An Improved Synthesis of Me4PCP and DMPE

Article abstract of DOI:10.1021/acs.organomet.7b00780

We present a new synthetic method for the bis(dimethyl)phosphines ^Me4PCP (C₆H₄-2,6-(CH₂P(CH₃)₂)₂) and DMPE ((CH₃)₂PCH₂CH₂P(CH₃)₂) that starts from an aminophosphine, Et₂NPMe₂. Two equivalents of Et₂NPMe₂ react with the corresponding bis(alkyl bromide) to afford an oxygen-and moisture-stable aminophosphonium salt. NaAlH₄ selectively reduces the aminophosphonium salt to the desired phosphine. Each step is high yielding and requires minimal purification.

Full text of DOI:10.1021/acs.organomet.7b00780

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
An Improved Synthesis of Me4PCP and DMPE
Travis T. Lekich, Phoebe G. Askelson,† Ryan K. Burdick,‡ and D. Michael Heinekey*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: We present a new synthetic method for the bis(dimethyl)phosphines Me4PCP (C6H4-2,6-(CH2P(CH3)2)2) and
DMPE ((CH3)2PCH2CH2P(CH3)2) that starts from an aminophosphine, Et2NPMe2. Two equivalents of Et2NPMe2 react with
the corresponding bis(alkyl bromide) to afford an oxygen- and moisture-stable aminophosphonium salt. NaAlH4 selectively
reduces the aminophosphonium salt to the desired phosphine. Each step is high yielding and requires minimal purification.
Scheme 1. Summary of Recently Reported Methods for
Heteroleptic Phosphines and Phosphine Oxides
igands featuring dimethylphosphino (Me2P−) moieties
Loffer an open steric environment but are underexplored
because their syntheses have involved dangerous reagents and
cumbersome methods.1,2 Previous syntheses of DMPE
((CH3)2PCH2CH2P(CH3)2)) have proceeded through pyro-
phoric primary phosphines or Me2P(S)P(S)Me2, whose
synthesis has caused laboratory accidents.3−6 A derivative of
the commonly used pincer PCP ligand framework, Me4PCP
(C6H4-2,6-(CH2P(CH3)2)2), has seen minimal use because of
its previously low yielding synthesis, which proceeds through
the pyrophoric gas HPMe2.7,8 Greater use of these ligands and
exploitation of their steric properties require a safer and more
convenient synthetic protocol.
Newly developed syntheses of heteroleptic phosphines
(R2PR′) solve some of these issues but introduce other
difficulties when R = Me. These synthetic strategies, shown in
Scheme 1, involve treating an alkyl halide with a nucleophilic
phosphorus(III) precursor to afford a phosphine oxide or
halophosphonium halide.9−12 The phosphine oxides can be
converted to halophosphonium halides and then reduced with
aluminum hydride reagents, magnesium, or nickel.10,11
We hypothesized that an aminophosphine, a common
precursor to small ClPR2 derivatives, could be used in place
of ClPR2 in a pathway like that described by Ozerov and co-
workers, and may be beneficial, as ClPMe2 is difficult to obtain
in large quantities.2,11,13−17 Aminophosphines and their
precursors, aminodichlorophosphines, are oxygen and water
sensitive but can be safely prepared and stored in large
quantities with the commercially available reagents PCl3,
HNR2, and MR′ (M = Li, MgX (X = Cl, Br, I)).13,17−19
Here, we use an aminophosphine, Et2NPMe2, as a convenient
synthetic precursor to Me4PCP and DMPE, which are
representative of commonly used ligand frameworks.
Two equivalents of methyllithium alkylate (diethylamino)-
dichlorophosphine (Et2NPCl2) to afford (diethylamino)-
dimethylphosphine (Et2NPMe2).17,18 Aminophosphines can
be conveniently prepared in multigram quantities.13,18
Like most phosphines, aminophosphines are known to
oxidatively add alkyl halides to form phosphonium salts.13,17,20
Thus, two equivalents of Et2NPMe2 react with 1,2-dibromo-
ethane or α,α′-dibromo-m-xylene to afford the respective
bis(aminophosphonium) bromide, 1a or 1b, shown in Table
Received: October 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00780
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
MeLi (in Et2O), PCl3, HNEt2, 1,2-dibromoethane, α,α′-dibromo-m-
xylene, and reagent grade 90% NaAlH4 were purchased from Sigma-
Aldrich. MeLi solutions in Et2O were titrated with salicylaldehyde
phenylhydrazone to determine their concentrations prior to use.27 1,2-
Dibromoethane and HNEt2 were stored over activated 3 Å molecular
sieves prior to use. α,α′-Dibromo-m-xylene was recrystallized from
hexanes prior to use. Elemental analysis was completed at the CENTC
facility at the University of Rochester (funded by NSF CHE-0650456)
and at Atlantic Microlab, Norcross, GA.
