A novel synthesis of unsymmetrical tertiary phosphines: Selective nucleophilic substitution on phosphorus(III)

Article abstract of DOI:10.1039/a706428d

A new synthesis of unsymmetrical tertiary phosphines has been developed employing selective, sequential alkylation of chloroaminophospnines by Grignard and organolithium reagents.

Full text of DOI:10.1039/a706428d

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A novel synthesis of unsymmetrical tertiary phosphines: selective nucleophilic
substitution on phosphorus(iii)
Sumita Singh and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73019, USA
A new synthesis of unsymmetrical tertiary phosphines has
been developed employing selective, sequential alkylation of
chloroaminophosphines by Grignard and organolithium
reagents.
Ph
Ph
Ph
Ph
RLi, RMgX
RLi
NR4R5
P
R
no reaction
P
(with 4c)
or R3Al
(with 4a,b)
4a R4 = R5 = Et
b R4 = R5 = Pri
c R4 = Me, R5 = Ph
1
Phosphines constitute the most important class of ligands used
in transition metal catalysed reactions.1 The activity and
selectivity of such catalysts are often acutely sensitive to the
structure of the phosphine, necessitating the synthesis and
testing of a variety of ligands to optimize the catalyst. Hence,
the development of efficient and selective preparative routes to
structurally diverse phosphine libraries, both in solution and on
solid supports, is an important objective. Initial approaches to
high throughput parallel syntheses of peptide-derived chiral
phosphines2 and of other ligands3 and catalysts4 for asymmetric
synthesis have been reported recently.
We sought to develop a general and efficient preparation of
tertiary phosphines which ultimately would be adaptable for
solid phase parallel synthesis. Solution phase preparation of
phosphines usually involves displacement of halide or alkoxide
using organometallic reagents5 (Scheme 1) but access to
unsymmetrical tertiary phosphines 1 is complicated by poly-
substitution. Selective displacement of chloride in the presence
of alkoxide is sometimes possible using a combination of
organocadmium and Grignard reagents,6 organozinc and
organolithium reagents,7 and via other approaches8 but these
methods often employ inconvenient organometallics, require
multiple steps, and/or lack selectivity or generality. We describe
herein a new approach (Scheme 2) which exploits the vastly
different leaving group abilities of chloride vs. amide and the
differential reactivity of organolithium vs. organomagnesium
reagents.
Scheme 3
with MeLi at room temperature, yielding the desired phosphine
(Scheme 3).
The key chloroaminophosphines 2 (a R = Ph; b R = Et) are
efficiently prepared (ca. 75%) by reaction of readily available
organodichlorophosphines‡§ with LiNMePh9 (THF, 20 °C,
Scheme 2).¶ These, in turn undergo selective reaction with
Grignard reagents (1.5 equiv, THF, 20 °C) producing amino-
phosphines 3a–j in excellent yields following aqueous workup
(Table 1).∑ A variety of substituents, including alkyl, vinyl and
aryl groups, are efficiently incorporated.
Organolithium reagents readily react with the aminophosph-
ines 3 (THF, 20 °C) giving unsymmetrical tertiary phosphines
1a–j (Scheme 2, Table 1).** Although isolated yields of volatile
dialkylaryl phosphines were only fair, diarylalkyl derivatives,
including sterically hindered ones (e.g. 1e–g), could be obtained
in high yield.
Finally, we note that the complete sequence from PR1Cl2 to
PR1R2R3 can be conveniently accomplished without the
isolation of intermediates. In this way phosphine 1f was
obtained in 59% yield by sequential treatment of PhPCl2 with
LiNMePh, o-tolMgBr and then MeLi.††
Application of this methodology for the solid-phase synthesis
of phosphine libraries is under investigation.
To first establish the leaving group ability of the dialkyl-
amino unit, the interaction of 4a–c9 with representative RLi,
RMgX, and R3Al reagents was investigated. Dialkylamino-
phosphines 4a,b proved unreactive even when these organ-
ometallics were employed in excess at elevated temperature.†
N-Methyl-N-phenylaminodiphenylphosphine 4c9 possessing an
expectedly better leaving group, however, reacted extremely
slowly with excess MeMgCl at high temperature but rapidly
We thank the National Science Foundation (in part) and the
University of Oklahoma Research Council for financial support
of this work.
Table 1 Preparation of unsymmetrical tertiary phosphines
R1
R2
NMePh
Cl
R2
R3
R2MgX
R3Li
R1
P
P
NMePh
R1
P
2
3
1
R2
R1M
R2M
R3M
R1
P
R1PX2
R1R2PX
PX3
Yielda
(%)
R3
2
R1 R2
X
3
Yielda (%)
R3
1
1
Scheme 1
2a Ph Pri
Cl 3a 86
Cl 3b 83
Br 3c 95
Br 3d 94
Br 3e 94
Br 3f 96
Me 1a 16
But 1b 44
Me 1c 54
Me 1d 95
But 1e 76
Me 1f 93
Me 1g 70
Me 1h 98b
Ph 1i 99
Ph 1j 78
2a Ph Me
2a Ph Vinyl
2a Ph p-tol
2a Ph p-tol
2a Ph o-tol
NR4R5
R1M
LiNR4R5
R1PX2
R1
P
PX3
X
2
2a Ph 2,6-Me2C6H3 Br 3g 89
R2M
2a Ph Me3SiCH2
2b Et p-tol
2b Et Bn
Cl 3h 87
Br 3i 90
Cl 3j 77
R1
R2
R3M
NR4R5
R1
P
P
R2
R3
3
1
a
b
1
Isolated yield. Mixture of phosphine and PhNHMe (3:1) by H NMR
Scheme 2
spectroscopy. Yield calculated via integration.
Chem. Commun., 1998
149

