Palladium-catalyzed asymmetric phosphination: Enantioselective synthesis of a P-chirogenic phosphine

Article abstract of DOI:10.1021/ja0267324

The racemic secondary phosphine PH(Me)(Is) (1, Is = 2,4,6-(i-Pr)₃C₆H₂) was coupled with PhI in the presence of NaOSiMe₃ and the catalyst Pd((R,R)-Me-Duphos)(Ph)(I) (3) to give P(Ph)(Me)(Is) (2) in up to 78% ee.

Full text of DOI:10.1021/ja0267324

Published on Web 10/18/2002
Palladium-Catalyzed Asymmetric Phosphination: Enantioselective Synthesis
of a P-Chirogenic Phosphine
Jillian R. Moncarz, Natalia F. Laritcheva, and David S. Glueck*
6128 Burke Laboratory, Department of Chemistry, Dartmouth College, HanoVer, New Hampshire, 03755
Received April 30, 2002
Table 1. Pd-Catalyzed Asymmetric Synthesis of 2 from 1a
Chiral phosphines, valuable ligands for metal-catalyzed asym-
1
metric reactions, are usually prepared either by resolution or by
entry
PhX
solvent
T (°
C)
yield (%)
ee (%)
2
using a stoichiometric amount of a chiral auxiliary. Surprisingly,
1
2
3
4
5
6
7
8
9
PhI
PhI
PhI
PhI
THF
21
21
21
4
50
50
21
21
21
69b
66
58
73
78
42
38
50
70
73
metal-catalyzed asymmetric syntheses of these ligands are rare.3
We report here that Pd-catalyzed asymmetric phosphination (cross-
coupling of a secondary phosphine PH(R)(R′) with an aryl halide
b
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
60
b
71
c
84
c
4
PhI
60
or triflate) can be used to prepare a P-chirogenic phosphine with
c
PhBr
PhOTf
PhI
53
control of stereochemistry at phosphorus. Observations of potential
intermediates in the catalytic cycle suggest that dynamic resolution
of rapidly inverting phosphorus stereocenters is responsible for the
enantiomeric excess (ee).
c
70
90d
d
PhI
88
a
)5 with
3 6 2
C H
and the catalyst Pd-
Base ) NaOSiMe3 (1.0 M in THF), catalyst ) 3 (5 mol %; 7 mol %
for entries 1-2, 2.5 mol % for entry 9), 2 equiv of PhX; 1 equiv of PhI for
entry 4, 1.05 equiv of PhI for entries 8-9. For experimental details and ee
determination, see the Supporting Information. b By H NMR integration
Coupling of racemic PH(Me)(Is) (1, Is ) 2,4,6-(i-Pr)
PhI in the presence of the base NaOSiMe
3
6
1
(
(
(R,R)-Me-Duphos)(Ph)(I) (3) gave enantioenriched P(Ph)(Me)-
c
7
after product isolation by column chromatography. Isolated yield after
Is) (2, Table 1). Related tertiary methylphosphines are precursors
column chromatography. d Isolated yield after workup in the text.
8
to a family of useful bidentate diphosphines, such as DiPAMP,
but incorporation of 2,6-disubstituted aryl groups by standard
methods is difficult.9
Scheme 1
With 5 mol % of 3, a typical catalytic reaction was complete in
about 1 h. 31P NMR monitoring showed quantitative conversion to
the tertiary phosphine 2, which could be isolated in good yields
after column chromatography as an oil which solidified on storage
in a freezer; its ee was established by NMR after complexation to
a chiral Pd amine complex.10 Toluene was the preferred solvent
at room temperature. Low-temperature 31P NMR showed that the
(entries 1-3), with increase and reduction in ee at lower and higher
phosphine reversibly displaced iodide to form the cation [Pd(Me-
Duphos)(Ph)(PH(Me)(Is))][I] (4) as a mixture of diastereomers; the
equilibrium favored neutral 3. Cation 4 was independently synthe-
sized as the isolable triflate salt (4-OTf) from 3, phosphine 1, and
temperatures (entries 4 and 5). Phenyl bromide and triflate could
also be used, although ee’s were lower (entries 6 and 7). After this
brief survey of reaction conditions, we scaled up the synthesis of
and improved its workup to avoid column chromatography.11
AgOTf.12 Treatment of 4 with NaOSiMe at low temperature gave
3
2
Coupling of 500 mg of 1 (2 mmol) with PhI using 5 mol % of 3
was complete after 2 h. After the solvent was removed, extraction
with petroleum ether and filtration through a short pad of silica,
followed by washing the silica with 9:1 petroleum ether/THF, gave
phosphine 2 in 90% yield and 70% ee (entry 8). Similar results
were obtained at lower catalyst loading (2.5 mol %, entry 9).
