Asymmetric catalytic synthesis of P-stereogenic phosphines via a nucleophilic ruthenium phosphide complex

Article abstract of DOI:10.1021/ja058100y

Ruthenium phosphido complexes have been shown to be excellent nucleophiles, reacting via two-electron processes with a variety of electrophiles. A catalytic alkylation reaction was developed using an achiral ruthenium complex, which was then elaborated into a catalytic enantioselective synthesis of P-stereogenic phosphines. These useful and synthetically challenging phosphines can now be accessed in a single step from simple secondary phosphines and alkyl halides. Optimization and scope of the enantioselective alkylation are discussed. Copyright

Full text of DOI:10.1021/ja058100y

Published on Web 02/10/2006
Asymmetric Catalytic Synthesis of P-Stereogenic Phosphines via a
Nucleophilic Ruthenium Phosphido Complex
Vincent S. Chan, Ian C. Stewart, Robert G. Bergman,* and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received November 29, 2005; E-mail: rbergman@berkeley.edu; fdtoste@berkeley.edu
Many reactions rely upon the activation of an electrophile via
coordination to a Lewis acidic metal catalyst, followed by attack
of an external nucleophile. The inverse situationsthe activation of
a nucleophile via coordination to an electron-rich metal centers
remains a largely unexplored area of catalysis.1 The high nucleo-
philicity at phosphorus of late transition metal phosphido (M-PR2)
complexes2 provides an excellent opportunity to investigate this
reactivity. We therefore sought to synthesize electron-rich metal
phosphido species and investigate their substitution chemistry. After
establishing its enhanced nucleophilicity, we hoped to utilize these
compounds in the asymmetric catalytic synthesis of P-stereogenic
phosphines.2b These enantioenriched phosphines are employed as
ligands in late transition-metal-catalyzed asymmetric reactions,3 but
have seen little use to date, due to the dearth of efficient methods
for their preparation.4 Herein, we report the synthesis and reactivity
of a highly nucleophilic Ru(II) phosphido complex and its applica-
tion in a novel catalytic enantioselective alkylation reaction.
dissociated from the ruthenium center to yield 6 (isolated as the
borane complex).
Two of the transformations discussed abovesdeprotonation (eq
1) and alkylation (eq 2)sprovide the basis for a proposed catalytic
cycle. As depicted in Scheme 1, phosphido complex A undergoes
Scheme 1
On the basis of the strong basicity and nucleophilicity of
previously reported iron and ruthenium amido complexes, particu-
larly (dmpe)2M(H)NH2 (dmpe ) 1,2-bis(dimethylphosphino)ethane,
M ) Fe,5 Ru6), an analogous phosphido complex (dmpe)2Ru(H)-
(PMePh) 1 was synthesized (eq 1).7 Abstraction of the chloride
ligand from (dmpe)2Ru(H)(Cl), followed by addition of 1 equiv of
methylphenylphosphine 3, afforded cationic phosphine complex
2-BPh4. Deprotonation of this complex with KHMDS afforded
ruthenium phosphido complex 1.
Crystals of 1 and 2-BPh4 suitable for X-ray diffraction analysis
were obtained from concentrated THF solutions cooled to -35 °C.
The Ru-P bond in the cationic complex 2-BPh4 is lengthened from
2.342 to 2.513 Å upon deprotonation to form 1. This bond lengthen-
ing is consistent with a filled-filled dπ-pπ repulsive interaction2a
between the phosphido moiety and the electron-rich and π-basic
ruthenium atom. The sum of the angles around the phosphido
phosphorus in 1 (327.1°) provides evidence that there is minimal
back-bonding to the ruthenium center from the phosphido ligand.
Having synthesized the desired phosphido complex, experiments
were conducted to evaluate its nucleophilicity at phosphorus.
Ruthenium phosphido 1 displaces halides and tosylates from a wide
variety of electrophiles.8 Two informative examples are discussed
(eq 2). Addition of 1 equiv of the bromomethylcyclopropane 4 to
a solution of 1 in THF afforded complex 5-Br; no cyclopropane
ring scission was detected, providing strong evidence against a
radical pathway for the substitution. 1 also underwent substitution
with neopentyl bromide, a traditionally poor SN2 substrate, within
36 h at 45 °C; the resulting methylneopentylphenylphosphine
alkylation with an electrophile. As observed in the reaction of 1
with neopentyl bromide, the tertiary phosphine of cationic complex
B can dissociate from the metal center, providing coordinatively
unsaturated Ru-H complex C. Association of a secondary phos-
phine to C generates complex D. Deprotonation of D regenerates
metal phosphido complex A, closing the catalytic cycle.
In developing a catalytic asymmetric alkylation reaction, the 1,2-
bis((2R,5R)-2,5-dimethylphospholano)ethane ((R,R)-Me-BPE) ana-
logue of 1 was synthesized as a single diastereomer.9 The
stoichiometric alkylation of diastereopure (R,R)-Me-BPE phosphido
complex 7 with benzyl chloride afforded the corresponding tertiary
phosphine 9 (following borane protection) with low, but promising,
enantioselectivity (eq 3).
Satisfyingly, a catalytic amount of [((R,R)-Me-BPE)2Ru(H)]-
[BPh4] 8-BPh4 also afforded phosphine borane 9 with enantiose-
lectivity. Thus, the proposed catalytic cycle is a potentially viable
method for the asymmetric alkylation of secondary phosphines.
