Hydrophosphinylation of unactivated terminal alkenes catalyzed by nickel chloride

Article abstract of DOI:10.1021/jo4008749

The room-temperature hydrophosphinylation of unactivated monosubstituted alkenes using phosphinates (ROP(O)H₂) and catalytic NiCl₂ in the presence of dppe is described. The method is competitive with prior palladium-catalyzed reactio

Full text of DOI:10.1021/jo4008749

Article
pubs.acs.org/joc
Hydrophosphinylation of Unactivated Terminal Alkenes Catalyzed
by Nickel Chloride
Stephanie Ortial, Henry C. Fisher, and Jean-Luc Montchamp*
́
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129, United States
S
* Supporting Information
ABSTRACT: The room-temperature hydrophosphinylation
of unactivated monosubstituted alkenes using phosphinates
(ROP(O)H2) and catalytic NiCl2 in the presence of dppe is
described. The method is competitive with prior palladium-
catalyzed reactions and uses a much cheaper catalyst and
simple conditions. The scope of the reaction is quite broad in terms
of unactivated terminal olefins, proceeds at room temperature,
often avoids chromatographic purification, and allows one-pot conversion to various organophosphorus compounds.
and internal alkynes (eq 1).10 In this reaction, ROP(O)H2 plays
several roles as a (a) reagent, (b) reducing agent to activate the
INTRODUCTION
■
Organophosphorus compounds constitute an important class
of industrial and fine chemicals because of their properties
nickel precatalyst, (c) ligand to stabilize the Ni(0) catalyst, and
(d) drying agent when NiCl2-hydrate or moisture is present.10
in flame-retardants, extractants, agrochemicals, ligands used in
Unfortunately, hydrophosphinylation of alkenes under similar
numerous metal-catalyzed reactions, pharmaceuticals, etc.1
conditions was not very successful (31P NMR yield <70%), and
Addition reactions are intrinsically atom-economical because
at least not competitive with our palladium-catalyzed version.10
formation of byproducts is avoided. As a result, various meth-
Still, a nickel-catalyzed version of alkene hydrophosphinylation
odologies for the addition of phosphorus reagents to alkenes
would be useful. Often in nickel catalysis, Ni(cod)2 is the
and alkynes have been reported.2 Our own interest in this area
precursor, but it is an expensive (as costly as standard palladium
salts) and highly air-sensitive species (requiring glovebox and
related stringent inert-atmosphere techniques). On the other
hand, nickel chloride is cheaper than palladium salts and its
focuses on the addition chemistry of phosphinates (ROP(O)H2)3,4
and H-phosphinates (R1P(O)(OR)H).5 Importantly, phosphi-
nates provide a more environmentally friendly alternative to
phosphorus trichloride, the intermediate commonly employed
in organophosphorus synthesis.6 Like PCl3, phosphinates are
derived industrially from elemental phosphorus; however, they
avoid the wasteful use of chlorine. Another advantage of phos-
phinates over other reagents such as H-phosphonates7 is the
synthetic flexibility H-phosphinates offer in accessing various
functionalities.6 The addition of phosphinates to unsaturated
hydrocarbons could be industrially relevant, whereas currently
only phosphine PH3 is employed for this purpose.8 Conjugate
addition of alkyl phosphinates to Michael acceptors is an
important method but requires substitution with an electron-
withdrawing group;9 therefore, addition to unactivated unsatu-
rated hydrocarbons is considerably more difficult and typically
uses a transition metal catalyst3 or a free radical initiator.4
complexes by 2 orders of magnitude or more. Herein, we report
our progress with this reaction and the successful addition of
phosphinates to unactivated alkenes catalyzed by nickel chloride,
in the presence of an external phosphine ligand.
RESULTS AND DISCUSSION
■
Although our early work indicated that phosphinates did add to
olefins under nickel catalysis,10 the yields were not satisfactory.
Prompted by the preliminary results and our work with alkynes,
we have investigated this nickel-catalyzed hydrophosphinylation
reaction in more details and are now reporting a successful
methodology to synthesize H-phosphinates through phosphi-
nate addition to alkenes.
1-Octene was chosen as a representative example of an un-
activated olefin. Ethyl phosphinate was prepared via our
alkoxysilane method and used as a 0.5 M stock solution.11a
Various conditions and catalysts were investigated as shown in
Table 1.
As previously reported,10 NiCl2 alone does not work well
with 1-octene (entry 1), but under similar conditions
Cl2Ni(PPh3)2 is more successful (entry 5), whereas heating in
In 2005, we disclosed the inexpensive and straightforward
nickel chloride-catalyzed addition of phosphinates to terminal
Received: April 29, 2013
© XXXX American Chemical Society
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1-octene, with or without dppe as an external ligand. Results are
summarized in Table 2.
Table 1. Nickel Catalysis in the Hydrophosphinylation of
1-Octene with EtOP(O)H2
Table 2. Optimization of the Hydrophosphinylation of
1-Octene with EtOP(O)H2 through Preactivation
a
entry
solvent
catalyst
31P NMR yield (%)
1
2
3
4
5
6
PhCH3, rt
NiCl2 (3 mol %)
25
30
47
45
65
61
a
entry
1
time
2 h
temp
rt
31P NMR yield (%)
CH3CN, reflux
THF, reflux
PhCH3, reflux
PhCH3, rt
Cl2Ni(PPh3)2 (4 mol %)
Cl2Ni(PPh3)2 (5 mol %)
Cl2Ni(PPh3)2 (4 mol %)
Cl2Ni(PPh3)2 (4 mol %)
NiCl2 (5 mol %)
100
61
57
98
87
59
24
89
b
2
2 h
rt
c
3
d
2 h
rt
4
2 h
rt
PhCH3, rt
5
6
7
8
8 h
rt
PPh3 (20 mol %)
30 min
2 h
rt
7
PhCH3, rt
PhCH3, reflux
PhCH3, rt
PhCH3, rt
PhCH3, rt
Ni(PPh3)4 (3 mol %)
Cl2Ni(dppp) (4 mol %)
Cl2Ni(dppp) (4 mol %)
Cl2Ni(dppe) (5 mol %)
NiCl2 (3 mol %)
0
20
69
96
87
85 °C
reflux
8
10 min
9
a
10
11
NMR yields are determined by integration of all the resonances in the
b
c
d
31P NMR spectra. Without dppe. Under air. Cl2Ni(dppe) was used.
dppe (3.3 mol %)
12
PhCH3, rt
NiCl2 (3 mol %)
93
This protocol results in clear improvements over the con-
ditions of Table 1. Even NiCl2 gives an almost 3-fold increase,
even though it remains a moderate yield (entry 2). Preactiva-
tion of NiCl2 at room temperature for 2 h before the addition
of dppe was ideal (entry 1), and the process gives comparable
results when preformed Cl2Ni(dppe) is used (entry 4).
Not surprisingly, when oxygen is present, the yield drops
significantly (entry 3). Longer preactivation at room temper-
ature resulted in a small drop in yield (entry 5), but a larger one
at the shorter 30 min time interval (entry 6). Consistent with
Ni(0) decomposition, this was worse when heating was applied
(entry 7); however, a short period of heating gave good results
(entry 8). Preactivation was also tried with other nickel cata-
lysts and ligands but failed to give better results.14
Scheme 1 shows possible mechanistic pathways for the reduc-
tion of the nickel(II) precursor into catalytically active Ni(0).
