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Organometallics 2010, 29, 378–388 DOI: 10.1021/om900800z
Platinum-Catalyzed Asymmetric Alkylation of Bis(isitylphosphino)ethane: Stereoselectivity Reversal in Successive Formation of Two P-C Bonds Timothy W. Chapp,† David S. Glueck,*,† James A. Golen,‡ Curtis E. Moore,‡ and Arnold L. Rheingold‡ †
6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 and ‡Department of Chemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 Received September 14, 2009
Alkylation of the bis(secondary) phosphine IsHP(CH2)2PHIs (1; Is = isityl = 2,4,6-(i-Pr)3C6H2) with 2-(bromomethyl)naphthalene using 10 mol % of the catalyst precursor Pt((R,R)-Me-DuPhos)(Ph)(Cl) and the base NaOSiMe3 selectively yielded meso-IsP(CH2Ar)(CH2)2P(CH2Ar)(Is) (2; Ar = 2-naphthyl; dr = meso/rac ratio = 3.4:1). Half-alkylated IsP(CH2Ar)(CH2)2PH(Is) (3), an intermediate in this reaction, was prepared from 1 by deprotonation (s-BuLi) and alkylation with 2-(chloromethyl)naphthalene. Analysis of the observed diastereo- and enantioselectivity in the Pt-catalyzed alkylations of 1 and 3 yielded quantitative information on the stereoselectivity of both P-C bond-forming steps. The first alkylation (1 f 3) resulted in diastereoselective formation of a tertiary phosphine stereocenter (∼2:1 ratio). In the second alkylation (3 f 2), however, both (RP)-3 and (SP)-3 (the label refers to the configuration of the tertiary phosphine) selectively formed meso-2, instead of (R,R)-2 or (S,S)-2, respectively (the ratios were ca. 3:1 and 7:1). Thus, the tertiary phosphine in 3 favored alternation of stereochemistry in the alkylation of the secondary phosphine (substrate control with negative cooperativity). Platinum-catalyzed alkylation of IsPH(CH2)2OSi(iPr)3 (6) gave IsP(CH2Ar)(CH2)2OSi(i-Pr)3 (9) in a 1.5:1 enantiomeric ratio (er). A related reaction of IsPH(CH2)2OSiMe3 (4) gave a mixture of IsP(CH2Ar)(CH2)2OR (R = SiMe3 (7); R = H (8)), while alkylation of IsPH(CH2)2OH (5) gave 8 in about 2:1 er. Thus, the nature, and even the absolute configuration, of the pendant group X three bonds from the reactive phosphorus center in the substrates IsHP(CH2)2X (X = PHIs (1), P(CH2Ar)(Is) (3), OSiMe3 (4), OH (5), OSi(i-Pr)3 (6)) had a strong influence on the selectivity of Pt-catalyzed phosphorus alkylation. Possible mechanistic explanations for this substrate control are discussed.
