bond-formation does occur, poor regiocon-
trol and variable amounts of reduction products were observed [32]. Improvements may still be possible, but it is un-
likely this reaction may be developed into a generally applicable approach, unless regiocontrol can be improved. We
have not yet tested all the possibilities with regards to the choice of hypophosphorous compound, or conditions (AIBN
vs Et3B). 1-Fluoroolefins have not been tried.
2.4.2. Alkynes
Once the radical hydrophosphinylation of alkenes developed, we turned our attention to alkynes. Nifantꢀev, once
again, had pioneered the hydrophosphinylation of alkynes using his conditions (Eq. (10)) [33]. Alkenyl-H-phosphinic

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2397
acids were always the major products (formed as a ꢁ2:1 trans/cis mixture), and 1,2-bis-H-phosphinic acids were pro-
duced in variable but minor amounts.
R
R
R
H2O2P
+
H3PO2
H2O2P
H+, peroxide
heat
ð10Þ
PO2H2
minor (25% max)
major (40-50%)
Our palladium-catalyzed cross-coupling reaction [18,23] provides an alternative approach to alkenyl-H-phosphi-
nates, especially because of its stereospecificity. It was hoped, however, that the radical reaction conducted at room
temperature may lead to increased selectivity over the Nifantꢀev approach. In addition, since we are able to use a broad
range of hypophosphorous compounds as starting materials, we thought our radical reaction may lead to a useful P–C
bond-forming reaction with alkynes. Our work in this area has not yet been published, except for some data contained
in a patent application [34].
The most interesting starting material turned out to be NaH2PO2. Under conditions identical to those developed for
alkenes (NaH2PO2 Æ H2O, MeOH, Et3B, RT), the previously unknown 1,1-bis-H-phosphinates were produced from
terminal alkynes (Eq. (11)) [34,35]. The formation of these compounds was completely unexpected, in light of the
above-mentioned
O
PO2HNa
R
R
H
H
NaO P
NaHO2P
ð11Þ
R3B, air
MeOH, RT
~30-60% isolated
literature precedent from Nifantꢀev et al. [33]. Besides the fact that the reaction is trivial to run (as was the case with
alkenes [27]), an added bonus is that disodium 1,1-bis-H-phosphinate salts spontaneously precipitate from the reaction
mixture. This property seems to hold throughout the substrates we have investigated to date and provides a simple
method to purify the products by filtration (and with a methanol wash if residual NaH2PO2 is present). The yields
are generally moderate (30–60%), but this is compensated by the fact that reaction and purification are so straightfor-
ward. In addition, the yields can sometimes be improved by adjusting the number of equivalents of NaH2PO2, the con-
centration, and by using co-solvents to modulate solubility. Regardless of the terminal alkyne employed, the soluble
portion of the reaction mixture generally contains only traces of other products deriving from P–C bond formation
[35].
Interestingly, AHP leads mostly to the soluble 1,2-bis-H-phosphinates in good yields. The reason for the difference
between AHP and NaH2PO2 is not completely clear at this time, but mechanistic issues are currently being investi-
gated. Alkyl phosphinates react to give mixtures of trans/cis H-alkenylphosphinate stereoisomers with either the
Et3B or the thermal, AIBN-initiated protocol, and alkenyl-H-phosphinates can be obtained in reasonable yield (Eq.
(12)) [31]. This may point to both steric and electronic factors influencing the course of the reaction, as bis-addition
is not observed with the alkyl phosphinates.