Some alcohol (ROH) is typically present as a result of phos-
phinate synthesis.11 The formation of H-phosphonates is always
observed in the process. It should be noted that the hydro-
phosphonylation of alkenes that could result from their presence
is not observed, even though various hydrophosphonylation
processes have been described in the literature.2,7
dppe (5 mol %)
a
NMR yields are determined by integration of all the resonances in the
31P NMR spectra.
various solvents gives poorer results (entries 2−4). Addition
of triphenylphosphine to NiCl2 gives roughly similar results
(entry 6), but the use of preformed Ni(PPh3)4 does not give
any addition product (entry 7). As before, the reaction at room
temperature is superior (entry 9 versus 8), but dppp (1, 3-
bis(diphenylphosphino)propane) does not result in a very
significant improvement over PPh3. On the other hand, dppe
(1, 2-bis(diphenylphosphino)ethane) gives much improved re-
sults (entries 10−12). Analysis of the reaction mixtures by gas
chromatography usually indicated the complete disappearance
of 1-octene with concomitant formation of octane and octene
isomers, especially pronounced at higher temperatures.
Expectedly, this indicated that transfer hydrogenation12 is
one of the significant competing pathways. Because alkynes are
more reactive than alkenes, competing pathways in hydro-
phosphinylation are less of a problem, and plain NiCl2 is
successful.10 The results in Table 1 also allowed us to draw a
few working hypotheses: (a) toluene is a good solvent, and
room temperature is a requirement to maximize the yields; (b)
the presence of a ligand has a significant influence on alkene
hydrophosphinylation, and dppe appears to be the best choice.
Fortunately, dppe is also the cheapest of the bidentate phos-
phine ligand family. Furthermore, on the basis of our prior work
with alkynes and the identification of a preactivation process,10
we knew that the reaction of NiCl2 with an alkyl phosphinate11
(at room temperature or with heating) results in the formation
of a nickel(0) species corresponding to Ni[(RO)P(OH)H]4
(31P NMR δ ∼170 ppm (d, JP−H = 341 Hz)) in the absence of
other ligands. This is not surprising since the reduction of
nickel salts with phosphinates is the basis of the electroless
plating process (Kanigen process), which is responsible for the
major industrial consumption of phosphinates.13
Only alkyl phosphinates (ROP(O)H2)11 gave good results in
this reaction, as was the case with alkynes. Hypophosphorous
acid or its salts did not provide any significant yield of hydro-
phosphinylation (results not shown). This might be due to
either increased transfer hydrogenation or less efficient forma-
tion of a nickel(0) species, the former being most likely.15
A plausible mechanism for the nickel-catalyzed hydrophos-
phinylation reaction is shown in Scheme 2. Complexation of
nickel(0) to the P(III) phosphinate tautomer gives an inter-
mediate, which can either decompose to a complexed dihydride
leading to transfer hydrogenation,12 or a monohydride that can
add to unsaturated hydrocarbons.
The role of the ancillary ligand (for example, dppe) would be
to stabilize the Ni(0) species and prevent/slow down the
formation of the dihydride through β-hydrogen elimination
leading to transfer hydrogenation. When alkynes are employed,
a faster reaction rate allows hydrophosphinylation to take place
under “ligandless” conditions.
A different experimental protocol was therefore investigated
in which a nickel catalyst precursor is first prereacted with the
phosphinate at room temperature for 2 h, before the addition of
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reaction generally proceeded satisfactorily in yields often similar
to our previously reported palladium-catalyzed methodology.3c For
example, hydrophosphinylation of 1-octene was conducted on a
20 g scale, and the product was obtained in 79% yield, without any
chromatography. However, some substrates such as allyl chloride,
styrene, and 1H,1H,2H-perfluoro-1-octene failed (<40% NMR
yield). Significant differences between Pd- and Ni-catalyzed
reactions of phosphinates have been noticed previously.16
Later on it was discovered that the nickel catalyst also lowers
the isolated yield through oxidation of the H-phosphinate product
into the corresponding phosphonate monoester R1P(O)(OR)(OH).
At this point, it was found that an extractive workup using
dimethylglyoxime (a known nickel complexant) prior to purifi-
cation helped improved the isolated yield.
Scheme 1. Mechanistic Pathways in the Formation of
Nickel(0) from Nickel(II) Species Using Alkyl Phosphinates
The potential for the desymmetrization of ROP(O)H2 using
a chiral phosphine ligand was briefly investigated (Table 3).
Although a number of other chiral ligands were screened,
results were unsatisfactory because the P−C bond-forming step
gave low or no yield. As expected, dppe-like ligands provided
good reactivity (entries 1 and 2). One josiphos-type ligand
displayed good reactivity, while others simply did not give any
hydrophosphinylation.
The highest enantiomeric excess observed was mediocre
(18% de), but this was expected on the basis of our prior work
with palladium-catalysts.17 Perhaps a detailed screening might result
in improved enantiomeric excesses, but this was not pursued further
at this point, as we have already reported on the difficulties asso-
ciated with the desymmetrization of phosphinates ROP(O)H2.17
Because of the occasional discrepancies between NMR yields
and isolated yields in Scheme 3, a different protocol was
investigated next for the synthesis of more stable H-phosphinic
acids. The idea was to prepare H-phosphinic acids through
saponification of the crude hydrophosphinylation mixture, and
purification through simple acidification/extraction. The results
of this study are summarized in Table 4.
Scheme 2. Possible Mechanism for the Nickel-Catalyzed
Hydrophosphinylation Reaction
As expected, this process not only allows for increased isolated
yields, but also avoids chromatographic purification altogether. On
the basis of the conditions shown in Scheme 4, our nickel-catalyzed
hydrophosphinylation/hydrolysis sequence was investigated with
4-phenyl-1-butene as the substrate (eq 2). Monopril (fosinopril) is a
(pro)drug used in the treatment of congestive heart failure
(angiotensin converting enzyme (ACE) inhibitor).18 Its current
synthesis involves the AIBN-initiated free radical hydrophosphi-
nylation of 4-phenyl-1-butene with H3PO2, but a few percents of
With the above results in hand, a study of reaction scope was
the logical next step. Thus, various terminal alkenes were ex-
plored as hydrophosphinylation substrates. Scheme 3 summa-
rizes the results.
Ethyl phosphinate was prepared using (diethoxy)dimethyl
silane and butyl phosphinate either through the analogous
alkoxysilane method, or the Dean−Stark esterification of
H3PO2, as reported previously.11 Reactions following the condi-
tions of Table 2 (entry 1) were then applied. Consistently high
NMR yields were observed; however, isolated yields varied
significantly, in large part because of the hydrolytic sensitivity of
H-phosphinate esters during purification on silica gel.10 None-
theless, the present nickel-catalyzed alkene hydrophosphinylation
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a
Scheme 3. Preliminary Scope of the Nickel-Catalyzed Hydrophosphinylation Reaction
a
31P NMR yield (isolated yield).
a regioisomeric impurity (formation of the branched isomer)
complicate the manufacture.18a With the nickel-catalyzed reaction,
excellent yield of product was obtained with little or no formation
of regioisomer (<0.5% as determined by 31P NMR) on a relatively
large laboratory scale, and again without any chromatography.
On the basis of the same idea, the conversion of crude
H-phosphinate esters into other important organophosphorus
compounds was examined next. Scheme 4 summarizes these
results.
Another one-pot process of interest is the cross-coupling of
the intermediate H-phosphinate (eq 3). Various literature
conditions related to the cross-coupling of H-phosphinate with
aryl halides have been reported.19 However, in eq 3, standard
conditions were employed since reactive iodobenzene was the
coupling partner.10
Additionally, the present nickel-catalyzed hydrophosphinyla-
tion of alkenes can be employed instead of our palladium
version in order to prepare various compounds more cheaply.
Scheme 5 shows three such examples and their application to
the synthesis of P-heterocycles.
Hydrophosphinylation of 5-bromo-1-pentene gives the
desired addition product contaminated with (EtO)2P(O)H,
which was removed in vacuo. Addition of LiHMDS20 to the
resulting crude mixture formed the corresponding 1-ethoxy-
phosphorinane 1-oxide heterocycle in good isolated yield.