Introduction Bifunctional symmetrical substrates with two equivalent reactive sites present special problems and opportunities in asymmetric catalysis. After the catalyst mediates formation of one chiral center, the selectivity of the second reaction may *To whom correspondence should be addressed. E-mail: Glueck@ Dartmouth.Edu. (1) Lagasse, F.; Tsukamoto, M.; Welch, C. J.; Kagan, H. B. J. Am. Chem. Soc. 2003, 125, 7490–7491. (2) (a) Takahata, H.; Takahashi, S.; Kouno, S.; Momose, T. J. Org. Chem. 1998, 63, 2224–2231. (b) El Baba, S.; Sartor, K.; Poulin, J.-C.; Kagan, H. B. Bull. Soc. Chim. Fr. 1994, 131, 525–533. (c) Rautenstrauch, V. Bull. Soc. Chim. Fr. 1994, 131, 515–524. (d) Tai, A.; Ito, K.; Harada, T. Bull. Chem. Soc. Jpn. 1981, 54, 223–227. (e) Muramatsu, H.; Kawano, H.; Ishii, Y.; Saburi, M.; Uchida, Y. J. Chem. Soc., Chem. Commun. 1989, 769–770. (f) Aggarwal, V. K.; Evans, G.; Moya, E.; Dowden, J. J. Org. Chem. 1992, 57, 6390–6391. (g) Hoye, T. R.; Mayer, M. J.; Vos, T. J.; Ye, Z. J. Org. Chem. 1998, 63, 8554–8557. (h) Kuwano, R.; Sawamura, M.; Shirai, J.; Takahashi, M.; Ito, Y. Tetrahedron Lett. 1995, 36, 5239–5242. (i) Hayashi, T.; Hayashizaki, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 215–218. (j) Kalck, P.; Urrutigoïty, M. Coord. Chem. Rev. 2004, 248, 2193–2200. (k) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. 1985, 24, 1–30. pubs.acs.org/Organometallics
Published on Web 12/28/2009
be the same (catalyst control) or different (substrate control).1 Catalyst control may result in asymmetric amplification and high enantiomeric ratio (er) for the rac product. Substrate control may reinforce the selectivity of the catalyst (positive cooperativity) or compete with it (negative cooperativity).2 These effects depend on the length of the linker between the reactive sites, as shown spectacularly in Ru(Binap)-catalyzed hydrogenation of diketones (Scheme 1). Catalyst control in reduction of A led to high diastereoselectivity, and the favored rac product was formed in high ee. While hydrogenation of B also gave the rac diol enantioselectively, the major product was meso, presumably as a result of substrate control.3 Understanding the structural basis for such effects is potentially useful in designing substrates for asymmetric catalysis.4 (3) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629–631. (4) (a) Glueck, D. S. Dalton Trans. 2008, 5276–5286. (b) Glueck, D. S. Chem. Eur. J. 2008, 14, 7108–7117. (c) Glueck, D. S. Coord. Chem. Rev. 2008, 252, 2171–2179. (d) Glueck, D. S. Synlett 2007, 2627–2634. r 2009 American Chemical Society
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Scheme 1. Catalyst vs Substrate Control in Ru(Binap)-Catalyzed Asymmetric Reduction of Diketones3 (dr = rac/meso Ratio)
Figure 1. ORTEP diagram of meso-1. Of all the hydrogen atoms, only the P-H hydrogen atom, which was located and refined, is shown. Scheme 2
Chart 1. Bis(secondary) phosphines C and 1 and Alkylation Product D Scheme 3. meso-Selective Pt-Catalyzed Alkylation of 1 with 2-(Bromomethyl)naphthalene
With this goal in mind, we recently reported studies of Ptcatalyzed asymmetric alkylation of bis(secondary) phosphines, including synthesis, from C, of the enantiomerically pure DiPAMP analogue D (Chart 1).5 Here we report mesoselective Pt-catalyzed alkylation of the related bulky bis(secondary) phosphine 1 (Chart 1), along with quantitative information on the stereoselectivity of both P-C bondforming steps.
Results and Discussion The diphosphine IsPH(CH2)2PHIs (1; Is = isityl = 2,4,6-(i-Pr)3C6H2) was synthesized from Cl2P(CH2)2PCl2 (Scheme 2) by selective arylation6 followed by LiAlH4 reduction and then protected as a borane adduct to simplify purification. Removing the borane using a polymersupported amine gave a mixture of rac and meso diastereomers of 1.7 The crystal structure of meso-1 is shown in Figure 1. See Table 1 for crystallographic data and the Supporting Information for additional details. (5) Anderson, B. J.; Glueck, D. S.; DiPasquale, A. G.; Rheingold, A. L. Organometallics 2008, 27, 4992-5001; 2009, 28, 386 (addition/ correction). (6) Chandrasekhar, V.; Sasikumar, P.; Boomishankar, R.; Anantharaman, G. Inorg. Chem. 2006, 45, 3344–3351. (7) Sayalero, S.; Pericas, M. A. Synlett 2006, 2585–2588. (8) (a) Scriban, C.; Glueck, D. S. J. Am. Chem. Soc. 2006, 128, 2788– 2789. (b) Scriban, C.; Glueck, D. S.; Golen, J. A.; Rheingold, A. L. Organometallics 2007, 26, 1788-1800; 2007, 26, 5124 (addition/ correction). (c) Anderson, B. J.; Guino-o, M. A.; Glueck, D. S.; Golen, J. A.; DiPasquale, A. G.; Liable-Sands, L. M.; Rheingold, A. L. Org. Lett. 2008, 10, 4425–4428. (d) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 2786–2787. (e) Chan, V. S.; Chiu, M.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6021–6032.
