Pd-catalyzed dynamic kinetic enantioselective arylation of silylphosphines

Article abstract of DOI:10.1021/ja076457r

Palladium-catalyzed cross-couplings represent a powerful method for the formation of new bonds. A catalytic, enantioselective P-C bond-forming reaction proceeding via a Pd-mediated arylation of silylphosphines was developed for the synthesis of P-stereoge

Full text of DOI:10.1021/ja076457r

Published on Web 11/16/2007
Pd-Catalyzed Dynamic Kinetic Enantioselective Arylation of Silylphosphines
Vincent S. Chan, Robert G. Bergman,* and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received August 27, 2007; E-mail: rbergman@berkeley.edu; fdtoste@berkeley.edu
Scheme 1. Proposed Catalytic Cycle
Chiral phosphines are essential ligands for asymmetric transition-
metal-catalyzed transformations.1 In 1972, Knowles and co-workers
reported the first practical and highly asymmetric hydrogenation
using P-stereogenic phosphines,2 yet planar chiral and point chiral
phosphines are the most commonly employed ligands today.
P-Stereogenic phosphines are less often utilized, in part due to the
lack of efficient and general methods for their enantioselective
synthesis. Traditionally, these molecules are prepared by resolutions
or the use of chiral auxiliaries.3 Recently, there have been reports
of asymmetric metal-catalyzed approaches to P-stereogenic phos-
phines via alkene hydrophosphination4 and the arylation5 or
alkylation6 of secondary phosphines. Herein, we describe a new
route to P-stereogenic phosphines that proceeds through the dynamic
kinetic7 enantioselective arylation of tertiary racemic silylphosphines
catalyzed by palladium.
The Pd-catalyzed coupling of achiral silylphosphines with aryl
iodides was first reported by Stille.8 The mechanism is believed to
proceed via oxidative addition, followed by transmetalation of the
silylphosphine, and reductive elimination to form a P-C bond
(Scheme 1). In rendering this transformation enantioselective, we
envisioned exploiting the low barrier to pyramidal inversion of metal
phosphido complexes.9 Rapid epimerization of the Pd(II) phosphide
(relative to reductive elimination) enables the dynamic kinetic
arylation of chiral racemic silylphosphines.5e
Table 1. Enantioselective Arylation with Iodoarenes
Optimization of the silylphosphine arylation was performed with
3-iodoanisole.10 After extensive screening, the highest levels of
enantioselectivity were achieved at 60 °C when methylphenyl-
(triisopropylsilyl)phosphine 1 was cross-coupled using 5 mol % of
5b
((R,R)-Et-FerroTANE)PdCl2 2 in N,N′-dimethylpropylene urea
(DMPU) (eq 1). Under these conditions, (3-anisyl)methylphe-
nylphosphine 3, which was isolated as the air-stable borane adduct,
was obtained in 56% ee and 91% yield. A variety of inorganic11a
and organic11b additives were evaluated, and none was found to
have a beneficial effect on the enantioselectivity. When the coupling
partner was modified such that 3-bromoanisole or 3-methoxyphenyl
trifluoromethanesulfonate was employed, similar enantioselectivity
was observed, but the reactions proceeded in much lower yields.
a Isolated yield of the protected phosphine. b Measured by chiral HPLC.
c Phosphine protected as the sulfide after heating at 60 °C for 2.5 h.
however, was less satisfactory (entry 3). o-Iodobenzoates (entries
4-6) and -benzamides (entries 7-9) were particularly selective
substrates; with 2-iodo(2,6-dimethylphenyl)benzoate, phosphine 4e
was isolated in 82% ee (entry 5). A clear steric limitation was
observed with the more bulky 2,6-diisopropylphenyl benzoate, as
the product was isolated in 75% ee (entry 6). However, a dramatic
change was observed with N,N-diisopropyl-2-iodobenzamide: when
coupled with 1, this substrate furnished the resulting phosphine
sulfide 4i in 98% ee (entry 9).12,13 The tether length of the amide
directing group was found to be crucial, as the benzylic N,N-
diisopropylamide provided the product in only 32% ee (entry 10).
Subsequent experiments took advantage of the apparently
privileged properties of the diisopropylbenzamide (Table 2).
Changing the electronics para to the iodide had no effect on the
enantioselectivity (entries 1 and 2): both methyl- (5a) and chloro-
substituted (5b) amides give 97% ee. Varying the electronics para
to the amide also had no effect on the outcome (entries 3-5). Both