O
P
O
Oct
BuO
H
H
H
BuO P
ð12Þ
AIBN
CH3CN, 0.1M, reflux
Oct
64% isolated
Our radical hydrophosphinylation of alkynes gives potentially valuable products. The most important of these
are undoubtedly the novel 1,1-bis-H-phosphinates, because those are precursors to the corresponding 1,1-bisphos-
phonates [36] via oxidation (H2O2, bleach). 1,1-Bisphosphonates are important medicinally, for example in the
treatment of bone-related diseases [37]. Various molecules (drugs, proteins) have also been conjugated to 1,1-bis-
phosphonates for bone-targeting, but the syntheses of these conjugates typically require multistep sequences and
protection–deprotection strategies [38]. Since the conditions for our radical hydrophosphinylation with NaH2PO2
are so mild, complex alkynes can be employed and conjugation can be conducted as the penultimate step (before
oxidation) without resorting to phosphonate protecting groups. The oxidation of the H-phosphinate to the phos-
phonate is also very mild and should be compatible with many complex molecules. Alternatively, 1,1-bis-H-phos-
phinates with a reactive tether for subsequent conjugation can be synthesized. An example is shown in Eq. (13).
Thus, the new reaction may constitute an original and expeditious approach toward biologically relevant bisphos-

2398
J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
phonates. Research along these lines is being actively pursued and includes plans to study the reaction in aqueous
media. The 1,2-bis-H-phosphinates (obtained with AHP) may also be interesting, but as far as we know, these
compounds have not been tested as pyrophosphate analogs.
O
ONa
O
H P
NaH2PO2, Et3B
H
ð13Þ
acetone, MeOH
RT, 2.5 h
O
P
O
O
ONa
O
50% isolated
2.5. Palladium-catalyzed hydrophosphinylation
2.5.1. Homogeneous catalysis
During our work on the cross-coupling reactions of hypophosphorous compounds, [18,21] we realized that the com-
peting transfer hydrogenation [20] pathway (Scheme 5) could provide unique synthetic opportunities for catalytic P–C
bond formation, if the reactivity of the postulated phosphinyl palladium hydride intermediate (boxed structures in
Scheme 7) could be harnessed before its decomposition to a palladium dihydride species. It was thought that the ligand
could control the lifetime and reactivity of this species. This mechanism-based idea (Scheme 7), perhaps simplistic,
turned out to be correct, at least in practice, and we were able to develop a unique catalytic P–C bond-forming reaction
[39].
Prior to this, Tanaka had reported the catalytic hydrophosphonylation of alkenes and alkynes with H-phospho-
nates (Scheme 8), using palladium- and rhodium-based catalysts [40]. There are many theoretical and practical dif-
ferences between Tanakaꢀs hydrophosphonylation and our hydrophosphinylation, much like there are significant
differences between the cross-coupling of H-phosphonates and the Schwabacher coupling of an alkyl phosphinate.
An important theoretical distinction is the much higher reducing power of hypophosphorous compounds relative
O
H
(R = Alk, PhNH3, etc)
hypophosphorous derivative
RO
P
H
O
P
Pd(0)Ln
R1-Pd(0)LnX
base
PdLnR1
+ B.HX
RO
oxidative addition
H
reductive
elimination
O
P
O
H
O
P
PdLnH
PdLnH
R1
RO
RO
P
RO
P
+ Pd(0)Ln
PdLn
H
RO
H
OH
H
hydropalladation
NuH (hydrogen donor,
H2O, ROH....)
C
C
H
C
C
O
P
RO
A (hydrogen acceptor)
PdLn
H
reductive
O
P
elimination
H
Nu
RO
+ AH2 + Pd(0)Ln
O
RO
H
H
P
+ Pd(0)Ln
C
C
HYDROPHOSPHINYLATION
TRANSFER HYDROGENATION
CROSS-COUPLING
Scheme 7. Mechanistic pathways in the Pd-catalyzed reactions of ROP(O)H2.

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2399
O
3 mol% PdMe2(Ph2Me)2
OR
OR
O
+
H
P
R'
(high regioselectivity)
R'
R'
P(OR)2
THF, reflux, 15-20 h
~ 41-95 %
(R = Me, Et)
O
O
P
O
O
O
O
3 mol% PdMe2(Ph2Me)2
H3C
P
H
P
R'
+
O
O
O
Ph
R' = Ph, >95%
THF, reflux, 15-20 h
~ 83-100 %
O
O
O
P
O
1-2 mol% RhBr(PPh3)3
P
H
+
R'
R'
O
O
THF, reflux, 15-20 h
~ 46-97 %
Scheme 8. Tanaka hydrophosphonylation of alkenes and alkynes.
to H-phosphonates, while in practice H-phosphinate products are considerably more versatile intermediates than
are phosphonates.