Addition of ethyl phosphinate to allyl carbamate followed by
acid hydrolysis gives the intermediate H-phosphinic acid in excellent
yield (actually higher than with our palladium-catalyzed method-
ology).21 Heterocyclization using the Kabachnick−Fields proto-
col21,22 gave the corresponding P,N-heterocycle uneventfully, as
we reported previously. Finally, hydrophosphinylation of the
terminal alkene of methyl (E)-3-methyl-2,6-heptadienoate,23
followed by cyclization through conjugate addition, delivered the
substituted phosphorinanic ester.
CONCLUSION
■
The nickel-catalyzed hydrophosphinylation of terminal alkenes
with alkyl phosphinates is described, using inexpensive nickel
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Table 3. Desymmetrization of EtOP(O)H2 through
Hydrophosphinylation Using a Chiral Ligand
Scheme 4. Nickel-Catalyzed Hydrophosphinylation/
Complexation Sequence
a
a
b
c
entry
ligand
31P NMR yield (%)
de (%)
1
2
3
4
5
6
(R,R)-DIPAMP
(S,S)-Chiraphos
(S,S)-Ph-BPE
90
89
69
96
0
12
18
16
17
−
JosiPhos-(R)-(S)-PDF-Pxyl2
JosiPhos-(R)-(S)-PPFPCy2
(S,S)-DIOP
0
−
a
b
3.3 mol %. NMR yields are determined by integration of all the
c
resonances in the 31P NMR spectra. ee determination was conducted
as in ref 17 using (S)-methyl-benzylamine and CCl4.
chloride and dppe as the ancillary ligand. Experiments relevant
to both synthetic and mechanistic aspects are described. A
mechanism for the phosphinate reduction of nickel chloride
into nickel(0) is provided and is relevant to the Kanigen elec-
troless plating process. Similarly, a mechanism for the nickel-
catalyzed hydrophosphinylation reaction is proposed, consis-
tent with the data, and which rationalizes reactivity differences
between alkenes and alkynes. Not only the method provides a
cheap and practical alternative to our palladium-based method-
ology, it also provides a simple method for the catalyzed
formation of phosphorus−carbon bonds from hypophospho-
rous derivatives. Indeed, in most cases the reaction is a one-pot
process, and chromatographic purification can be completely
avoided in many cases. The work is important as it establishes
another dimension to the chemistry of phosphinates and is
competitive with the traditional use of phosphorus trichloride
in the synthesis of organophosphorus compounds. The con-
version of phosphinates to H-phosphinates and other inter-
mediates is indeed an important goal because it alleviates the
a
31P NMR yield (isolated yield).
need for toxic intermediates like elemental phosphorus (P4),
phosphine (PH3), red phosphorus, and of course phosphorus
trichloride. Our method could have industrial potential and
provides a new link in the quest for environmentally more benign
organophosphorus chemistry.
EXPERIMENTAL SECTION
■
General Chemistry. All starting materials were purchased from
commercial sources and used as received. The solvents were distilled
under N2 and dried according to standard procedures (toluene and
acetonitrile from CaH2; THF from Na/benzophenone ketyl; N,N-
diisopropylethylamine was distilled from CaH2 and stored over 4 Å
Table 4. Nickel-Catalyzed Hydrophosphinylation/Hydrolysis
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alcohol (375 mmol) in reagent grade PhCH3 (0.5 M) was equipped
with a Dean−Stark trap prefilled with PhCH3 and fitted with a
condenser. The solution was refluxed under N2 for 3 h and then
cooled to room temperature. The solution was bottled and sealed with
a septum, and the headspace was flushed with N2. The solution was
used for the subsequent hydrophosphinylation reactions directly
without further purification.
Scheme 5. Nickel-Catalyzed Hydrophosphinylation Applied
to the Preparation of P-Heterocycles
General Procedure for the Preparation of Alkyl H-Phosphinates
Using NiCl2/dppe (Scheme 3). In an oven-dried 25 mL round-
bottomed flask, NiCl2 (0.075 mmol, 3 mol %) was suspended in 10 mL
of a ROP(O)H2 solution in PhCH3 (0.5 M, 5 mmol, 2 equiv). The
mixture was stirred at rt for 2 h, and dppe (0.0825 mmol, 3.3 mol %)
was added. After 30 min, the alkene (2.5 mmol, 1 equiv) was added and
the mixture was stirred at rt for 24 h. The solution was then washed with
H2O (10 mL × 2), sat. NaHCO3 (10 mL), and brine (10 mL). Drying
over MgSO4 followed by rapid column chromatography on silica gel using
EtOAc/Hexane mixtures afforded the corresponding H-phosphinate. The
H-phosphinate compounds should be stored in CH2Cl2 solution (at least
0.5M) at 0 °C until ready to use.
Ethyl octylphosphinate (Scheme 3, 1a).4b Colorless oil, 20.638
1
g (79%): H NMR (CDCl3, 300 MHz) δ 7.01 (d, 1H, J = 526 Hz),
4.15−3.95 (m, 2H), 1.69 (m, 2H), 1.64 (m, 2H), 1.28 (t, 3H, J = 7.0
Hz), 1.19 (m, 10H), 0.80 (t, 3H, J = 6.2 Hz); 31P NMR (CDCl3,
121.47 MHz) δ 40.1 (d, JPH = 526 Hz).
Butyl octylphosphinate (Scheme 3, 1b).3c Colorless oil, 0.369 g
1
(63%): H NMR (CDCl3, 300 MHz) δ 7.08 (d, 1H, J = 527 Hz),
4.17−3.93 (m, 2H), 1.82−1.27 (m, 18H), 0.95 (t, 3H, J = 7.3 Hz),
0.88 (t, 3H, J = 6.7 Hz); 31P NMR (CDCl3, 121.47 MHz) δ 40.8 (d,
JPH = 526 Hz).
Ethyl norbornylphosphinate (Scheme 3, 2a).4b Colorless oil,
0.301 g (64%): 1H NMR (CDCl3, 300 MHz) δ 6.95 and 6.88 (d, 1H,
2R and 2S isomers, J = 521 Hz), 4.21−3.02 (m, 2H), 2.60 (dd, 1H, J =
36.6 Hz and J = 8.2 Hz); 2.38 (s, 1H), 1.92−1.22 (m, 9H), 1.36 (t, 3H,
J = 7.0 Hz); 31P NMR (CDCl3, 121.47 MHz) δ 44.2 and 42.4 (d, 2R
and 2S isomers, JPH = 521 Hz).
Butyl norbornylphosphinate (Scheme 3, 2b). Colorless oil,
0.470 g (87%): 1H NMR (CDCl3, 300 MHz) δ 6.93 and 6.87 (d, 1H,
2R and 2S isomers, J = 522 and 521 Hz), 4.16−3.92 (m, 2H), 2.60
(dd, 1H, J = 34.9 Hz and J = 8.9 Hz); 2.38 (s, 1H), 1.88−1.21 (m,
13H), 0.95 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 75.45 MHz) δ 66.0
(d, CH2, JPOC = 7.7 Hz), 40.4 (d, CH, JPC = 95 Hz), 37.2 (CH2), 37.1
(d, CH, JPCCC = 10.1 Hz), 36.1 (d, CH, JPCC = 9.2 Hz), 32.5 (d, CH2,
molecular sieves). TLC analyses were performed on sheets precoated
with silica gel 60F254. Compound detection was achieved by exposure
to UV light (254 nm), by immersion in anisaldehyde stain (by volume:
93% ethanol, 3.5% H2SO4, 1% AcOH and 2.5% anisaldehyde) fol-
lowed by heating at 150 °C. Flash chromatography experiments were
carried out on Silica Gel premium Rf grade (40−75 μm). Ethyl
acetate/hexane mixtures were used as the eluent for chromatographic
1
purifications. The H, 13C, and 31P NMR spectra were recorded on a
300 MHz spectrometer. Chemical shifts for 1H NMR are given in ppm
relative to internal tetramethylsilane (δ = 0 ppm), using CDCl3 as
solvent. Chemical shifts for 13C NMR are given in ppm relative to
CDCl3 (δ = 77.0 ppm). Chemical shifts for 31P NMR spectra are given
relative to external 85% phosphoric acid (δ = 0 ppm). Abbreviations
used for signal patterns are as follows: s, singlet; d, doublet; t, triplet; q,
quadruplet; m, multiplet. High resolution mass spectra (HRMS) were
obtained either by direct probe (EI/CI) and analyzed by magnetic
sector, or by electrospray using a TOF analyzer.