Alkylation8 of 1 with 2-(bromomethyl)naphthalene using 10 mol % of the catalyst precursor Pt((R,R)-Me-DuPhos)(Ph)(Cl) and the base NaOSiMe3 gave ca. a 3.5:1 ratio of diastereomeric products 2, according to 31P NMR monitoring of the crude reaction mixture (Scheme 3).5 After protection of 2 with BH3(SMe2), the major diastereomer of bis(phosphine) borane 2-BH3 was isolated by recrystallization in 44% yield. The crystal structures of meso-2 and rac-2BH3 (see Figures 2 and 3, Table 1, and the Supporting Information) as well as HPLC and NMR analyses (see below) showed that the Pt-catalyzed reaction was mesoselective. The bis(phosphine) oxide 2-O (Chart 2; see Figure 4 for the crystal structure of the meso diastereomer) was prepared in high yield from 2 and hydrogen peroxide; such oxidations are known to proceed with retention of configuration at phosphorus.9 Complementary HPLC and NMR assays of the diastereomeric ratio (dr) and the enantiomeric ratio (er) of 2-O provided information on the selectivity of the catalytic alkylation which formed 2. The three diastereomers of 2-O could be separated by HPLC on a ChiralPak AD-H column. Integration of the peaks in the chromatogram gave the meso/rac ratio (dr) and the er of the rac diastereomers. Unusually, isomer separation improved when the column was heated to slightly above (9) Quin, L. D. A Guide to Organophosphorus Chemistry; WileyInterscience: New York, 2000, pp 300-303.
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Table 1. Crystallographic Data for meso-1, meso-2, rac-2-BH3, meso-2-O, and 5 meso-1
meso-2
rac-2-BH3
meso-2-O
5
C32H52P2 C54H68P2 C54H74B2P2 C54H68O2P2•C3H8O C17H29OP 498.68 779.02 804.68 871.12 280.37 Pbcn C2/c P42/n C2/c P1 34.140(5) 9.5176(8) 30.6779(6) 22.621(5) 23.7985(14) 5.9658(9) 10.9546(9) 18.9288(3) 11.064(3) 23.7985(14) 16.029(2) 12.5468(11) 16.8358(3) 21.618(5) 5.9808(3) 90 64.4770(10) 90 90 90 107.001(2) 80.3910(10) 90 111.474(5) 90 90 73.5900(10) 90 90 90 3122.0(8) 1130.86(17) 9776.5(3) 5035(2) 3387.3(3) 4 1 8 4 8 1.061 1.144 1.093 1.149 1.100 0.156 0.131 1.043 0.129 0.155 208(2) 100(2) 100(2) 100(2) 150(2) 5.10 3.41 7.81 6.79 4.12 14.07 8.88 20.69 18.42 9.76 P P P P a Quantity minimized: Rw(F2) = [w(Fo2 - Fc2)2]/ [(wFo2)2]1/2; R = Δ/ (Fo), Δ = |(Fo - Fc)|, w = 1/[σ2(Fo2) þ (aP)2 þ bP], P = [2Fc2 þ Max(Fo2,0)]/3. A Bruker CCD diffractometer was used in all cases.
formula formula wt space group a, A˚ b, A˚ c, A˚ R, deg β, deg γ, deg V, A˚3 Z D(calcd), g/cm3 μ(Mo KR), mm-1 temp, K R(F), %a Rw(F2), %a
Figure 4. ORTEP diagram of meso-2-O. Figure 2. ORTEP diagram of meso-2.