Tanaka established the insertion of palladium into the P–H bond of H-phosphonates, but this insertion was
certainly not a surprise with H-phosphinates, considering the large body of literature on the transfer hydrogena-
tion of H3PO2 and its derivatives, and our cross-coupling work. In addition, Tanakaꢀs reaction uses relatively elab-
orate catalysts and with alkenes the hydrophosphonylation is limited to pinacol H-phosphonate. The latter is a
significant limitation because the pinacol phosphonate esters require harsh conditions for cleavage [41]. Therefore
the overall approach may not provide significant advantages over the classical Arbuzov or Michaelis–Becker phos-
phonate syntheses.
Our hydrophosphinylation reaction turns out to be very general and practical, and a variety of catalysts can
be employed. While much of this work remains unpublished, we have already reported in a communication the
successful reaction of H3PO2, AHP, and alkyl phosphinates with both alkenes and alkynes [39]. Some dienes
and allenes also react [31]. Excellent selectivity for hydrophosphinylation is always observed, even though H-
phosphonates [(RO)2P(O)H] are present in the reaction mixture due to the catalyzed (and uncatalyzed) decom-
position of the hypophosphorous starting materials. Even with alkynes, the Tanaka-like addition of these side-
products [40a] is not observed. Several ligands were found to be capable of steering the reaction toward addi-
tion instead of transfer hydrogenation. N-Heterocyclic carbene (NHC) ligands can be employed [11] to give high
yields of hydrophosphinylation (>80% yield), but some phosphine ligands remain superior (ꢁ100% yield). The
two best ligands seem to be xantphos and dppf, but many other ligands which have been tested still deliver
H-phosphinates in good yields when alkyl phosphinates are employed. For example, Cl2Pd(PPh3)2/2 MeLi is
quite successful, and we have since found that MeLi is often not necessary, and similarly high yields can be
observed in its absence. Alkyl phosphinates are sufficiently strong reducing agents to generate the reactive
Pd(0) catalyst from a variety of Pd(II) precatalysts (this was certainly established in the case of the base-free
cross-coupling we mentioned earlier), and a variety of palladium sources can be employed (PdCl2, Pd(OAc)2,
Pd2dba3, and Pd–C). Xantphos emerged as perhaps the most widely useful ligand to conduct the addition reac-
tion with all the hypophosphorous compounds investigated. In fact, suppression of the transfer hydrogenation is
so efficient that even aqueous H3PO2 can be employed. Very low catalyst loadings (as little as 0.02 mol% Pd)
still provide good conversions [39].
In many instances, the reaction can be conducted at room temperature.
Table 3 shows some examples of the Pd-catalyzed hydrophosphinylation. 1,2-Disubstituted alkenes are poor sub-
strates, possibly because of the reversible dehydropalladation. In this case, radical hydrophosphinylation [27] is com-
plementary in its scope and can be used instead. Functional groups are well-tolerated, and in the case of terminal
alkynes, useful selectivity can be observed. This selectivity can be controlled depending on the catalyst employed:
Pd/xantphos or Pd/dppf give the linear product (>3:1), whereas Cl2Pd(PPh3)2/2MeLi gives the branched isomer
(Eq. (14)).