JPOCC = 5.8 Hz), 31.4 (d, CH2, JPCC = 17.4 Hz), 30.1 (d, CH2, JPCCC
=
21.7 Hz), 28.6, 18.8 (CH2), 13.6 (CH3); 31P NMR (CDCl3, 121.47
MHz) δ 44.7 and 43.0 (d, 2R and 2S isomers, JPH = 520 and 521 Hz);
HRMS (EI+) m/z calcd. for C11H21O2P ([M]+) 216.1279, found
216.1276.
31P NMR Yield Measurements. The NMR yields are determined
by integration of all the resonances in the 31P spectra, an approach that
is valid if no phosphorus-containing gas (i.e., PH3) evolves, or if the
precipitate in a heterogeneous mixture does not contain phosphorus.
The yields determined by NMR are generally accurate within ∼10% of
the value indicated, and are reproducible. Isolated yields are sometimes
significantly lower in the case of H-phosphinate esters because these
are polar compounds and hydrolytically labile. This does not reflect an
inaccuracy in the NMR yield, but instead the fact that H-phosphinates can
be difficult to purify. Validation of NMR yields was conducted in ref 10.
Preparation of AlkOP(O)H2 Stock Solution Using Alkoxysilanes.
The preparation of these compounds was conducted as described in
the literature.11a In a typical procedure, a solution of the precon-
centrated H3PO2 (125 mmol), alkoxysilane (125 mmol for (RO)4Si, or
250 mmol for (RO)2SiMe2, in reagent grade toluene (to 0.5 M con-
centration) is refluxed for 2 h under N2. After cooling to room
temperature, the solution was bottled and sealed with a septum, and
the headspace was flushed with N2. The solution was used for the
subsequent hydrophosphinylation reactions directly without further
purification.
Ethyl 4-(diethylmaleonate)propylphosphinate (Scheme 3, 3a).
Colorless oil, 0.449 g (61%): 1H NMR (CDCl3, 300 MHz) δ 7.12 (d,
1H, J = 530 Hz), 4.20 (q, 4H, J = 7.0 Hz), 4.09 (m, 2H), 3.34 (t, 1H,
J = 7.3 Hz), 1.99 (m, 2H), 1.81 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J =
7.0 Hz), 1.27 (t, 6H, J = 7.0 Hz); 13C NMR (CDCl3, 75.45 MHz) δ
168.9, 168.8 (C), 62.4, 61.3 (3 CH2), 51.3 (CH), 29.2 (d, CH2, JPCC
=
17.0 Hz), 28.5 (d, CH2, JPC = 96.2 Hz), 18.7 (CH2), 16.2, 14.0, 13.9
(CH3); 31P NMR (CDCl3, 121.47 MHz) δ 38.3 (d, JPH = 530 Hz);
HRMS (methane chem ion) m/z calcd. for C12H24O6P ([M + H]+)
295.1311, found 295.1308.
Butyl 4-(diethylmaleonate)propylphosphinate (Scheme 3,
3b). Colorless oil, 0.355 g (44%): 1H NMR (CDCl3, 300 MHz) δ 7.09
(d, 1H, J = 530 Hz), 4.20 (q, 4H, J = 7.3 Hz), 4.15−3.96 (m, 2H), 3.34
(t, 1H, J = 7.3 Hz), 2.00 (m, 2H), 1.84−1.63 (m, 6H), 1.42 (m, 2H),
1.28 (t, 3H, J = 7.0 Hz), 0.95 (t, 6H, J = 7.0 Hz); 13C NMR (CDCl3,
75.45 MHz) δ 169.1 (2 C), 66.4 (d, CH2, JPOC = 6.9 Hz), 61.6 (2
CH2), 51.5 (CH), 32.4 (d, CH2, JPOCC = 6.0 Hz), 29.4 (d, CH2, JPCC
=
17.0 Hz), 28.5 (d, CH2, JPC = 94.1 Hz), 18.9 (2 CH2), 14.1, 13.6 (3
CH3); 31P NMR (CDCl3, 121.47 MHz) δ 38.8 (d, JPH = 530 Hz);
HRMS (ammonia chem ion) m/z calcd. for C14H28O6P ([M + H]+)
323.1624, found 323.1620.
Formation of AlkOP(O)H2 with Alcohol Using Azeotropic
Removal of Water. Augmented procedure previously reported in the
literature.4a A flask containing preconcentrated H3PO2 (75 mmol) and
Ethyl hex-5-enyl-1-phosphinate (Scheme 3, 4).4b Colorless oil,
0.198 g (45%): 1H NMR (CDCl3, 300 MHz) δ 7.62 (d, 1H, J = 540 Hz),
F
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5.40 (m, 2H), 5.05−4.95 (m, 1H), 4.26−4.03 (m, 2H), 2.07 (m, 2H),
1.81−1.51 (m, 6H), 1.456 (t, 3H, J = 6 Hz); 31P NMR (CDCl3, 121.47
MHz) δ 39.8 (d, JPH = 525 Hz).
Ethyl 2-(trimethylsilyl)ethylphosphinate (Scheme 3, 10).
Colorless oil, 0.383 g (79%): H NMR (CDCl3, 300 MHz) δ 7.02
1
(d, 1H, J = 526 Hz), 4.23− 4.04 (m, 2H), 1.68 (m, 2H), 1.37 (t, 3H,
J = 7.0 Hz), 0.71 (m, 2H), 0.00 (s, 9H); 13C NMR (CDCl3, 75.45
MHz) δ 64.4 (d, CH2, JPOC = 6.9 Hz), 25.0 (d, CH2, JPC = 91.6 Hz),
18.5 (d, CH3, JPOCC = 5.8 Hz), 8.3 (d, CH2, JPCC = 6.9 Hz), 0.00
(3 CH3); 31P NMR (CDCl3, 121.47 MHz) δ 43.5 (d, JPH = 525 Hz);
HRMS (ESI) calcd. for C7H20O2PSi ([M + H]+) 195.0970, found
195.0963.
Ethyl (5-oxohexyl)phosphinate (Scheme 3, 5a). Colorless oil,
1
0.293 g (61%): H NMR (CDCl3, 300 MHz) δ 7.11 (d, 1H, J =
529 Hz), 4.09 (m, 2H), 3.83 (m, 2H), 2.48 (t, 2H, J = 3 Hz), 2.15 (s,
3H), 1.83−1.59 (m, 4H), 1.36 (t, 3H, J = 7 Hz); 13C NMR (CDCl3,
75.45 MHz) δ 207.8 (C), 62.1 (d, CH2, JPOC = 6.5 Hz), 42.5 (CH2),
29.6 (CH3), 28.1 (d, CH2, JPC = 93 Hz), 23.9 (d, CH2, JPCC = 16 Hz),
19.9 (d, CH2, JPCCC = 2.7 Hz), 15.9 (d, CH3, JPOCC = 6.04 Hz);
31P NMR (CDCl3, 121.47 MHz) δ 39.2 (d, JPH = 528 Hz). HRMS
(EI+) m/z calcd. for C8H17O3P ([M]+) 192.0915, found 192.0922.