Using catalyst 2, ortho-functionalized iodoarenes were evaluated
in the arylation with 1. In a recent report by Glueck,5e ortho-
substituted arenes were coupled to secondary phosphines using an
Et-FerroTANE catalyst in low enantiomeric excess. As shown in
Table 1, an array of coordinating substituents was tolerated in the
“phospha-Stille” reaction with modest to excellent enantioselec-
tivities. Whereas 2-iodoanisole afforded the corresponding phos-
phine 4a in 52% ee (entry 1), the more π-releasing 2-iodothioanisole
furnished 4b in 63% ee (entry 2). The amine directing group,
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10.1021/ja076457r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Phosphine Scope in Enantioselective Arylation
Table 2. Enantioselective Arylation with Iodobenzamides
a Isolated yields of the phosphine sulfide. b Measured by chiral HPLC.
scenario, formation of the five-membered palladacycle, through
binding of the amide oxygen, is instrumental in conferring the high
enantioselectivities observed.
In conclusion, we have developed a Pd-catalyzed arylation of
silylphosphines, which represents a powerful method for the
asymmetric synthesis of P-stereogenic phosphines. The method
relies on the unique ability of the ortho-benzamide substituent to
enhance the enantioselectivity of these coupling reactions. Studies
toward the elucidation of the role of the directing group and its
application to other transition-metal-catalyzed coupling processes
are currently underway.
Acknowledgment. R.G.B. acknowledges financial support from
the National Science Foundation (CHE-0345488). F.D.T. thanks
Merck Research Laboratories, Bristol-Myers Squibb, Amgen Inc.,
Boehringer Ingelheim, and Novartis for funding.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield of the phosphine sulfide. b Measured by chiral HPLC.
c Reaction mixture heated at 60 °C for 4.5 h. d Reaction proceeded to
completion after 8 h at 60 °C.
References
the methoxy (5c) and trifluoromethyl substrates (5d) yielded the
product in 97% ee. Comparison of phosphines 5c and 3 clearly
demonstrated the beneficial effect of the ortho-amide group. More
electron-rich iodides required prolonged heating but proceeded
equally enantioselectively: 4,5-dimethoxy- and piperonyl-derived
benzamides reacted with 1 in 97% ee (entries 6 and 7). Extended
conjugation was also tolerated as phosphinonaphthamide 5h was
recovered in 93% ee. Electron-rich heteroarenes were also discov-
ered to be competent coupling partners; a pyridine carboxamide
furnished the product in 94% ee (5i, entry 9), and the thiophenyl14
substrate reacted in 92% ee (5j, entry 10). Even the sterically
encumbered amide (entry 11) proved effective for the arylation of
1, proceeding at 93% ee. As an extension of the benzamide directing
effect, the N,N-diisopropylcarbamoyl moiety was used as a N-
protecting group for 2-iodoindole, yielding phosphine 5l in 86%
ee (entry 12).
The phospha-Stille coupling was also extended to other phos-
phines (Table 3). Coupling of the electron-poor (3,5-difluorophe-
nyl)methylphosphine afforded a dramatic decrease in the enanti-
oselectivity (entry 1). Variation of the alkyl substituent, however,
was well-tolerated: the less sterically differentiated benzylphenyl-
(triisopropylsilyl)phosphine was coupled to N,N-diisopropylben-
zamide to give phosphine sulfide 6b in 92% ee (entry 2).
Oxygenated alkyl groups were also tolerated, furnishing products
6c and 6d, potential P,O-bidentante ligands, in 92 and 93% ee,
respectively.
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(10) For selected optimization results, see Supporting Information.
(11) (a) Representative inorganic salts added: LiBr (42% ee), K3PO4 (52%
ee), CsF (52% ee), CuI (28% ee). (b) Some organic additives which were
evaluated: TBAF (12% ee), MeOH (51% ee).
(12) Coupling with methylphenyl(trimethylsilyl)phosphine furnished 4i in 93%
ee and 31% yield.
(13) Under conditions reported in ref 5b, no reaction was observed.
(14) The cross-coupling of 3-iodothiophene with 1 under the optimized
conditions afforded the corresponding phosphine in only 43% ee.
Given the significant dependence of the enantioselectivity on
the amide substituents and tether length (Table 1, entries 7-10),
we postulate the coordination of the amide to the Pd center. In this
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