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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
Table 3
Palladium-catalyzed hydrophosphinylationa
31
Entry
1
Alkene
H-phosphinate product
R@
P NMR yield
Isolated yield
H
Bu
100
89
67b
76
O
H
Hex
RO P
Hex
2
H
Et
100
100
100
92
84
–
O
H
Ph
RO P
Ph
PhNH3
3
4
H
Et
100
100
83b
61
Br
O
H
RO P
Br
H
Et
0
10
–
–
O
H
RO
P
5
6
–
45
–
Pr
PO2H2
Pr
Pr
Pr
H
Bu
100
42
93
–
O
P
H
RO
7
8
Bu
100
69 (4.4:1)
O
Ph
H
O
RO P
H
Me
+
RO P
Ph
Ph
H
Bu
100
81
81
–
O
H
P
RO
Br
Br
9
Et
Bu
75
78 (5:1)
70 (3.7:1)
–
Oct
O
H
O
RO P
H
H
+
Oct
RO P
Oct
10
H
Bu
100
35
88
–
Bu
Bu
O
RO P
Bu
Bu
H
O
11
–
64
57
HO P
TMS
TMS
a
All reactions were catalyzed by 0.025–0.5 mol% Pd2dba3, and 0.06–1.2 mol% xantphos in refluxing CH3CN. Alkyl phosphinates ROP(O)H2 (1.5
eq.) were prepared as shown in Eq. (2), using (BuO)4Si or (EtO)2SiMe2.
b
Conducted at room temperature.

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2401
1) toluene
PPh2
PPh2
PPh2
PPh2
PPh2
O
O
reflux
1) Pd2dba3
2) wash
N
N
O
N C O
+
N
N
O
HN
O
Pd
H
H
2) i-Pr2NH
(polystyrene)
PPh2
active catalyst
supported ligand
Scheme 9. Preparation of the polymer-supported catalyst.
Table 4
Hydrophosphinylation with the heterogeneous catalyst
Entry
1
Substrate
Product
H3PO2
50% aq
Conditions
Runs
3
Isolated yield%
70
Reflux, N2CH3CN
PO2H2
PO2H2
Hex
Hex
2
3
4
50% aq
50% aq
50% aq
Reflux, N2CH3CN
Reflux, N2CH3CN
Reflux, N2CH3CN
4
3
5
50
Oct
Ph
Oct
Ph
96
PO2H2
90 (2:1)
PO H
2
2
+
Ph
PO H
2 2
Ph
Ph
5
6
conc.
conc.
Reflux, N2CH3CN
RT, N2CH3CN
1
1
92
42
PO2H2
Ph
PO2H2
Ph
7
8
conc.
conc.
Reflux, N2CH3CN
Reflux, N2CH3CN
1
1
53 (2:1)
PO H
Hex
Pr
2
2
PO
H
+
2
2
Hex
Hex
Pr
46
Pr
PO2H2
Pr
O
P
O
O
P
H
R'
R'
cat. Pd/xantphos
H
H
H
RO
RO P
RO
ð14Þ
R'
cat. PdCl2(PPh3)2
/2MeLi
R'
R = Alk
major
The power of the Pd-catalyzed hydrophosphinylation lies in its broad scope as well as the synthetic flexibility pro-
vided by the H-phosphinate products (Scheme 1). For example, phosphonates can be obtained simply through known
methods, as seen in Eq. (15). Tanakaꢀs reaction would give the corresponding pinacol phosphonate which then requires
manipulations for cleavage or transesterification [41]. Other more interesting tandem reactions for a second P–C bond
formation in one pot are being studied.

2402
J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
1) MeOP(O)H2, CH3CN, reflux
cat. Pd2dba3/xantphos
O
P
OMe
OMe
ð15Þ
Ph
Ph
2) CCl4, Et3N, MeOH, RT
72% isolated
2.5.2. Heterogeneous catalysis
We have also developed a polymer-supported hydrophosphinylation catalyst [42]. Even if low catalyst loadings can be
employed in the homogeneous version of the reaction (ca. 1 mol% Pd or less), palladium remains expensive and recycling is
alwaysdesirable.Theuseofheterogeneouscatalystsallowstherecoveryofthemetalandsimplifiespurification.Wealready
knew that palladium on carbon gives satisfactory result when xantphos is added [39]. However, even if xantphos is inex-
pensive and easy to prepare, a fully reusable catalyst would be ideal. We focused more particularly on the reaction of hypo-
phosphorousacid,andwewantedaneasilypreparedandrobustcatalysttomaximizethepossibilityforapplicationinother
laboratories. We settled on a polystyrene framework to prepare a polymer-supported ligand in a single step from commer-
cially available starting materials (Scheme 9) [43]. The active catalyst is obtained by treating the ligand with Pd2dba3 either
in situ, or in a separate step. The resulting catalyst is air stable and does not require special handling precautions [42].