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dissolved in 10 ml THF, treated with MeLi (5.5 equiv.) at 0 °C, and then
stirred at room temperature for 3 h. Phosphine 1f was isolated as described
for the preparation of 1 above.
Footnotes and References
* E-mail: knicholas@ou.edu
† Synthesis of tertiary phosphines via reaction of Grignard reagents with
aminoarylphosphines bearing a coordinating heteroatomic group at the
ortho position on the phenyl ring has been previously reported (ref. 10).
Based on the non-reactivity of unsubstituted aryldialkylaminophosphines
observed by us, the ligating ortho substituent seems to be a prerequisite.
‡ Some organodichlorophosphines are commercially available; they also
can be obtained via reaction of phosphorus trichloride with organometallic
reagents (ref. 5).
§ Reactions and transfers for the preparation of 1–3 were conducted under
N2. All compounds exhibited satisfactory 1H and 31P NMR spectra.
¶ Preparation of 2: BunLi (35 mmol in hexane) was added slowly to
PhNHMe (30 mmol) in THF (5 ml) at 0 °C and the resulting white
suspension was stirred at room temp. for 45 min. The solvent was
evaporated, the white solid was dissolved in THF (150 ml), and the solution
was added dropwise to RPCl2 in THF (1.25 m, R = Et, Ph) at 0 °C. After
stirring at room temp. for 2 h, the solvent was evaporated, CH2Cl2 (40 ml)
was added, the mixture filtered, and the solvent evaporated to provide crude
2a,b which could be purified by vacuum distillation.
∑ Preparation of 3: To a stirred solution of 2a or b in THF (1 m) at 0 °C was
added 1.5 equiv. of Grignard reagent. The mixture was stirred at room
temp. until all of 2 had reacted (by 1H and 31P NMR spectroscopy). The
mixture was then cooled in ice and 1 m NH4Cl was added slowly for
complete neutralization. The organic layer was separated, dried over
Na2SO4, and the solvent evaporated to give the aminophosphines 3a–j as
pale yellow liquids which could be used in the next step without further
purification.
** Preparation of 1: To a solution of 3 in THF (1 m) at 0 °C was added 1.5
equiv. of RLi. After warming to room temp., the mixture was stirred until
reaction completion was indicated (by 1H and 31P NMR spectroscopy). The
solvent was evaporated and hexane (30–40 ml) was added. After stirring for
a few minutes, the mixture was filtered, and the solvent was evaporated to
yield the phosphines.
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†† ‘No isolation’ preparation of 1: PhMeNLi was prepared and added to
PhPCl2 in THF as described for the preparation of 2. When the starting
material was consumed (2 h, by NMR spectroscopy), o-tolylMgBr (1.5
equiv.) was added at 0 °C and the reaction mixture was then warmed to
room temperature. Once the formation of aminophosphine was complete
(1.5 h), the solvent was evaporated and the residue was triturated with 50 ml
benzene. The combined extracts were evaporated and the residue was
Received in Corvallis, OR, USA, 29th August 1997; 7/06428D
150
Chem. Commun., 1998