A mild and efficient CsOH-promoted synthesis of ditertiary phosphines

Article abstract of DOI:10.1080/10426500490262261

A mild and efficient method for the synthesis of ditertiary phosphines has been developed. In the presence of cesium hydroxide, molecular sieves, and DMF, various dihalides were coupled with diphenylphosphine at room temperature, and the results have demonstrated that this methodology offers a general synthetic procedure producing a variety of ditertiary phosphines in high yields.

Full text of DOI:10.1080/10426500490262261

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Phosphorus, Sulfur, and Silicon and the Related
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A MILD AND EFFICIENT CsOH-PROMOTED SYNTHESIS OF
DITERTIARY PHOSPHINES
Matthew T. Honaker a & Ralph Nicholas Salvatore a
a Western Kentucky University, Bowling Green, Kentucky, USA
Published online: 11 Aug 2010.
To cite this article: Matthew T. Honaker & Ralph Nicholas Salvatore (2004): A MILD AND EFFICIENT CsOH-PROMOTED
SYNTHESIS OF DITERTIARY PHOSPHINES, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:2, 277-283
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Phosphorus, Sulfur, and Silicon, 179:277–283, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490262261
A MILD AND EFFICIENT CsOH-PROMOTED
SYNTHESIS OF DITERTIARY PHOSPHINES
Matthew T. Honaker and Ralph Nicholas Salvatore
Western Kentucky University, Bowling Green, Kentucky, USA
(Received June 25, 2003; accepted August 15, 2003)
A mild and efficient method for the synthesis of ditertiary phosphines
has been developed. In the presence of cesium hydroxide, molecular
sieves, and DMF, various dihalides were coupled with diphenylphos-
phine at room temperature, and the results have demonstrated that this
methodology offers a general synthetic procedure producing a variety
of ditertiary phosphines in high yields.
Keywords: Alkylation; cesium hydroxide; ditertiary phosphines; ligand
Ditertiary phosphine ligands have been shown to have excellent metal
complexation properties.1,2 These complexes have a wide variety of
uses, serving as antitumor agents,3 oxygen transfer reagents,4 catalysts
for homogenous hydrogenation,5 and applications in thin-film electronic
device manufacture.6 In addition, these ligands can be used in the ex-
traction of rare earths, uranium, and transuranium elements.6 As use-
ful as these complexes are, the starting phosphine chelating agents are
notoriously difficult to prepare employing mild reaction conditions. Tra-
ditional synthetic methods for ditertiary phosphines involve multistep
reactions, free-radical catalysis, or the use of alkali metal phosphides in
liquid ammonia, THF, or dioxanes, often at elevated temperatures.7−9
Moreover, many of these protocols suffer from several disadvantages,
such as significant, if not exclusive, oxidation of the phosphine, cum-
bersome reaction procedures, poor product yields, and the use of phos-
phorus protecting groups.10−13 Therefore, we have embarked on the
search for a convenient and mild reaction procedure better suited for
Financial support from the National Science Foundation-Kentucky EPSCoR (596166)
is gratefully acknowledged, as is support from Western Kentucky University. Also, we
wish to thank Chemetall for their generous supply of cesium bases.
Address correspondence to Ralph Nicholas Salvatore, Department of Chemistry,
Western Kentucky University, 1 Big Red Way, Bowling Green, KY 42101. E-mail:
ralph.salvatore@wku.edu
277