1. These bis(aminophosphonium) salts are air and moisture
stable. X-ray crystallography confirmed the structure of 1a, as
shown in Figure S18 in the Supporting Information.
Table 1. Synthesized Aminophosphonium Salts and
Phosphines with Their Respective Yields
Compound 1a. 2,6-Dibromomethylbenzene (1.53 g, 5.77 mmol)
was added to a solution of N,N-diethylamino-P,P-dimethylphosphine
(1.69 g, 12.7 mmol) in MeCN (30 mL). The solution was stirred for
15 h. The resulting white precipitate was collected by vacuum filtration
in air and then washed with cold MeCN (0 °C, 3 × 5 mL) and diethyl
ether (3 × 5 mL) to afford 1a (2.76 g, 5.19 mmol, 90% yield). Crystals
of 1a suitable for X-ray diffraction were grown from a saturated MeCN
1
solution at −30 °C. H NMR (300 MHz, CD3CN): δ 7.52−7.29 (m;
4H; Ar-H), 3.83 (d; 2JHP = 15.5 Hz; 4H; Ar(−CH2−)), 3.10 (m; 8H;
−N((CH2)CH3)2), 1.96 (d; 2JHP = 14.8 Hz; 12H; −P(CH3)2), 1.02 (t;
3JHH = 7.3 Hz; −N((CH2)CH3)2). 31P{1H} NMR (121 MHz,
CD3CN): δ 60.0. 13C{1H} NMR (125.8 MHz, CD3CN): δ 131.0 (t,
2
2JCP = 2.7 Hz, CAr), 130.8 (t; JCP = 3.7 Hz; CAr), 41.73 (s;
1
−N((CH2)CH3)2), 33.89 (d; JCP = 49.1 Hz; Ar(−CH2−)), 14.77(s;
−N((CH2)CH3)2) 10.03 (d; 1JCP = 65.8 Hz; −P(CH3)2). Anal. Calcd:
C, 45.30; H, 7.60; N, 5.28. Found: C, 45.20; H, 7.53; N, 5.27.
Me4PCP. Compound 1a (2.14 g, 4.03 mmol) and NaAlH4 (0.87 g,
16.0 mmol) were stirred together in THF (15 mL) for 2 h at room
temperature. The reaction mixture was cooled to 0 °C, and a 15%
NaOH aqueous solution was added dropwise to quench the reductant
and byproducts. The volume of the solution was reduced under
vacuum, and pentane (3 × 10 mL) was used to extract from the
aqueous layer. The organic layer was dried over anhydrous sodium
sulfate. The drying agent was removed by filtration, and the volatiles
were removed under vacuum to afford Me4PCP (0.80 g, 88% yield).
The spectroscopic data are consistent with previous reports.7,8 1H
NMR (300 MHz, C6D6): δ 7.11 (t; 3JHH = 7.8 Hz; 1H), 6.90 (d; 3JHH
= 7.8 Hz; 2H), 2.50 (br s; 4H), 0.79 (d; 2JHP = 3.4 Hz; 12H). 31P{1H}
NMR (121 MHz, C6D6): δ −49.0. 13C{1H} NMR (125.8 MHz,
a
b
Conditions: 80 °C in MeCN for 15 h. Conditions: room
c
temperature in MeCN for 15 h. Conditions: 4 equiv of NaAlH4,
room temperature in THF for 2 h.
We hypothesized that traditional reagents for reducing
phosphoniums should also reduce aminophosphoniums.10,21
Four equivalents of NaAlH4 provided the highest purity and
yield of Me4PCP and DMPE. Table 1 summarizes the reaction
conditions and yields for these syntheses. We observed side
products, likely the mono- or bis-ylide, when 1a was reduced
with LiAlH4 in THF. In contrast, we did not observe undesired
products when reducing 1b with excess LiAlH4 in THF. Others
have attributed the differences in reactivity between NaAlH4
and LiAlH4 to the differing solubilities of the resulting NaX or
LiX salt and variable speciation in solution.22−25 Unlike the
reduction of halophosphonium halides reported by Ozerov and
co-workers, we found that nonhydridic reductants, such as Mg,
do not reduce 1a or 1b in MeCN or THF.
The presented synthetic method provides a straightforward
template to synthesize dimethyl (aliphatic and benzyl)
heteroleptic phosphines starting from an aminophosphine,
which can be prepared and stored in large quantities. We
hypothesize that these methods may be generalized to
synthesize a variety of heteroleptic and mixed phosphines.
Further research from our group will focus on the coordination
and catalytic chemistry of the corresponding Me4PCP complexes
with late transition metals and application of this synthetic
method to other ligands.