Butyl (5-oxohexyl)phosphinate (Scheme 3, 5b). Yellow oil,
Ethyl 4-bromobutylphosphinate (Scheme 3, 11a).24 Colorless
1
oil, 0.303 g (53%): H NMR (CDCl3, 300 MHz) δ 7.13 (d, 1H, J =
530 Hz), 4.24−4.04 (m, 2H), 3.43 (t, 2H, J = 6.5 Hz), 1.99 (m, 2H),
1.80 (m, 4H), 1.38 (t, 3H, J = 7.0 Hz); 31P NMR (CDCl3, 121.47
MHz) δ 38.8 (d, JPH = 532 Hz).
1
0.248 g (45%): H NMR (CDCl3, 300 MHz) δ 7.10 (d, 1H, J = 529
Butyl 4-bromobutylphosphinate (Scheme 3, 11b). Colorless
oil, 0.270 g (42%): H NMR (CDCl3, 300 MHz) δ 7.12 (d, 1H, J =
Hz), 4.07 (m, 2H), 2.48 (t, 2H, J = 3 Hz), 2.16 (s, 3H), 1.73 (m, 8H),
1.43 (m, 2H), 0.95 (t, 3H, J = 7 Hz); 13C NMR (CDCl3, 75.45 MHz)
δ 208.1 (C), 66.1 (d, CH2, JPOC = 7.09 Hz), 42.7 (CH2), 32.2 (d, CH2,
JPOCC = 6.1 Hz), 29.8 (CH3), 28.3 (d, CH2, JPC = 95 Hz), 24.1 (d,
CH2, JPCC = 16 Hz), 20.1 (d, CH2, JPCCC = 2.7 Hz), 18.6 (CH2), 13.3
(CH3) 31P NMR (CDCl3, 121.47 MHz) δ 39.6 (d, JPH = 529 Hz).
HRMS (EI+) calcd. for C10H21O3P ([M]+) 220.1228, found 220.1224.
Diethyl 3-(butoxy-H-phosphinoyl)propylphosphonate
1
530 Hz), 4.19−3.95 (m, 2H), 3.42 (t, 2H, J = 6.5 Hz), 2.00−1.60 (m,
8H), 1.41 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 75.45
MHz) δ 66.4 (d, CH2, JPOC = 6.8 Hz), 33.0 (d, CH2, JPCCC = 15.5 Hz),
32.8 (CH2), 32.5 (d, CH2, JPOCC = 5.8 Hz), 27.9 (d, CH2, JPC = 93.2
Hz), 19.6, 18.9 (CH2), 13.7 (CH3); 31P NMR (CDCl3, 121.47 MHz)
δ 39.1 (d, JPH = 529 Hz); HRMS (methane chem ion) calcd. for
C8H19BrO2P ([M + H]+) 257.0306, found 257.0305.
1
(Scheme 3, 6). Yellow oil, 0.638 g (85%): H NMR (CDCl3, 300
MHz) δ 7.12 (d, 1H, J = 531 Hz), 4.15−4.09 (m, 6H), 1.92 (m, 6H),
1.70 (m, 2H), 1.46 (m, 2H), 1.33 (t, 6H, J = 7.5 Hz), 0.95 (t, 3H, J =
7.2 Hz); 13C NMR (CDCl3, 75.45 MHz) δ 66.3 (d, CH2, JPOC = 6.9
Hz), 61.7 (d, 2 CH2, JPOC = 6.5 Hz), 32.3 (d, CH2, JPOCC = 6.04 Hz),
29.2 (dd, CH2, JP(H)C = 93 Hz and JP(OEt)2CCC = 14.7 Hz), 26.2 (dd,
CH2, JP(OEt)2C = 141 Hz and JP(H)CCC = 15.1 Hz), 18.8 (CH2), 16.4 (d,
2 CH3, JPOCC = 6.04 Hz), 14.6 (d, CH2, JPCC = 2.04 Hz), 13.6 (CH3)
Ethyl 5-bromopentylphosphinate (Scheme 3, 12a).3 Color-
1
less oil, 0.292 g (48%): H NMR (CDCl3, 300 MHz) δ 7.14 (d, 1H,
J = 528 Hz), 4.26−4.01 (m, 2H), 3.42 (t, 2H, J = 6.5 Hz), 1.93−1.75
(m, 4H), 1.72−1.53 (m, 4H), 1.37 (t, 3H, J = 7.0 Hz); 31P NMR
(CDCl3, 121.47 MHz) δ 39.9 (d, JPH = 522 Hz).
Butyl 5-bromopentylphosphinate (Scheme 3, 12b). Colorless
oil, 0.386 g (57%): 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J =
525 Hz, 1H), 4.20−3.95 (m, 2H), 3.42 (t, J = 6.5 Hz, 2H), 1.93−1.53
(m, 12H), 1.37 (t, J = 7.0 Hz, 3H); 31P NMR (CDCl3, 121.47 MHz)
δ 39.9 (d, JPH = 522 Hz).
31P NMR (CDCl3, 121.47 MHz) δ 37.3 (dd, JPH = 532 Hz and 4JP,P
=
4.0 Hz), 30.1 (4JP,P = 4.0 Hz). HRMS (methane chem ion) calcd. for
C11H27O5P2 ([M + H]+) 301.1334, found 301.1340.
Ethyl 4-phenylbutylphosphinate (Scheme 3, 13a).25 Yellow
Ethyl 3-(N-ethylcarbamoyl)propylphosphinate (Scheme 3,
7a). Colorless oil, 0.368 g (66%): 1H NMR (CDCl3, 300 MHz) δ 7.13
(d, 1H, J = 533 Hz), 4.99 (m, 1H), 4.26−4.01 (m, 4H), 3.28 (m, 2H),
1.83 (m, 4H), 1.37 (t, 3H, J = 7.0 Hz), 1.24 (t, 3H, J = 7.0 Hz); 13C
NMR (CDCl3, 75.45 MHz) δ 156.9 (C), 62.6 (d, CH2, JPOC = 6.8 Hz),
60.7 (CH2), 40.9 (d, CH2, JPCCC = 16.9 Hz), 26.0 (d, CH2, JPC = 94.6
Hz) 21.5 (CH2), 16.3 (d, CH2, JPOCC = 6.3 Hz), 14.7 (CH3); 31P
NMR (CDCl3, 121.47 MHz) δ 38.9 (d, JPH = 534 Hz); HRMS
(methane chem ion) calcd. for C8H19NO4P ([M + H]+) 224.1017,
found 224.1014.
1
oil, 0.283 g (50%): H NMR (CDCl3, 300 MHz) δ 7.30−7.14 (m,
5H), 7.07 (d, 1H, J = 527 Hz), 4.20−3.98 (m, 2H), 2.63 (t, 2H, J = 7.3
Hz), 1.79−1.60 (m, 6H), 1.34 (t, 3H, J = 7.0 Hz); 31P NMR (CDCl3,
121.47 MHz) δ 39.6 (d, JPH = 527 Hz).
Butyl 4-phenylbutylphosphinate (Scheme 3, 13b).25 Yellow
1
oil, 0.280 g (44%): H NMR (CDCl3, 300 MHz) δ 7.37−7.18 (m,
5H), 7.14 (d, 1H, J = 527 Hz), 4.19−4.01 (m, 2H), 2.67 (t, 2H, J =
7.0 Hz), 1.89−1.65 (m, 8H), 1.43 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz);
31P NMR (CDCl3, 121.47 MHz) δ 40.2 (d, JPH = 530 Hz).