A study of the individual steps in a potential mechanism for the
catalytic reaction (Scheme 1) provided mechanistic information on
the phosphido complex Pd(Me-Duphos)(Ph)(P(Me)(Is)) (5). Be-
cause neither iodide complex 3 nor phosphine 1 reacts directly with
NaOSiMe
step process shown in Scheme 1.
Low-temperature 31P NMR showed that 5, generated either by
deprotonation of cation 4 or directly from 3, phosphine 1, and
3
2
, Pd-PR bond formation appears to proceed by the two-
13
NaOSiMe
3
, exists as a mixture of diastereomers 5a-b (ratio ca.
40:1, THF/THF-d
8
, -60 °C), which presumably interconvert
4
through inversion at phosphorus.14 The signals due to the minor
the origin of the ee. Treatment of Pd(Me-Duphos)(Ph)(I) with PH-
Me)(Is) led to broadening of the 31P NMR peaks of the phosphine
diastereomer broadened considerably on warming, but coalescence
could not be observed because reductive elimination of the tertiary
phosphine 2 was also observed starting at -20 °C. After reductive
(
*
To whom correspondence should be addressed. E-mail: glueck@dartmouth.edu.
1
3356 J. AM. CHEM. SOC. 2002, 124, 13356-13357
9
10.1021/ja0267324 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
provided information both on the mechanism of the reaction and
on the origin of enantioselectivity (via dynamic resolution). We
are currently investigating the scope of the catalysis, optimizing
yields, ee’s, and catalyst loading, and investigating other, structurally
related catalysts.
Acknowledgment. We thank the National Science Foundation
and Union Carbide (Innovation Recognition Program) for support.
Supporting Information Available: Experimental procedures and
characterization data (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
(
(
1) (a) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis: The Applications
and Chemistry of Catalysis by Soluble Transition Metal Complexes, 2nd
ed.; Wiley: New York, 1992. (b) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley-Interscience: New York, 1994.
2) (a) Pietrusiewicz, K. M.; Zablocka, M. Chem. ReV. 1994, 94, 1375-1411.
(
b) Kagan, H. B.; Sasaki, M. In The Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; John Wiley and Sons: Chichester, 1990;
Vol. 1, pp 51-102.
elimination of 2, oxidative addition of PhI occurred smoothly to
regenerate 3, consistent with the standard cross-coupling mechanism
shown in Scheme 1.
3) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125-10138. (b) Kovacik, I.; Wicht, D. K.; Grewal, N.
S.; Glueck, D. S.; Incarvito, C. D.; Guzei, I. A.; Rheingold, A. L.
Organometallics 2000, 19, 950-953. (c) Pd-catalyzed coupling of
enantiopure secondary phosphine-boranes with aryl iodides yields tertiary
phosphine-boranes in high ee. See: Al-Masum, M.; Kumaraswamy, G.;
Livinghouse, T. J. Org. Chem. 2000, 65, 4776-4778. Oshiki, T.; Imamoto,
T. J. Am. Chem. Soc. 1992, 114, 3975-3977.
During catalysis with PhI at room temperature, 31P NMR
monitoring initially showed the presence of phosphido complex 5
2
and Pd(Me-Duphos)(PH(Me)(Is)) (6), which undergoes rapid
exchange on the NMR time scale with PH(Me)(Is).15 As catalysis
proceeded, complex 3 was also observed; it became the dominant
Pd species present near the end of the reaction. In catalysis with
(
4) (a) Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52, 748-753. (b) For
recent examples, see: Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek,
C.; Nickel, T.; Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet.
Chem. 2002, 645, 14-26.
16
PhOTf, the same Pd complexes were observed, but the ratio of 6
to 5 was greater, consistent with faster oxidative addition of PhI.17
These observations suggest that the rates of oxidative addition and
reductive elimination during catalysis are similar and that Pd-P
bond formation can be faster than both steps under the appropriate
conditions.
(
5) Brauer, D. J.; Bitterer, F.; Dorrenbach, F.; Hessler, G.; Stelzer, O.; Kruger,
C.; Lutz, F. Z. Naturforsch., B 1996, 51, 1183-1196.
(6) Drago, D.; Pregosin, P. S. Organometallics 2002, 21, 1208-1215.
7) Imamoto, T.; Takeyama, T.; Kusumoto, T. Chem. Lett. 1985, 1491-1492.
(
(8) Yamanoi, Y.; Imamoto, T. ReV. Heteroat. Chem. 1999, 20, 227-248.