Hydrophosphinylation with hypophosphorous compounds takes place in good yield with the polymer-supported
catalyst (Table 4). The scope is narrower than with the homogeneous system, particularly with alkynes. However, mul-
tiple runs can be conducted without addition of palladium. The polymer catalyst is also more air and water tolerant
than its homogeneous counterpart, and provides an environmentally friendly synthesis of H-phosphinic acids from
aqueous H3PO2. The ligand can even be employed with palladium on carbon to furnish a doubly heterogeneous reus-
able catalyst [42]. Since the reaction can be conducted under mild conditions (sometimes at room temperature) and in
the presence of water and even air, and since the H-phosphinic acid products can be obtained in good purity via a
simple extractive work-up, possible future applications include the preparation of radiolabeled organophosphorus
compounds from T3PO2 or even H3 [32]PO2. We have shown that the polymeric catalyst can be employed to conduct
deuteration of alkenes and alkynes (75–90% D-incorporation) [42].
The homogeneous and heterogeneous palladium-catalyzed hydrophosphinylation of unsaturated compounds pro-
vide a novel P–C bond forming reaction of broad applicability. The scope and mechanism of this reaction continue
O
O
R'xSi(OR)4-x
O
O
Si(OR')4
H
H
H
H
OH
H
OR'
H
MO P
RO P
R P
R P
solvent, heat
~ 2 h
toluene
reflux, 24 h
M = H, PhNH3, NH4
Esterification
X
R1
R2
R3
X
or
Pd-Catalyzed
P-C bond formation
R1
R2
R
(X = Br, OTf, I)
(X = OTf, I, Br, CH2Cl)
metal-catalyzed
hydrophosphinylation
O
P
O
cross-coupling
H
H
H
H
R'O
R'O P
O
O
H
O
H
H
R'O P
H
R'O P
O
R1
R2
R1
R2
OR'
H
*
R P
radical
addition/substitution
EWG
hydrophosphinylation
Radical Reactions
R' = H, PhNH3, Na, Alkyl...
R = Aryl, Alkenyl, Allylic, Alkyl...
R-X
Nucleophilic Reactions
O
O
P
R2
OR'
R1
R2
*
*
*
R1
P
R2
R1
P
H
R3
Scheme 10. Methodological summary.

J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
2403
to be delineated and improvements remain to be made. In addition, the uses of chiral auxiliaries and chiral catalysts are
also being investigated, particularly in the context of P-chiral compound synthesis [44]. Since chiral auxiliaries have
generally been developed to induce diastereofacial differentiation, we are faced with the problem of finding an efficient
auxiliary for a tetrahedral structure instead of a planar one. This will require designing an auxiliary for our specific
purpose. Nonetheless, some encouraging results have been secured.
3. Conclusions and future directions
Several new methodologies for the preparation of H-phosphinic acids and esters have been and continue to be devel-
oped in our laboratory (Scheme 10). These reactions provide general methods for phosphorus–carbon bond formation
which are valuable not only for the synthesis of H-phosphinates but also for a variety of other organophosphorus com-
pounds which can be derived from them [1]. H-Phosphinates are ideal synthons in organophosphorus chemistry, but
their use has been hampered by the paucity of synthetic methodology available. It is hoped that the synthetic potential
of H-phosphinates will be more fully exploited once practical and general methods are available for their synthesis.
Practical and scalable reactions are the key to both academic and industrial applications. Our ultimate objective is
to develop approaches for the preparation of virtually any H-phosphinate using chemistry which can be conducted in
any laboratory with standard equipment and widely available, inexpensive, reagents and catalysts. In the past months,
we have discovered a ligand-free NiCl2-catalyzed hydrophosphinylation of alkynes with alkyl phosphinates [45,46].