Butyl 3-(N-ethylcarbamoyl)propylphosphinate (Scheme 3,
7b). Colorless oil, 0.270 g (43%): 1H NMR (CDCl3, 300 MHz) δ 7.11
(d, 1H, J = 533 Hz), 5.60 (m, 1H), 4.10 (q, 2H, J = 6.2 Hz), 4.02 (m,
2H), 3.26 (m, 2H), 1.82 (m, 4H), 1.69 (m, 2H), 1.42 (m, 2H), 1.24 (t,
3H, J = 7.0 Hz), 0.95 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 75.45
MHz) δ 157.1 (C), 66.4 (d, CH2, JPOC = 6.8 Hz), 60.8 (CH2), 41.0 (d,
CH2, JPCCC = 15.9 Hz), 32.5 (d, CH2, JPOCC = 6.3 Hz), 26.1 (d, CH2,
JPC = 94.6 Hz), 21.7, 18.9 (CH2), 14.8, 13.7 (CH3); 31P NMR (CDCl3,
121.47 MHz) δ 39.7 (d, JPH = 533 Hz); HRMS (methane chem ion)
calcd. for C10H23NO4P ([M + H]+) 252.1365, found 252.1362.
Ethyl 3-(N-tert-butylcarbamoyl)propylphosphinate (Scheme
3, 8).4b Colorless oil, 0.210 g (33%): 1H NMR (CDCl3, 300 MHz) δ
7.11 (d, 1H, J = 534 Hz), 4.78 (br, 1H), 4.26−4.01 (m, 2H), 3.23 (m,
2H), 1.83 (m, 4H), 1.42, (s, 9H), 1.37 (t, 3H, J = 7.0 Hz); 31P NMR
(CDCl3, 121.47 MHz) δ 39.0 (d, JPH = 532 Hz).
Ethyl 3-(2-hydroxyphenyl)propylphosphinate (Scheme 3,
1
14). Light brown oil, 0.302 g (53%): H NMR (CDCl3, 300 MHz)
δ 7.39 (m, 1H), 7.12 (d, 1H, J = 535 Hz), 7.06 (m, 2H), 6.84 (m, 2H),
4.20−4.07 (m, 2H), 2.78 (t, 2H, J = 6.7 Hz), 2.05−1.74 (m, 4H), 1.36
(t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 75.45 MHz) δ 155.3 (C),
130.4, 127.7 (CH), 127.1 (C), 119.8, 115.8 (CH), 63.0 (d, CH2,
JPOC = 6.9 Hz), 30.7 (d, CH2, JPCC = 15.3 Hz), 27.9 (d, CH2, JPC = 95.3
Hz), 21.3 (d, CH2, JPCCC = 2.3 Hz), 16.4 (d, CH3, JPOCC = 6.0 Hz); 31
P
NMR (CDCl3, 121.47 MHz) δ 41.5 (d, JPH = 534 Hz); HRMS (EI+)
calcd. for C11H17O3P ([M]+) 228.0915, found 228.0916.
Ethyl 4,4-diethoxybutylphosphinate (Scheme 3, 15a). Yellow
1
oil, 0.167 g (28%): H NMR (CDCl3, 300 MHz) δ 7.10 (d, 1H, J =
528 Hz), 4.48 (t, 1H, J = 4.7 Hz), 4.20−4.09 (m, 2H), 3.64 (m, 2H),
3.49 (m, 2H), 1.71 (m, 6H), 1.37 (t, 3H, J = 7.0 Hz), 1.21 (t, 6H, J =
7.0 Hz); 13C NMR (CDCl3, 75.45 MHz) δ 102.5 (CH), 62.5 (d, CH2,
JPOC = 6.9 Hz), 61.1 (2 CH2), 34.4 (d, CH2, JPCCC = 15.3 Hz), 28.7 (d,
Isobutyl 4-(butoxy-H-phosphinoyl)butanoate (Scheme 3, 9).
Colorless oil, 0.469 g (71%): 1H NMR (CDCl3, 300 MHz) δ 7.11 (d,
1H, J = 531 Hz), 4.12 (m, 2 H), 3.87 (d, 2H, J = 6.90 Hz), 2.46 (t, 2H
J = 7.2 Hz), 1.92 (m, 4H), 1.69 (m, 2H), 1.41 (m, 2H), 0.93 (d, 6H,
J = 6.7 Hz) 13C NMR (CDCl3, 75.45 MHz) δ 171.5 (C), 69.7 (CH2),
65.3 (d, CH2, JPOC = 7.2 Hz), 33.3 (d, CH2, JPCCC = 15.5 Hz), 31.4 (d,
CH2, JPOCC = 6.04 Hz), 26.9 (d, CH2, JPC = 93.9 Hz), 26.6 (CH), 18.0
CH2, JPC = 93.6 Hz), 16.4 (d, CH2, JPCC = 2.9 Hz), 15.5 (3 CH3); 31
P
NMR (CDCl3, 121.47 MHz) δ 39.5 (d, JPH = 528 Hz); HRMS (EI+)
calcd. for C10H23O4P ([M − H]+) 237.1256, found 237.1257.
Butyl 4,4-diethoxybutylphosphinate (Scheme 3, 15b). Yellow
1
oil, 0.240 g (36%): H NMR (CDCl3, 300 MHz) δ 7.08 (d, 1H, 526
Hz), 4.47 (m, 1H), 4.05 (m, 2H), 3.65−3.39 (m, 4H), 1.83−1.34 (m,
8H), 1.20 (t, 2H, J = 7.0 Hz) 0.93 (m, 9H); 13C NMR (CDCl3, 75.45
MHz) δ 13C NMR (CDCl3, 75.45 MHz) δ 102.5 (CH), 66.3 (d, CH2,
JPOC = 5.13 Hz), 65.7 (CH2), 34.0 (d, CH2, JPCCC = 11.4 Hz), 32.4
(d, CH2, JPOCC = 4.60 Hz), 28.8 (d, CH2, JPC = 93.9 Hz), 18.8 (CH2),
(2 CH3), 17.7 (CH2), 15.4 (d, CH2, JPCC = 2.26 Hz), 12.6 (CH3); 31
P
NMR (CDCl3, 121.47 MHz) δ 39.0 (d, JPH = 531 Hz) HRMS
(ammonia chem ion) calcd. for C12H26O4P ([M + H]+) 265.1569,
found 265.1566.
G
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16.3 (CH2), 15.3(CH3), 13.6 (CH3). HRMS (EI+) calcd. for C12H27O4P
([M − H]+) 265.1624, found 265.1621.
Ethoxy(triisopropylsilyloxy)phenylbutylphosphine-borane
(23).26 TIPSCl (1.5 mL, 7 mmol, 1.4 equiv) was placed into a oven-
dried round-bottom flask and cooled to 0 °C, under N2. Et3N (1 mL,
7.5 mmol, 1.5 equiv) was then added dropwise, and the reaction
mixture was stirred for approximately 10 min at 0 °C. In a separate
oven-dried round-bottom flask, a solution of crude ethyl 4-phenyl-
butylphosphinate (5 mmol, 1 equiv) in freshly distilled CH3CN
(10 mL) was cooled to 0 °C, under N2. The mixture of TIPSCl/Et3N
was slowly added to the H-phosphinate solution via syringe, and the
reaction mixture was maintained at 0 °C for 10−15 min, at which time
the reaction was allowed to warm up to room temperature and stirred
for 14 h under N2. The reaction mixture was treated with BH3·Me2S
(2.0 M in THF, 5 mL, 10 mmol, 2 equiv) by dropwise addition at
room temperature. After 5 h, the reaction mixture was concentrated
under reduced pressure, and the residue was partitioned between
deionized H2O and EtOAc. The aqueous layer was extracted with
EtOAc (3×), and the combined organic layers were washed with brine
(1×), dried over MgSO4, and concentrated in vacuo to afford the
crude compound. Purification by column chromatography over silica
gel (Hexane/PhCH3, 100:0 to 90:10, v/v) afforded 0.476 g (48%) of
Representative Procedure for the Hydophosphinylation of
Alkenes Followed by Hydrolysis (Table 4 and eq 2). In an oven-
dried 25-mL round-bottom flask, anhydrous NiCl2 (0.075 mmol,
3 mol %) is suspended in 10 mL of a BuOP(O)H2 solution in PhCH3
(0.5 M, 5 mmol, 2 equiv). The mixture is heated for 10 min until the
nickel starts to dissolve, and the reaction mixture is cooled to room
temperature (∼15 min). Dppe (0.0825 mmol, 3.3 mol %) is added,
and after 30 min of stirring, the alkene (2.5 mmol, 1 equiv) is added,
and the mixture is stirred at room temperature for 24 h. Upon com-
pletion of the first reaction, aqueous NaOH solution (2 mL, 10 mmol,
4 equiv) is poured into the flask and refluxed for 12−14 h. The
reaction mixture is first extracted with 10 mL of t-PhCH3, acidified
with 10 mL of saturated NaHSO4 solution (pH < 2), and then ex-
tracted with 10 mL of EtOAc three times. The organic layer was dried
over MgSO4 and concentrated by rotary evaporation.