In optimizing the catalytic, asymmetric phosphido alkylation,
sodium tert-amyloxide was selected as the most suitable base with
regard to two critical criteria: (1) its ability to regenerate a Ru
9
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10.1021/ja058100y CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Alkylation with Alkyl Chlorides
Table 1. Catalyst Optimization
entry
ligand
temp (
°
C)
time
% eea
1
2
3
4
5
6
7
8
9
(R,R)-Me-BPE
(R)-Me-PHOX
(R)-Ph-PHOX
23
23
23
23
23
-30
-30
-30
-30
20 min
1 h
1 h
1 h
1 h
48 h
60 h
60 h
60 h
-21 (-19b)
-24
10
(S)-Bn-PHOX
7
(R)-i-Pr-PHOX (10)
(R,R)-Me-BPE
(R)-Me-PHOX
(R)-i-Pr-PHOX (10)
(S)-i-Pr-PHOX
27 (8c)
19
11
-79d
75
a Measured by chiral HPLC. Negative ee denotes opposite enantiomer.
b With 2 mol % catalyst loading. c Reaction with benzyl bromide. d The %
ee reported as an average of four trials.
phosphido complex (D to A in Scheme 1), and (2) its noncompeti-
tive background reaction.
Having demonstrated proof of principle (eq 3), the catalytic
alkylation of 3 with benzyl chloride was examined with a variety of
chiral hydrido ruthenium complexes (Table 1). The substituted phos-
phine was isolated as the air-stable benzylmethylphenylphosphine
borane 9. Ruthenium catalysts with C2-symmetric diphosphine
ligands overall gave low enantioselectivities.10 Notably, reducing the
catalyst loading from 10 to 2 mol % resulted in only a slight de-
crease in the enantiomeric excess, demonstrating the efficiency of
the metal-catalyzed reaction (entry 1). Phosphino-oxazoline (PHOX)
ligands also resulted in low enantioselectivities (entries 2-5).
Reaction with the more reactive benzyl bromide gave a significant
decrease in the enantioselectivity (entry 5). Upon lowering the
reaction temperatures to -30 °C, however, the i-Pr-PHOX catalyst
10 afforded phosphine borane 9 in 79% ee (entry 8).
The temperature-optimized conditions with catalyst 10 were then
applied to the asymmetric alkylation of secondary phosphine 3 with
a variety of substituted benzylic chlorides (Table 2). The reaction
tolerates para-substitution, particularly electron-donating groups
(entries 3 and 4). Chloro substitution was also tolerated in the
reaction (entry 2). Substrates with substitution in the ortho position
reacted efficiently, although with lower enantioselectivities (entries
5-7). Chelating bisphosphines were efficiently synthesized (entries
7 and 8); a chiral pincer ligand (entry 8) was obtained from the
double substitution in 95% ee. Heteroaryl substrates were tolerated
(entries 9-11), giving a chiral pyridyl-pincer ligand in 84% ee
(entry 9). The reaction was demonstrated to take place efficiently
with a nonbenzylic electrophile to give ethylmethylphenylphosphine
borane in 57% ee (entry 12).
a Isolated yields. b Measured by chiral HPLC. c The % ee after a single
recrystallization. d A 33:67 mixture of C2:meso diastereomers determined
by HPLC. e A 74:26 C2:meso dr. f A 58:42 C2:meso dr. g Reaction with
ethyl bromide.
Supporting Information Available: XRD for 1 and 2-BPh4,
experimental procedures, and characterization data are available. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J.
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In conclusion, the enhanced nucleophilicity of electron-rich
ruthenium phosphido complexes was exploited in the development
of a catalytic system for the asymmetric synthesis of P-stereogenic
phosphines. This enantioselective alkylation reaction provides access
to useful and synthetically challenging phosphine ligands in a single
step from secondary phosphines and alkyl halides. In a broader
sense, this reaction represents the activation of a nucleophile via
coordination to an electron-rich transition metal; this reactivity,
which differs from typical Lewis acid activation of an electrophile,
offers many new exciting avenues in catalysis.11
(7) An alternative method of preparing 1 from (dmpe)2RuH2 is described in
the Supporting Information.
(8) The full scope of electrophiles that react with 1 will be reported in due
course.
(9) Metal phosphido complexes typically exhibit low barriers to pyramidal
inversion: Rogers, J. R.; Wagner, T. P. S.; Marynick, D. S. Inorg. Chem.
1994, 33, 3104-3110. We are currently investigating the barrier to
pyramidal inversion in 7.
(10) Other diphosphine ligands afforded 9 with low or no enantiomeric
excess: (R,R)-DIOP (0%); (R,R)-i-Pr-DuPhos (0%); (R,R)-Me-DuPhos
(-10%); (R,R)-Et-DuPhos (-9%).
(11) By agreement of the authors, this paper should have appeared simulta-
neously on the ASAP version of the journal with the paper by Scriban
and Glueck that immediately follows this one in the paginated version of
the journal (Scriban, C.; Glueck, D. S. J. Am. Chem. Soc. 2006, 128,
2788-2789.
Acknowledgment. The authors wish to thank Dr. Jennifer
Krumper for helpful discussions. We are grateful to Prof. David
Glueck for disclosure of results prior to publication and for agreeing
to simultaneous publication of our closely related studies. We
acknowledge financial support from NSF Grant CHE-0345488 to
R.G.B., from an NSF predoctoral fellowship to I.C.S., and from
DuPont and Merck Research Laboratories to F.D.T.
JA058100Y
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