278
M. T. Honaker and R. N. Salvatore
the synthesis of phosphine macrocycles and their congeners. As part
of these current investigations, we have discovered a new, mild and
efficient way to prepare tertiary phosphines using cesium hydroxide
(Scheme 1). Application of this novel method to the facile synthesis of
ditertiary phosphines at ambient temperature, while employing easy
reaction procedures is reported here.
SCHEME 1 Tertiary phosphine synthesis.
RESULTS AND DISCUSSION
The “cesium effect”14−16 has been well utilized in the alkylation of
amines17−20 and alcohols,21−23 but to our knowledge there are no re-
ports regarding the alkylations of phosphines using cesium bases. Given
its utility in similar reactions, we decided to explore this methodology
in P-alkylation, and its applications toward the synthesis of ditertiary
phosphines. At the outset of this study LiOH, NaOH, KOH, CsOH,
and RbOH, as well as organic bases including triethylamine (TEA) and
1,8-diazobicycloundec-7-ene (DBU) were screened. The use of cesium
hydroxide gave excellent yields, while the other bases failed, giving
rise to either no product or poor yields (Scheme 1).24 Thus, CsOH was
determined to be the base of choice. Furthermore, the choice of reac-
tion solvent was also determined to be crucial. Therefore, we examined
the reaction in several different solvents. We found that anhydrous
DMF was the solvent of choice, although NMP, DMAC, acetonitrile, and
DMSO also were screened, but did not give successful results. Moreover,
˚
water also proved to be problematic. When dry, powdered, activated 4 A
molecular sieves were added to the reaction vessel to sequester any wa-
ter, the reaction proceeded smoothly, resulting in high product yields.
However, in the absence of molecular sieves, the reaction was sluggish
and resulted in the predominant recovery of the starting phosphine.
All reactions were performed under a nitrogen atmosphere to prevent
oxidation.
Given our success with P-alkylations using this CsOH procedure,24
we decided to apply this protocol toward the synthesis of various diter-
tiary phosphines. Several ditertiary phosphine ligands were prepared
using these new conditions (Scheme 2). Diphenylphosphine (2 equiv.)

CsOH-Promoted Synthesis of Ditertiary Phosphines
279
SCHEME 2 Synthesis of ditertiary phosphines.
was reacted with various dihalides (1 equiv.) to give the correspond-
ing products (Table I). For example, when diphenylphosphine (1) was
reacted with dibromomethane (2), ditertiary phosphine 3 formed in ex-
cellent yield (95%) after 16 h (entry 1). Increasing the length of the
carbon chain of the dihalide was also quite successful and resulted in
high product yields. For instance, 1,2-dibromoethane (4) generated dppe
(5) in outstanding yield (entry 2). Likewise, 1,3-dibromopropane (6) and
1,4-dibromobutane (8) also produced the desired phosphine products,
1,3-dppp (7) and 1,4-dppb (9), respectively in excellent yields (entries
3–4). Similarly, when 1,5-dibromopentane (10) and 1,6-dibromohexane
(12) were used, the reaction time had to be increased to 72 h, and yields
were slightly less, though still very good (entries 5–6). To further assess
the generality of this protocol, cis-1,3-dichloropropene (14), a dihalide
containing a double bond, also reacted efficiently (entry 7). All of the lig-
ands were formed without appreciable side products under these mild
and effective conditions.
To further probe the feasibility of these conditions, we decided to
investigate other chelating moieties embedded into these phosphine
substrates. Toward this end, we have synthesized a ditertiary phos-
phine product containing a secondary amine, a P-N-P ligand, as shown
in Scheme 3. The product was formed in good yield, and protection
of the primary amine proved unnecessary, further emphasizing the
high chemoselectivity of the “cesium effect.” Both parts of the ligand
SCHEME 3 Synthesis of a P-N-P ligand.

