Chiral trifluoromethylphosphines: A new stereoselective synthesis of Josiphos-type ligands containing two stereogenic phosphorus atoms

Article abstract of DOI:10.1039/c0cc04606j

Intramolecular nucleophilic substitution of a trifluoromethyl group to form a 1,2-diphosphole derivative followed by the sequential addition of an alkylating agent and a carbanion are the key steps in the stereoselective synthesis of novel ferrocenyl diph

Full text of DOI:10.1039/c0cc04606j

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Chiral trifluoromethylphosphines: a new stereoselective synthesis
of Josiphos-type ligands containing two stereogenic phosphorus atomsw
Jonas F. Buergler and Antonio Togni*
Received 25th October 2010, Accepted 22nd November 2010
DOI: 10.1039/c0cc04606j
Intramolecular nucleophilic substitution of a trifluoromethyl
group to form a 1,2-diphosphole derivative followed by the
sequential addition of an alkylating agent and a carbanion are
the key steps in the stereoselective synthesis of novel ferrocenyl
diphosphines for asymmetric catalysis.
substituent. So far, trifluoromethyl substituted bidentate
phosphines are rather uncommon ligands in organometallic
chemistry and homogeneous catalysis.7,8 The high electron-
withdrawing character and its relatively small steric demand
makes CF3 an excellent substituent to tune the electronic
properties of phosphines. Among others,7 our group is involved
in the synthesis of mono as well as bis(trifluoromethyl)-
substituted phosphines and their application in catalysis.8
The reaction of the bis(trifluoromethyl) phosphino derivative
19 with adamantylphosphine or cyclohexyl-phosphine affords
the secondary diphosphines 2a and 2b, respectively, in high
yields. Deprotonation of compounds 2 with a strong base such
as KOtBu leads to the unexpected formation of the corres-
ponding ferrocenodiphospholes 3 which can be isolated as
single stereoisomers in up to 79% yield after flash column
chromatography (Scheme 1). Notably, in the course of these
intramolecular nucleophilic substitution reactions one of the
diastereotopic CF3 substituents is behaving as a leaving group.
Thus, the fact that in the course of this process an intact
trifluoromethyl anion is generated was shown by carrying out
the reaction in the presence of benzophenone (4a) as an
efficient trapping agent for CF3ꢀ. In this case, both 3a
and the trifluoromethyl alcohol 5a were isolated in 75% yield
(Scheme 2). However, the reaction with 2-naphthaldehyde (4b)
as a prochiral electrophile gave a much lower yield of the
corresponding racemic alcohol 5b, indicating no asymmetric
induction by the enantiomerically pure starting material.
The structure of diphosphole 3a was confirmed by an X-ray
crystal structural analysis (Fig. 1).z The newly formed five-
membered ring is only slightly puckered, with P2 displaying a
distance of 0.39 A from the plane of the remaining four atoms.
The bulky adamantyl group on P2 assumes an endo10
equatorial orientation, trans to both the trifluoromethyl
group on P1 as well as to the methyl group on C11. This
minimizes possible steric interactions between these substi-
tuents and explains the highly stereoselective outcome of the
cyclization reaction. The observed absolute configuration
of both newly formed P stereogenic centers P1 and P2 is
S and R, respectively, in the case of a R,SFc-configured starting
material 1.
Planar-chiral ferrocenyl diphosphine ligands of the Josiphos-type1
are one of the most successful ligand classes used in asymmetric
catalysis,2 as they afford high enantioselectivities in a large
number of applications. Besides their relative conformational
rigidity and thermal stability, one of their major advantages is
the modular synthesis by which the two phosphino groups are
introduced by two consecutive operations. Thus, a systematic
variation of the substituents on the two phosphorus atoms is
easily achieved, thereby allowing for an easy tuning of the
electronic and steric properties of the ligands. Starting from a
common precursor a library of a large variety of diphosphines
with very different properties is readily accessible.
Although a large variety of ferrocene-based bidentate
ligands are known, there are only few derivatives combining
carbon, planar and phosphorus chirality. We reported the
synthesis of two different types of P-stereogenic Josiphos-like
ligands having the P-stereogenic phosphino group either
directly bound to the cyclopentadienyl ring3 or on the side
chain.4 However, because their syntheses turned out to be non
diastereoselective and the separation of the isomers difficult,
such ligands did not find applications in asymmetric catalysis.