(
9) Maienza, F.; Spindler, F.; Thommen, M.; Pugin, B.; Mezzetti, A. J. Org.
Chem. 2002, 67, 5239-5249.
(
10) (a) Roberts, N. K.; Wild, S. B. J. Am. Chem. Soc. 1979, 101, 6254-
6
260. (b) Wild, S. B. Coord. Chem. ReV. 1997, 166, 291-311. We have
The observation of both diastereomers of 5 in an unequal ratio
suggests two possible extreme routes to enantioselection. If 5a and
not established the absolute configuration of 2; a single enantiomer is
shown for convenience.
5b undergo reductive elimination at similar rates, faster than P
2
(11) Because 2 is air-sensitive, chromatography (under N ) is inconvenient.
12) Using a stoichiometric amount of PH(Me)(Is) yields a 1:1 mixture of
(
inversion, then the ee of product 2 would reflect their thermody-
namic ratio (Keq, Scheme 2). Alternatively, if interconversion of
diastereomers of 4. Heating this material in THF, or use of excess
phosphine in the original synthesis, gives 4 in 1:1.4 ratio.
(
13) However, we cannot rule out formation, in an unfavorable equilibrium,
5
a and 5b is faster than reductive elimination, their relative rates
-
of the anion [P(Me)(Is)] , which could displace iodide from 3.
of reductive elimination could control the ee (k * k
1
2
, Scheme 2).18
(14) (a) Wicht, D. K.; Glueck, D. S.; Liable-Sands, L. M.; Rheingold, A. L.
Organometallics 1999, 18, 5130-5140. (b) Wicht, D. K.; Kovacik, I.;
Glueck, D. S.; Liable-Sands, L. M.; Incarvito, C. D.; Rheingold, A. L.
Organometallics 1999, 18, 5141-5151. (c) Zhuravel, M. A.; Glueck, D.
S.; Zakharov, L. N.; Rheingold, A. L. Organometallics 2002, 21, 3208-
To probe the relative rates of phosphorus inversion and reductive
elimination in intermediates 5a-b, we deprotonated diastereomeric
mixtures of cations 4 to give phosphine 2. If reductive elimination
occurs more quickly than inversion, the initial ratio of diastereomers
3214.
(15) Complex 6 was generated free of 5 by running catalysis with a
substoichiometric amount of PhI, or by addition of excess PH(Me)(Is) to
Pd(Me-Duphos)(trans-stilbene). At -40 °C, phosphine exchange in 6 is
slow on the NMR time scale, and the expected mixture of four
diastereomers was observed.
16) Reaction mixtures with PhOTf contain 1 equiv of NaI per Pd, derived
from precursor 3. Independent generation of Pd(Me-Duphos)(Ph)(OTf)
(from Pd(Me-Duphos)(trans-stilbene) and PhOTf) in the presence of NaI
gave 3, consistent with the observations in the catalytic system.
17) Alcazar-Roman, L. M.; Hartwig, J. F. Organometallics 2002, 21, 491-
502.
(dr) should be carried through to the product. Instead, if phosphido
complexes 5a and 5b could interconvert before reductive elimina-
tion, their relative abundance and reductive elimination rates might
result in an enantiomeric ratio (er) of 2 different from the original
dr of cations 4.19 Because this was observed (dr ) 1:1 or 1:1.4,
but er ) 6:1), the rate of inversion is greater than or equal to that
of reductive elimination under these conditions. Treatment of 3 with
3
phosphine 1 and NaOSiMe at room temperature led to analogous
results (er ) 6:1). The similar product ratio observed in the catalytic
reactions provides a rationale for the observed enantioselection,
which is apparently controlled by inversion and reductive elimina-
tion in phosphido intermediates 5a,b.20
In conclusion, the new catalytic asymmetric phosphination is a
potentially useful method for the synthesis of P-chirogenic phos-
phines. In addition to identifying an active catalyst, we have
(
(
(
(
18) Halpern, J. Science 1982, 217, 401-407.
19) Seeman, J. R. Chem. ReV. 1983, 83, 83-134.
(20) Deprotonation of diastereomers 4a and 4b at different rates to give 5a
and 5b, which undergo reductive elimination faster than P inversion, might
also result in enantioselection if 4a and 4b can interconvert before
deprotonation is complete, perhaps via reversible proton transfer. However,
the observation that different diastereomeric mixtures of 4 lead to the
same product ratio in 2 makes this unlikely. Moreover, the ee of 2 in the
catalytic reaction does not depend on [NaOSiMe
of the base per PH(Me)(Is)).
3
] (1, 2, 3, or 10 equiv
JA0267324
J. AM. CHEM. SOC.
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VOL. 124, NO. 45, 2002 13357