280

CsOH-Promoted Synthesis of Ditertiary Phosphines
281
subsequently were formed using the aforementioned protocol, as well
as the final coupling. The overall yield for the formation of the P-N-P
ligand, 18 was 84%.
In conclusion, we have developed a mild and convenient syn-
thetic method for the synthesis of ditertiary phosphine ligands us-
ing a secondary phosphine and a dihalide in the presence of cesium
˚
hydroxide, 4 A molecular sieves and DMF. This new method is simple,
effective, and circumvents many of the problems seen using traditional
procedures. Furthermore, our mild reaction conditions were compatible
with numerous substrates and avoid the use of unnecessary protecting
groups.
EXPERIMENTAL
All substrates and solvents were commercially available and used with-
out further purification. All reactions were run under a dry inert atmo-
sphere with scrupulously dried glassware, and molecular sieves were
1
activated by drying in a 120◦C oven for 24 h prior to use. H, 13C, and
31P NMR spectra were recorded on a JEOL 270 MHz NMR spectrome-
ter, using TMS as an internal reference (δ = 0.00 ppm). The appropriate
precautions in handling moisture and/or air-sensitive compounds were
observed. Elemental analysis was performed by the Materials Charac-
terization Center at Western Kentucky University.
General Procedure for Preparation
of Ditertiary Phosphines
˚
Under a dry nitrogen atmosphere, 4 A powdered molecular sieves (1 g)
were added to a flame dried round bottom flask containing anhydrous
DMF (12 mL). 2 equiv. of CsOH (2.30 mmol) were added to the flask,
and stirred for 10 min. 2 equiv. of Ph2PH (2.30 mmol) were added, and
the dark orange solution was subsequently stirred for 1 h. 1 equiv. of
the dihalide (1.15 mmol) was added, and the reaction was stirred for
the time listed in Table I for each entry. The progress of the reaction
was monitored by TLC. After the completion of the reaction, the prod-
uct was extracted with methylene chloride (3 × 50 mL) and degassed
water made slightly basic with CsOH (20 mL). The organic layers were
combined, washed with basic degassed water (5 × 50 mL), and dried
over anhydrous sodium sulfate. Evaporation of the solvent followed by
recrystallization from benzene afforded the respective products (Table I,
entries 1–7).

282
M. T. Honaker and R. N. Salvatore
1-Amino-(2-diphenylphosphino)ethane (16)
˚
Under a dry nitrogen atmosphere, 4 A powdered molecular sieves
(500 mg) were added to a flame dried round bottom flask containing
13 mL of anhydrous DMF. CsOH (2.5 mmol) was added, and the mix-
ture was stirred for 10 min. Ph2PH (1.15 mmol) was added via syringe,
and the reaction was subsequently stirred for 1 h. 2-Bromoethylamine
HBr (1.38 mmol) was added, and the reaction was stirred for 23 h until
1 was consumed. The product was extracted with methylene chloride
(3 × 50 mL), followed by degassed water made slightly basic with CsOH
(20 mL). The methylene chloride layers were combined, washed with
the basic degassed water (5 × 50 mL), dried over anhydrous sodium
sulfate, decanted, and the solvent was subsequently removed in vacuo.
The crude product was purified by flash column chromatography (neu-
tral alumina), using ethyl acetate: methanol (1:1) to afford 16 as a pale
yellow oil in 99% yield.
1-Bromo-(2-diphenylphosphino)ethane (17)
˚
Under a nitrogen atmosphere, 4 A powdered molecular sieves (500 mg)
were added to a flame dried round bottom flask containing 6 mL of
anhydrous DMF. CsOH (1.15 mmol) was added, and the reaction was
stirred for 10 min. Ph2PH (1.15 mmol) was added, and the reaction
was stirred for 1 h. 1,2-Dibromoethane (1.38 mmol) was added drop-
wise, and the reaction was stirred for 19 h. The product was extracted
with methylene chloride (3 × 50 mL), followed by degassed water made
slightly basic with CsOH (20 mL). The organic layers were combined,
washed with basic degassed water (5 × 50 mL), and dried over anhy-
drous sodium sulfate. The organic solvent was removed and the crude
product was recrystallized from benzene to afford a white crystalline
product in 89% yield.
P-N-P Ligand (18)
˚
Under a nitrogen atmosphere, 4 A powdered molecular sieves (500 mg)
were added to a flame dried round bottom flask containing 6 mL
anhydrous DMF. CsOH (1.15 mmol) was added, and the reaction
was stirred for 10 minutes. 1-Amino-(2-diphenylphosphino)ethane (16)
(1.15 mmol) was added, and the reaction was stirred for 1 h. 1-Bromo-
(2-diphenylphosphino)ethane (17) (1.15 mmol) was subsequently added
and the reaction was stirred for an additional 31 h. The product was
extracted with methylene chloride (3 × 50 mL), followed by degassed
water made slightly basic with CsOH (20 mL). The combined organic
layers were washed with basic degassed water (5 × 50 mL), dried over

CsOH-Promoted Synthesis of Ditertiary Phosphines
283
anhydrous sodium sulfate, and the solvent was removed in vacuo. The
product was recrystallized from benzene to afford 18 an 84% overall
yield.
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