Figure 3. ORTEP diagram of rac-2-BH3. One naphthyl ring was disordered over two positions, only one of which is shown. The naphthyl groups were constrained to idealized rigid bodies.
ambient temperature (see the Supporting Information for details and chromatograms).10 Similarly, treatment of 2-O with the chiral shift reagent11 Fmoc-Trp(Boc)-OH (Chart 2) and integration of the 31P NMR spectra of these mixtures enabled measurement of dr and er of samples of diphosphine 2. The two methods gave consistent results (see the Supporting Information). (10) (a) Meyer, V. R. Pitfalls and Errors of HPLC in Pictures, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) Vecchi, M.; Englert, G.; Maurer, R.; Meduna, V. Helv. Chim. Acta 1981, 64, 2746–2758.
Chart 2. Phosphine Oxide 2-O, Used for HPLC and NMR Measurements of dr and er, and the Shift Reagent Fmoc-Trp(Boc)-OH11
Although overlap in the NMR spectra and broad HPLC peaks in the chromatograms increased the error in these measurements, they showed that the dr (meso/rac ratio) in Pt-catalyzed alkylation of 1 to form 2 (10% catalyst loading) was 3.4(2), which was consistent with the original NMR observations from crude reaction mixtures, while the er was 3.9(3).12 During Pt-catalyzed alkylation of 1 to give 2, the half-alkylated intermediate IsHP(CH2)2P(Is)(CH2Ar) (3; Ar = 2naphthyl) was observed by 31P NMR spectroscopy in the reaction mixture along with 1 and 2. Selective monodeprotonation (11) Li, Y.; Raushel, F. M. Tetrahedron: Asymmetry 2007, 18, 1391– 1397. (12) Reported errors are standard deviations from several duplicate runs. See the Supporting Information for additional details.
Article Scheme 4. Synthesis and Pt-Catalyzed Alkylation of Secondary/ Tertiary Bis(phosphine) 3a
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The values of x, a, and b may be determined from the observed product ratios in separate Pt-catalyzed alkylations of 1 and 3, using eqs 1 and 2 (dr = meso/rac ratio for 2).2 For alkylation of 3, its 1:1 dr means that x = 0.5.
dr ¼
ðxÞð1 -aÞ þ ð1 -xÞð1 -bÞ xa þ ð1 -xÞðbÞ
ð1Þ
xa ð1 -xÞðbÞ
ð2Þ
er ¼
a
Legend: Ar = 2-naphthyl, [Pt] = Pt((R,R)-Me-DuPhos).
Scheme 5. Stereoselectivity of Pt-Catalyzed Alkylation of 1 (To Yield 3) and of 3 (To Yield 2), Defined by the Mole Fractions x, a, and b
of 1 and treatment of the resulting anion with 2-(chloromethyl)naphthalene gave 3 as the major component of a mixture which included the under- and overalkylation products 1 and 2 (Scheme 4). After chromatographic separation, Pt-catalyzed alkylation of a 1:1 mixture of diastereomers of 3 gave 2. As for 1, this reaction was meso-selective, with dr = 4.8(6) and er = 2.1(5) for 10 mol % catalyst loading.12 Origin of meso Selectivity. These observations enabled quantitative analysis of the selectivity of both Pt-catalyzed alkylations (1 f 3; 3 f 2), which provided information on catalyst vs substrate control and on the origin of the meso selectivity (Scheme 5). To describe the selectivity in conversion of 1 to 3, we define the mole fractions x for the diastereomers of the R-tertiary phosphine ((R,R)-3 plus (R,S)-3; the labels refer to the tertiary and secondary phosphine stereocenters, respectively) and 1 - x for the S-tertiary phosphine ((S,R)-3 plus (S,S)-3). Conversion of 3 to 2 then occurs in two parallel channels, which differ only in the configuration of the tertiary phosphine in substrate 3. (We assume that alkylation of PHMe(Is) via the diastereomeric intermediates Pt((R,R)-Me-DuPhos)(Ph)(PMeIs), which interconvert by P inversion, is a good model for the analogous reactions of 1.8a,b Then, the selectivities of alkylation of the diastereomers ((R,R)-3 and (R,S)-3) are expected to be identical, since both will form the same mixture of Pt-phosphido intermediates.) Therefore, R-tertiary phosphines (R,R)-3 and (R,S)-3 yield a mixture of (R,R)-2 and meso-2 with mole fractions a and 1 - a. Similarly, (S,S)-3 and (S,R)-3 yield (S,S)-2 and meso-2 with mole fractions b and 1 - b. The absolute configuration of rac-2 is unknown; therefore, the major isomer was assigned as R,R by analogy to the favored R configuration of PMeIs(CH2Ph) formed by alkylation of PHMe(Is) using the same precatalyst.8a,b