3
C6D6): δ 138.4 (s; CAr), 130.2 (t; Jcp = 4.0 Hz; CAr), 128.5 (s; CAr),
3
2
126.8 (d; JCP = 3.6 Hz, CAr), 39.09 (d; JCP = 15.5 Hz; Ar(−CH2‑ 68
2
(d; JCP = 16.5 Hz; −P(CH3)2).
Compound 1b. 1,2-Dibromoethane (1.76 g, 9.37 mmol) was
added to a solution of N,N-diethylamino-P,P-dimethylphosphine (2.74
g, 20.6 mmol) in MeCN (30 mL). The solution was stirred for 15 h at
80 °C. The volatiles were removed under vacuum, and the resulting
white solid was washed with cold MeCN (−45 °C, 3 × 5 mL) and
diethyl ether (3 × 5 mL) to afford 1b (3.20 g, 7.04 mmol, 75% yield).
1H NMR (300 MHz, CD3CN): δ 3.20 (m; 8H; −N((CH2)CH3)2),
2.81 (d; 2JHP = 4.5 Hz; 4H; −CH2CH2−), 2.18 (vt; 12H; −P(CH3)2),
3
1.16 (t; JHH = 7.0 Hz; 12H; −N((CH2)CH3)2). 31P{1H} NMR (121
MHz, CD3CN): δ 61.4. 13C{1H} NMR (125.8 MHz, CD3CN): δ
40.62 (s; −N((CH2)CH3)2), 18.75 (vt; −CH2CH2−), 13.90 (s;
−N((CH2)CH3)2), 9.55 (vt; −P(CH3)2). Anal. Calcd: C, 37.02; H,
7.99; N, 6.17. Found: C, 36.99; H, 8.11; N, 6.05.
DMPE. Compound 1b (2.32 g, 4.91 mmol) and NaAlH4 (1.06 g,
19.6 mmol) were stirred together in THF (15 mL) for 2 h at room
temperature. The reaction mixture was cooled to 0 °C, and a 15%
NaOH aqueous solution was added dropwise to quench the reductant
and byproducts. The volume of the solution was reduced under
vacuum, and pentane (3 × 10 mL) was used to extract from the
aqueous layer. The organic layer was dried over anhydrous sodium
sulfate. The drying agent was removed by filtration, and the volatiles
were removed under vacuum to afford DMPE (0.60 g, 4.00 mmol,
81% yield). The spectroscopic data are consistent with previous
reports.10 1H NMR (300 MHz, C6D6): δ 1.30 (vt; 4H; −CH2CH2−),
0.81 (vt; 12H; −P(CH3)2). 31P{1H} NMR (121 MHz, C6D6): δ
−47.3. 13C{1H} NMR (125.8 MHz, C6D6): δ 28.16 (vt; −CH2CH2−),
14.01 (dd; −P(CH3)2).
EXPERIMENTAL SECTION
■
General Considerations. All manipulations and reactions used
standard Schlenk techniques under an argon atmosphere unless
otherwise stated. Glassware, diatomaceous earth, and sodium sulfate
were stored in an oven maintained at 140 °C for at least 24 h prior to
use. All protio solvents were passed through activated alumina and
activated 3 Å molecular sieves prior to use. Deuterated solvents (C6D6
and THF-d8) were dried over calcium hydride or sieves. CD3CN was
1
used as received. H, 31P, and 13C NMR spectra were recorded on a
Bruker AV-500, DRX-499, or AV-300 instrument. 1H NMR and
13C{1H} NMR spectra were referenced to residual solvent signals.26
31P{1H} NMR spectra were referenced to an 85% H3PO4 standard.
Et2NPMe2 was synthesized as previously described.18,19 Reagents
B
DOI: 10.1021/acs.organomet.7b00780
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00780.
■
S
NMR spectra and crystallographic structure and data
(PDF)
Accession Codes
CCDC 1580835 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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1131.
AUTHOR INFORMATION
Corresponding Author
*E-mail for D.M.H.: heinekey@chem.washington.edu.
ORCID
■
(26) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I.
Organometallics 2010, 29 (9), 2176−2179.
(27) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64 (10), 3755−
3756.
D. Michael Heinekey: 0000-0002-7431-3603
Present Addresses
†P.G.A.: Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States.
‡R.K.B.: Department of Chemistry, University of Michigan, 930
N. University Avenue, Ann Arbor, Michigan 48109, United
States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Louise M. Guard, Dr. Jonathan M. Goldberg, and
Dr. Sophia D. T. Cherry for insightful discussions and Dr.
Werner Kaminsky for the solution of the solid-state structure of
1a. This work was supported by the NSF under the Center for
Enabling New Technologies through Catalysis CCI (CENTC)
(CHE-1205189).
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DOI: 10.1021/acs.organomet.7b00780
Organometallics XXXX, XXX, XXX−XXX