Chen and co-workers demonstrated the importance of
P-stereogenicity with the ligand PingFer5 and a corresponding
derivative of BoPhoz.6 The use of the appropriate combina-
tion of planar and carbon central chirality with P-centered
chirality led to ligands showing enhanced enantioselectivities
in the asymmetric hydrogenation of a-dehydroamino acids, as
compared to the non P-stereogenic analog. Thus, efficient and
stereoselective preparation of Josiphos ligands bearing one or
two P-stereogenic phosphino groups and their application in
asymmetric catalysis appears to be an important task in the
area of ferrocenyl ligands.
Here we report the highly stereoselective synthesis of
new bidentate ferrocenyl ligands having two P-stereogenic
phosphines, one of which is bearing the rare trifluoromethyl
Department of Chemistry and Applied Biosciences,
Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich,
¨
Switzerland. E-mail: atogni@ethz.ch; Fax: +41 44 632 13 10;
Tel: +41 44 632 22 36
¨
w Electronic supplementary information (ESI) available: Experimental
details for the preparation and characterization of new compounds,
including 1H, 13C, 19F and 31P NMR spectra. CCDC 793469 (3a) and
793470 (7b). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc04606j
Scheme 1 Synthesis of 1,2-diphospholes 3. Reagents and conditions:
(i) RPH2, TFA, AcOH, 95 1C, 20 h; (ii) KOtBu, 18-Crown-6, THF.
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Scheme 2 Nucleophilic trifluoromethylation of aryl ketones and
aldehydes upon formation of diphosphine 3.
Scheme 4 Pd and Pt complexes of ligands 6a and 6b. Reagents and
conditions: (i) [MCl2(COD)], CH2Cl2, rt; (ii) PPh3, TlPF6, CH2Cl2, rt.
yield (Scheme 4). Complex 7a was also converted to the
cationic complex 8a upon chloride abstraction and addition
of triphenylphosphine. As ascertained by 31P and 19F NMR
spectroscopy, P1, the PCF3 phosphino group, shows two small
coupling constants of 26.6 and 15.4 Hz to P2 and PPh3,
respectively, typical for its cis arrangement. Therefore, PPh3
is in trans position to P2, the bulky trialkyl phosphino group,
thus indicating the significantly weaker trans effect of the
PCF3 donor on chloride dissociation. Another important
Fig. 1 ORTEP drawing of diphosphole derivative 3a. Hydrogen
atoms are omitted for clarity, thermal ellipsoids are set to 30%
probability. Selected bond lengths (A) and angles (1): P1–P2
2.2178(12), P1–C13 1.878(3), P2–C14 1.856(3); C2–P1–P2 92.04(10),
P1–P2–C11 97.25(11).
1
spectroscopic feature of complex 8a is the large JP,Pt value
of 3614 Hz for P1, compared to 2334 and 2304 Hz for P2 and
PPh3, respectively. This is indicative of the strong s character
of the lone pair at P1, according to Bent’s rule.14
The X-ray crystal structure of the Pd complex 7b (Fig. 2)
confirms the anticipated absolute configuration R for P1 and
S for P2 in the free ligand 6b (under the reasonable assumption
that no selective epimerization takes place upon complex
formation). Thus, this indicates that electrophilic alkylation
at P2 takes place from the exo side, whereas the nucleophilic
attack of PhMgCl at P1 occurs endo.10 Overall, an inversion of
absolute configuration occurs at both phosphorus atoms upon
ring-opening.
The chemistry of derivatives of 1,2-diphosphacyclopentanes
is relatively underdeveloped.11 However, 1,2-diphospholanes
have been used as precursors for the synthesis of diphosphanes
having two or three different substituents at each phosphorus
atom.12 Thus, the cleavage of the P–P bond is achieved by
the reaction sequence involving an electrophilic alkylation
followed by the addition of a nucleophile.13 By virtue of both
the significantly different electronic properties of the two
phosphorus atoms and the directing effects of the substituents,
we anticipated both a high regio- and stereoselectivity for such
a reaction sequence as applied to compounds 3. Indeed,
electrophilic methylation using methyl triflate takes place
exclusively at the electron-rich P2, the adamantyl (3a) or
cyclohexyl (3b) phosphine moiety. The subsequent ring-opening
step using methyl lithium, phenyl magnesium chloride, or iso-
propyl magnesium chloride gave the Josiphos-like diphosphines
6a, 6b, and 6c, respectively (Scheme 3). These new compounds
were isolated in moderate yields as single diastereoisomers in
enantiopure form.