This reaction bridges the gap which existed in the low-yielding Pd-catalyzed hydrophosphinylation of internal alkynes
with alkyl phosphinates (see Table 3, entry 10). These results will be communicated in the near future [45]. We have
also found that a number of our reactions can be conducted with microwave irradiation to furnish high yields of prod-
ucts in minutes.
Several reactions have been developed in our laboratory (Scheme 10) and the arsenal of phosphorus–carbon form-
ing reactions continues to expand. Several methodological and synthetic opportunities are being created for new re-
search. Perhaps the most intriguing and challenging one is in asymmetric synthesis. Because the configurational
stability of P-chiral H-phosphinates has been previously established [47] future work will focus on the development
of asymmetric versions for the reactions outlined in this account. The synthesis of P-chiral compounds remains a major
frontier in organophosphorus chemistry, and while many obstacles remain, we are optimistic that, in time, they will be
overcome.
Acknowledgments
I gratefully acknowledge the generous financial support of our research by the following: the National Institute of
General Medical Sciences/NIH (1R01 GM067610-01A1), the National Science Foundation (CHE-0242898), the Ro-
bert A. Welch Foundation (P-1435), The Petroleum Research Fund administered by the ACS (34334-G1 and
36915-AC1), and the TCU Research and Creative Activities Fund. I am also indebted to the students and postdoctoral
research associates, past and present, who contributed to this research and whose names can be found in the references.
References
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`
[14] I. Abrunhosa-Thomas, P. Ribiere, J.-L. Montchamp, unpublished results.
[15] A note about yields. We usually report both 31P NMR yields and isolated yields. The NMR yields are determined by integration of all the
resonances in the 31P NMR spectra, an approach which is valid if no phosphorus-containing gas (i.e., PH3) evolves, or if the precipitate in an
heterogeneous mixture does not contain phosphorus. The yields determined by NMR are accurate within ꢁ10% of the value indicated, and are
reproducible. The method is particularly useful to gauge the intrinsic efficiency of a specific reaction under various conditions or with various
substrates. Some experiments with internal standards and gas chromatography also confirmed the validity of the method. In several cases, the
isolated yields are very close to the NMR yields. However, isolated yields are often significantly lower. This reflects the fact the H-phosphinic
acids and their esters are difficult to purify, rather than some inaccuracy in NMR yield measurements. In the case of the acids, which are typically
isolated by extraction, the corresponding isolated yields directly reflect the water-solubility of these compounds. In the case of H-phosphinate
esters, chromatography is often complicated by the very polar nature of these compounds, and their relative ease of hydrolysis. For a discussion,
see Ref. [27]..
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`
[31] (a) S. Deprele, J.-L. Montchamp, unpublished results;
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`
[34] S. Deprele, J.-L. Montchamp, Bis-H-Phosphinic Acid Derivatives as Precursors to Therapeutic Bisphosphonates and Uses Thereof, US Patent
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`
[35] S. Deprele, A. Sutor, J.-L., Montchamp, manuscript in preparation.
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´ ´
[38] Bisphosphonate Conjugates: [methotrexate] (a) G. Sturtz, G. Appere, K. Breistol, O. Fodstad, G. Schwartsmann, H.R. Hendriks, Eur. J. Med.
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J.-L. Montchamp / Journal of Organometallic Chemistry 690 (2005) 2388–2406
(g) [carboranes]R.G. Kultyshev, J. Liu, S. Liu, W. Tjarks, A.H. Soloway, S.G. Shore, J. Am. Chem. Soc. 124 (2002) 2614;
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`
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`
[42] S. Deprele, J.-.L. Montchamp, Org. Lett. (2004), ASAP article.
[43] Polystyryl isocyanate is available from Aldrich or Chemtech. Nixantphos is available from Strem.
`
[44] (a) K. Bravo-Altamirano, S. Deprele, J.-L. Montchamp, unpublished results;
(b) see also Ref. [31b].
`
[45] (a) P. Ribiere, K. Bravo-Altamirano, M.I. Antczak, J.D. Hawkins, J.-L. Montchamp, manuscript in preparation;
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