Octylphosphinic acid (Table 4, Entry 1, 16).4a Yellow oil, 5.699 g
1
(82%): H NMR (CDCl3, 300 MHz) δ 11.55 (br, 1H), 7.11 (d, 1H, J =
541 Hz), 1.78 (m, 2H), 1.61 (m, 2H), 1.29 (m, 10 H), 0.90 (t, J = 4.4 Hz,
3H); 31P NMR (CDCl3 121.47 MHz) δ 37.8 (d, JPH = 540 Hz).
Decylphosphinic acid (Table 4, Entry 2, 17).4a Yellow oil, 0.361 g
(70%): 1H NMR (CDCl3, 300 MHz) δ 8.81 (br, 1H), 7.05 (d, 1H, J =
537 Hz), 1.90−1.05 (m, 18H), 0.88 (t, 3H, J = 6 Hz); 31P NMR
(CDCl3, 121.47 MHz) δ 38.1 (d, JPH = 540 Hz).
1
the desired product as a colorless oil: H NMR (CDCl3, 300 MHz) δ
7.06 (d, 1H, J = 529 Hz), 7.3−7.1 (m, 5 H), 4.25−3.95 (m, 2 H), 2.63
(t, 2H, J = 7 Hz), 1.90−1.55 (m, 6 H), 1.34 (t, 3 H, J = 7 Hz), 1.06 (m,
21 H); 13C NMR (CDCl3, 75.45 MHz) δ 141.9, 128.6, 126.1 (5 CH,
1 C), 62.5 (d, CH2, JPOC = 7 Hz), 35.6 (CH2), 32.4 (d, CH2, JPCCC
=
15 Hz), 28.9 (d, CH2, JPC = 94 Hz), 20.6 (CH2), 16.6 (6 CH3), 16.5
(d, CH3, JPOCC = 6 Hz), 11.6 (3 CH) 31P NMR (CDCl3, 121.47 MHz)
δ 134.7 (q, JPB = 48 Hz) HRMS (EI+) calcd. for C21H42BO2PSi ([M]+)
396.2785, found 396.2788.
Norbornylphosphinic acid (Table 4, Entry 3, 18). Yellow oil,
0.348 g (87%): 1H NMR (CDCl3, 300 MHz) δ 10.59 (br s, 1H), 6.95
(d, 1H, J = 536 Hz), 2.63 (m, 1H), 2.40 (m, 1H), 1.83−1.23 (m, 9H);
13C NMR (CDCl3, 75.45 MHz) δ 40.4 (d, CH, JPC = 97 Hz), 37.4
(CH2), 37.2, 36.3 (CH), 31.6 (d, CH2, JPCC = 16 Hz), 30.2, 28.7
(CH2); 31P NMR (CDCl3 121.47 MHz) δ 40.8 (d, JPH = 531 Hz).
HRMS (EI+) calcd. for C7H13O2P ([M]+) 160.0653, found 160.0654.
Hex-5-enyl-1-phosphinic acid (Table 4, Entry 4, 19).4a Yellow
oil, 0.301 g (81%): 1H NMR (CDCl3, 300 MHz) δ 9.93 (br, 1H), 7.12
(d, 1H, J = 530 Hz), 5.60−5.20 (m, 3H), 2.07 (m, 2H), 1.65 (m, 6H);
31P NMR (CDCl3, 121.47 MHz) δ 41.3 (d, JPH = 530 Hz).
Representative Example of Hydrophosphinylation Followed
by Cross-Coupling (eq 3, 24).20 Nickel-catalyzed hydrophosphinyl-
ation was conducted as described in the procedure for Scheme 3 using
1-octene as the alkene (2.5 mmol, 1 equiv). The crude reaction mix-
ture was washed once with deionized H2O and concentrated under a
vacuum at 50 °C to remove the residual diethyl phosphite. To a solu-
tion of crude ethyl octylphosphinate (2.5 mmol, 1.0 equiv) in freshly
distilled CH3CN (10 mL), was added an iodobenzene (2.5 mmol,
1.0 equiv), DIPEA (5.2 mmol, 1.3 equiv), Pd(OAc)2 (0.025 mmol,
1 mol %) and dppf (0.028 mmol, 1.1 mol %) at room temperature.
The solution was heated for 24 h at reflux in CH3CN, under N2. After
cooling to room temperature, the crude mixture was concentrated in
vacuo, and the residue was partitioned between deionized H2O and
EtOAc, followed by extraction of the aqueous phase with EtOAc (3×).
The organic fractions were combined and washed with brine (1×).
Drying and concentration furnished the crude compound, which was
purified by column chromatography using EtOAc/Hexane mixtures to
(4-Phenylbutyl)phosphinic acid (eq 2, 20).4a Yellow oil, 21.554 g
1
(87%): H NMR (CDCl3, 300 MHz) δ 10.35 (br, 1H), 7.08 (d, 1H,
J = 540 Hz), 7.25 (m, 5H), 2.64 (t, 2H, J = 7 Hz), 1.75 (m, 6H); 31P
NMR (CDCl3, 121.47 MHz) δ 38.0 (d, JPH = 540 Hz).
Representative Procedure for the Hydrophosphinylation of
Alkenes Followed by Formation of Phosphonothioic Acid O-
Ethyl Ester (Scheme 4).10 Nickel-catalyzed hydrophosphinylation of
alkenes was conducted as described in the procedure for Scheme 3.
The crude reaction mixture was washed once with deionized H2O and
concentrated under a vacuum at 50 °C to remove the residual diethyl
phosphite. The crude reaction mixture was dissolved in 10 mL of
freshly distilled CH3CN. To this solution was added sulfur (0.24 g,
7.5 mmol, 3 equiv) and Et3N (0.762 g, 7.53 mmol, 3 equiv) at room
temperature. The resulting mixture was stirred at room temperature
overnight. The solution was extracted with hexane, and the CH3CN
layer was partitioned between 1 M HCl and EtOAc. The organic
layer was dried over MgSO4 and concentrated to afford the crude
compound. Purification over silica gel (Hexane to Hexane/EtOAc,
90/10 v/v) produced the expected compounds as brown oils.
O-Ethyl O-hydrogen octylphosphonothioate (21). Brown oil,
0.309 g (52%): 1H NMR (CDCl3, 300 MHz) δ 418 (m, 2H), 2.01 (m,
2H), 1.66 (m, 2H), 1.36−1.27 (m, 14H), 0.88 (t, 3H, J = 6.6 Hz); 13C
NMR (CDCl3, 75.45 MHz) δ 61.9 (CH2), 34.6 (d, CH2, JPC = 109
Hz), 31.7, 30.4, 30.3, 30.1, 29.0, 22.6 (CH2), 16.1 (d, CH3, JPOCC = 7.3
Hz), 14.0 (CH3); 31P NMR (CDCl3, 121.47 MHz) δ 94.6 (s); HRMS
(EI+) calcd. for C10H23O2PS ([M]+) 238.1156, found 238.1152.
O-Ethyl O-hydrogen (4-phenylbutyl)phosphonothioate (22).