The unique combination of substituents at the phosphorus
atoms in the new ligands of type 6 calls for their application in
asymmetric catalysis and for a comparison with more common
ligands, in particular the parent compound Josiphos. Thus,
using ligands 6b and 6c we performed Rh-catalyzed hydro-
genation experiments with two substrates, dimethyl itaconate
and 2-acetamido methyl acrylate, very commonly used as
benchmarks. Table 1 shows that both ligands give active
catalysts and that 6c, in addition, performs exceptionally well
in terms of enantioselectivity. Indeed both hydrogenation
products are obtained quantitatively in more than 99% ee.
This ranks ligand 6c among the best ones for this kind of
To the best of our knowledge, this is the first stereoselective
synthesis of a P-stereogenic phosphine bearing a trifluoro-
methyl group.
To assess the coordination behaviour of these new diphosphines
with late transition-metals, 6a and 6b were reacted with
[PtCl2(COD)] or [PdCl2(COD)] in dichloromethane to obtain
the corresponding platinum and palladium complexes in good
Fig. 2 ORTEP drawing of 7b. Hydrogen atoms are omitted for
clarity, thermal ellipsoids are set to 50% probability. Selected bond
lengths (A) and angles (1): Pd1–P1 2.2247(18), Pd1–P2 2.3009(19),
Pd1–Cl1 2.3405(17), Pd1–Cl2 2.3415(19); P1–Pd1–P2 93.26(7).
Scheme 3 1,2-Diphosphole ring opening leading to diphosphines 6.
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Table 1 Rhodium-catalyzed hydrogenation of olefinsa
TOF/hꢀ1 ee (%)
reflections (Rint = 0.0626), R1[I > 2s(I) = 0.0430, wR2 (all data) =
0.0761. 7b: C30H35F3FeP2Pd, M = 747.67, T = 100 K, orthorhombic,
space group P212121, a = 11.2036(16), b = 13.4658(19), c = 19.135(3) A,
V = 2886.9(7) A3, Z = 4, m(MoKa)= 0.71073, 4937 indepen-
dent reflections (Rint = 0.0912), R1[I > 2s(I) = 0.0504, wR2
(all data) = 0.1064.
Entry Ligand Substrate
Solvent
1
2
3
6b
6c
CF3CH2OH 5450
CF3CH2OH 6000
81
1 A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert and
A. Tijani, J. Am. Chem. Soc., 1994, 116, 4062.
2 (a) T. J. Colacot, Chem. Rev., 2003, 103, 3101; (b) L. X. Dai, T. Tu,
S. L. You, W. P. Deng and X. L. Hou, Acc. Chem. Res., 2003, 36,
659; (c) P. Barbaro, C. Bianchini, G. Giambastiani and
S. L. Parisel, Coord. Chem. Rev., 2004, 248, 2131;
(d) R. G. Arrayas, J. Adrio and J. C. Carretero, Angew. Chem.,
Int. Ed., 2006, 45, 7674.
3 C. Gambs, G. Consiglio and A. Togni, Helv. Chim. Acta, 2001, 84,
3105.
4 A. Togni, C. Breutel, M. C. Soares, N. Zanetti, T. Gerfin,
V. Gramlich, F. Spindler and G. Rihs, Inorg. Chim. Acta, 1994,
222, 213.
>99
6b
6c
MeOH
MeOH
4000
3000
88
4
>99
5 W. P. Chen, S. M. Roberts, J. Whittall and A. Steiner, Chem.
Commun., 2006, 2916.
6 W. P. Chen, W. Mbafor, S. M. Roberts and J. Whittall, J. Am.
Chem. Soc., 2006, 128, 3922.
a
Conditions: 0.5 mol% [Rh(NBD)2]PF6, 0.55 mol% 6b/6c, 1 bar H2,
room temperature.
7 (a) J. J. Adams, A. Lau, N. Arulsamy and D. M. Roddick, Inorg.
Chem., 2007, 46, 11328; (b) E. J. Velazco, A. J. M. Caffyn, X. F. Le
Goff and L. Ricard, Organometallics, 2008, 27, 2402;
(c) J. J. Adams, N. Arulsamy and D. M. Roddick, Inorg. Chim.
Acta, 2009, 362, 2056.
8 (a) P. Eisenberger, I. Kieltsch, N. Armanino and A. Togni, Chem.
Commun., 2008, 1575; (b) N. Armanino, R. Koller and A. Togni,
Organometallics, 2010, 29, 1771; (c) A. Sondenecker, J. Cvengros,
R. Aardoom and A. Togni, Eur. J. Org. Chem., 2010, DOI:
10.1002/ejoc.201001162.
catalytic reactions and demonstrates that the small and
electron-withdrawing substituent CF3 does not need to be
detrimental to both catalytic activity and stereoselectivity.