Brown oil, 0.381 g (59%): 1H NMR (CDCl3, 300 MHz) δ 7.31−7.14
(m, 5H), 4.22−4.09 (m, 2H), 2.65 (m, 2H), 2.06 (m, 2H), 1.74 (m,
4H), 1.31 (t, 3H, J = 10 Hz); 13C NMR (CDCl3, 75.45 MHz) δ 140.9
(C), 127.3, 124.8 (5 CH), 60.8, 34.3, 32.7, 31.1, 21.4 (CH2), 15.1
(CH3); 31P NMR (CDCl3, 121.47 MHz) δ 94.3 (s); HRMS (EI+)
calcd. for C12H19O2PS ([M]+) 258.0843, found 258.0839.
1
obtain 0.501 g (71%) of compound 24 as a brown oil: H NMR
(CDCl3, 300 MHz) δ 7.78 (m, 2H), 7.49 (m, 3H), 4.13−3.85 (dm,
2H), 1.84 (m, 2H), 1.70 −1.22 (m, 15H), 0.85 (t, 3H, J = 6.1 Hz); 31P
NMR (CDCl3, 121.47 MHz) δ 44.9 (s).
1-Ethoxy-phosphinane-1-oxide (Scheme 5, 25).27 Compound
12a, ethyl 5-bromopentylphosphinate (5 mmol, 1 equiv), was pre-
pared by the standard hydrodrophosphinylation procedure. The crude
product was partioned between deionized H2O and EtOAc to remove
the formed diethyl phosphite. The dried and concentrated product was
diluted with anhydrous THF (25 mL) under N2. The flask was placed
at −78 °C and deoxygenated under a vacuum for 5 min. The reaction
flask was backfilled with N2, and LHMDS (1.0 M in THF, 5 mL,
5 mmol, 1 equiv) was added at −78 °C. After 10 min, the temperature
of the solution was slowly allowed to warm to rt. After 3 h at rt, the
reaction mixture was quenched with NH4Cl/brine, extracted with
EtOAc (3×), dried over anhydrous MgSO4, and concentrated in
vacuo. The resulting oil was purified by column chromatography on
silica gel using mixtures of EtOAc/Hexane to afford 0.603g (74%) of a
1
yellow oil: H NMR (CDCl3, 300 MHz) δ 4.06 (m, 2 H), 2.03−1.63
(m, 10H), 1.37 (t, 3H, J = 6.9 Hz); 31P NMR (CDCl3, 121.47 MHz) δ
50.08 (s).
3-Hydroxy-2-phenyl-1,3-azaphosphorinane-3-oxide (Scheme 5,
26).21 Compound 7a, ethyl 3-(N-ethylcarbamoyl)propylphosphinate
(10 mmol), was prepared by the standard hydrophosphinylation procedure.
H
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Upon completion, the reaction mixture was concentrated in vacuo to
remove PhCH3, and aq. HCl (12 N, 50 mL) was added to the flask.
After 16 h of reflux, the mixture was concentrated under a high
vacuum. The residue was diluted with H2O and washed with EtOAc
(3 × 20 mL). Concentration of the aqueous layer afforded 1.830 g (82%)
of 3-aminopropyl-H-phosphinic acid hydrochloride as a yellow oil.
Immediately following, the H-phosphinic acid was diluted in n-butanol
(0.2 M), and 1 equiv of the benzaldehyde was added. The mixture was
refluxed for 16 h. After cooling, the precipitate was filtered and washed
with n-butanol and then with Et2O and dried under a high vacuum to
(g) Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.; Wiley:
New York, 1999; Vol. 18.
(2) Reviews: (a) Tanaka, M. Top. Organomet. Chem. 2013, 43, 167−
202. (b) Xu, Q.; Han, L. B. J. Organomet. Chem. 2011, 696, 130−140.
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(d) Ananikov, V. P.; Khemchyan, L. L.; Beletskaya, I. P.; Starikova,
Z. A. Adv. Synth. Catal. 2010, 352, 2979−2992. (e) Ananikov, V. P.;
Khemchyan, L. L.; Beletskaya, I. P. Synlett 2009, 2375−2381.
(f) Ananikov, V. P.; Khemchyan, L. L.; Beletskaya, I. P.; Starikova,
Z. A. Adv. Synth. Catal. 2010, 352, 2979. (f) Coudray, L.; Montchamp,
J.-L. Eur. J. Org. Chem. 2008, 3601−3613. (g) Delacroix, O.; Gaumont,
A.-C. Curr. Org. Chem. 2005, 9, 1851−1882. (h) Schwan, A. L. Chem.
Soc. Rev. 2004, 33, 218−224. (i) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2004, 104, 3079−3159. (j) Tanaka, M. Top. Curr. Chem.
2004, 232, 25−54. (k) Engel, R.; Cohen, J. I. Synthesis of Carbon-
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1
obtain 0.970 g (56%) of the expected compound as a white solid: H
NMR (D2O, 300 MHz) δ 7.31 (m, 5H), 4.21 (d, 1H, J = 6.6 Hz), 3.42
(d, Jgem = 13 Hz, 1H equatorial), 3.05 (m, 1H axial), 2.20−2.06 (m,
2H), 1.74 (m, 2H); 31P NMR (D2O, 121.47 MHz) δ 23.4 (m).
Ethyl 2-(1-ethoxy-2-methyl-1-oxidophosphinanyl)acetate
(Scheme 5, 27). An ethyl H-phosphinate was prepared from ethyl
3-methylhepta-2,6-dienoate using the standard nickel hydrophoshinyl-
ation procedure. Ethyl 7-(ethoxy-H-phosphinoyl)-3-methyl-2-hepte-
noate was obtained as a yellow oil in 66% isolated yield. To a solution
of H-phosphinate in THF (0.08 M, 0.76 mmol) at 0 °C, was added
tBuOK (0.76 mmol, 1 equiv). The solution was stirred for 1 h at 0 °C
and rt for 16 h. The reaction mixture was neutralized with 1 N HCl
and extracted with EtOAc (3× 10 mL). Initial analysis of the product
showed significant cleavage of the ester group. The compound was
diluted in CH3CN and treated with EtOH (1.16 mmol, 1.5 equiv),
EDC (1.16 mmol, 1.5 equiv) and DMAP (0.076 mmol, 10 mol %). After
2 h of stirring at rt, the solution was extracted with saturated NaHSO4
(1 × 10 mL), 1 N NaHCO3 (1 × 10 mL), and brine (1 × 10 mL).
After drying with MgSO4 and concentrating in vacuo, 0.116 g (57%)
Catalytic Heterofunctionalization; Togni, A., Grutzmacher, H., Eds;
̈
Wiley-VCH: Weinheim, 2001.
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1
of a brown oil was obtained: H NMR (CDCl3, 300 MHz) δ 4.19−
4.08 (m, 4H); 2.65 (m, 2H); 2.05−1.43 (m, 8H); 1.35−1.25 (m, 9H);
13C NMR (CDCl3, 75.45 MHz) δ 171.1 (C), 60.6 (d, CH2, JPOC
=
8.68 Hz), 37.5 (C), 36.6 (d, CH2, JPC = 88 Hz), 35.3, 30.9 (CH2), 24.1
(d, CH2, JPCCC = 3.40 Hz), 23.1, 21.2 (CH2), 18.9 (CH3), 16.9 (d,
CH3, JPOCC = 5.36 Hz), 14.1 (CH3); 31P NMR (CDCl3, 121.47 MHz)
δ 53.3 (m); HRMS (EI+) calcd. for C12H23O4P ([M]+) 262.1334,
found 262.1334.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Tables S1 and S2 and copies of the NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.montchamp@tcu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is mainly based upon work supported by the
National Science Foundation under Grant No. 0953368. The
Robert A. Welch Foundation supported S.O. (P-1666). Partial
support from the Texas Christian University Invest in Scholarship
(TCU-IS) Program is also acknowledged for H.C.F.
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