In conclusion, we have disclosed a new access to ferrocenyl
diphosphines in which both phosphorus atoms are stereogenic
and one of them bears a trifluoromethyl group. The uniqueness
of the synthesis of ligands 6 is based upon the leaving group
ability of CF3 and both the highly stereoselective ring-closure
process to afford intermediates 3 and the sequential addition
of two substituents upon ring opening. Thus, it contrasts the
9 R. Koller and A. Togni, unpublished results. Compound 1 has been
prepared using the method reported by Caffyn and co-workers
(see ref. 7b).
10 For the use of the descriptors endo/exo in ferrocenyl ligand
systems, see: A. Togni, U. Burckhardt, V. Gramlich,
P. S. Pregosin and R. Salzmann, J. Am. Chem. Soc., 1996, 118,
1031.
11 For examples, see: (a) J. Grobe, T. Grosspietsch, D. Levan,
J. Schulze, B. Krebs and M. Dartmann, J. Organomet. Chem.,
´
1990, 385, 255; (b) R. W. Alder, D. D. Ellis, J. K. Hogg, A. Martın,
well-established method developed by Juge for the synthesis
´
of P-stereogenic phosphines.15 We are continuing our efforts
towards a broader application of chiral trifluoromethyl
phosphines in asymmetric catalytic reactions.
We thank R. Koller and P. Battaglia for their assistance in
synthesis, K. Niedermann and R. Aardoom for the X-ray struc-
tural analyses, Solvias AG for hydrogenation experiments and
the Swiss CTI (Innovation Promotion Agency) for financial
support.
A. G. Orpen and P. N. Taylor, Chem. Commun., 1996, 537;
(c) B. Deschamps, L. Ricard and F. Mathey, Organometallics,
2003, 22, 1356; (d) T. Mizuta, S. Kunikata and K. Miyoshi,
J. Organomet. Chem., 2004, 689, 2624; (e) N. A. Piro,
J. S. Figueroa, J. T. McKellar and C. C. Cummins, Science,
2006, 313, 1276; (f) V. Miluykov, I. Bezkishko, A. Zagidullin,
Notes and references
O. Sinyashin, P. Lonnecke and E. Hey-Hawkins, Eur. J. Org.
Chem., 2009, 1269.
¨
z Crystallographic data were recorded on a Bruker CCD diffracto-
meter (Bruker SMART PLATFORM, with CCD detector, graphite
monochromator, Mo Ka radiation). The program SMART served for
data collection. Integration was performed with SAINT. The structure
solution and refinement on F2 were accomplished with SHELXTL 97.
Model plots were made with ORTEP32. All non hydrogen atoms were
refined freely with anisotropic displacement parameters. Due to low
data-to-parameters ratio the carbon atoms were refined anisotropically
in combination with the ISOR instruction for complex 7b. For both
structures hydrogen atoms were refined at calculated positions riding
on their carrier atoms. Weights were optimized in the final refine-
ment cycles. 3: C23H27F3FeP2, M = 478.24, T = 100 K, monoclinic,
space group P21, a = 10.743(3), b = 8.260(3), c = 13.016(4) A,
V = 1067.7(6) A3, Z = 2, m(MoKa)= 0.71073, 5342 independent
12 T. Kauffmann, E. Antfang and J. Olbrich, Chem. Ber., 1985, 118,
1022.
13 R. W. Alder, C. Canter, M. Gil, R. Gleiter, C. J. Harris,
S. E. Harris, H. Lange, A. G. Orpen and P. N. Taylor, J. Chem.
Soc., Perkin Trans. 1, 1998, 1643.
14 H. A. Bent, Chem. Rev., 1961, 61, 275. For an analysis of
stereoelectronic parameters of fluorinated phosphines, see:
A. L. Fernandez, M. R. Wilson, A. Prock and W. P. Giering,
Organometallics, 2001, 20, 3429.
15 F. Chaux, S. Frynas, H. Laureano, C. Salomon, G. Morata,
M.-L. Auclair, M. Stephan, R. Merdes, P. Richard, M. Ondel-
Eymin, J.-C. Henry, J. Bayardon, C. Darcel and S. Juge,
´
C. R. Chim., 2010, 13, 1213, and references therein.
c
1898 Chem. Commun., 2011, 47, 1896–1898
This journal is The Royal Society of Chemistry 2011