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These equations hold only if the reaction is clean, forming no byproducts, and if all the products are formed by the catalyst, not in a background reaction or in a process mediated by products of catalyst decomposition. Monitoring the reactions by 31P NMR spectroscopy showed complete conversion of 1 (or 3) to the diastereomers of 2; no other organophosphorus products were observed. Once reactions were complete, the catalyst precursor was converted to Pt((R,R)-Me-DuPhos)(Ph)(Br), as observed previously in alkylation of PHMe(Is).8a,b Control experiments showed that the catalytic alkylations of 1 and 3 were faster than the Pt-free background process. Thus, conversion of 1 to 2 catalyzed by 10 mol % Pt was complete in 9 h, at which point the background reaction resulted in formation of 21% of intermediate 3 and a trace of product 2. Similarly, Pt-catalyzed alkylation of 3 yielded 2 in 3 h, when the background conversion over this time was 7%. In the catalytic alkylation, contributions from the background reaction should be reduced from these values, since the concentrations of the substrates, and hence the background reaction rate, will be reduced. Corrections for the background reactions changed the values of x, a, and b negligibly, within experimental error (see the Supporting Information for details). Further, the dr of 2 in Pt-catalyzed alkylation of 1 was the same, within experimental error, at 5 and 10 mol % catalyst loading, suggesting that the background reaction is insignificant.13 For these reasons, we have neglected corrections due to the background alkylation and used eqs 1 and 2 directly. Scheme 6 shows the resulting values of x, a, and b.14 Although the error in quantitative determination of these parameters was relatively large, the qualitative conclusion is clear: the absolute configuration of the tertiary phosphine in 3 had a striking effect on the selectivity of Pt-catalyzed alkylation of the secondary phosphine. This substrate control resulted in alternation of stereochemistry ((RP)-3 f (R, S)-2; (SP)-3 f (S,R)-2) by margins of about 3:1 and 7:1. This meso selectivity appears to result from negative cooperativity, in which the first-formed tertiary phosphine favors alkylation of the second, originally identical P stereocenter with opposite configuration. Because of the likely epimerization of secondary phosphines under the reaction conditions,15 deconvoluting the (13) (a) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802– 1803. (b) The er values of 2 were similar at the two different catalyst loadings. (14) Values of x, a, and b are not independent, which affects the reported values and makes the error bars reported for b artificially low. See the Supporting Information for more details. (15) (a) Albert, J.; Magali Cadena, J.; Granell, J.; Muller, G.; Panyella, D.; Sa~ nudo, C. Eur. J. Inorg. Chem. 2000, 1183–1186. (b) Bader, A.; Pabel, M.; Willis, A. C.; Wild, S. B. Inorg. Chem. 1996, 35, 3874– 3877. (c) Bader, A.; Nullmeyers, T.; Pabel, M.; Salem, G.; Willis, A. C.; Wild, S. B. Inorg. Chem. 1995, 34, 384–389. (d) Bader, A.; Pabel, M.; Wild, S. B. J. Chem. Soc., Chem. Commun. 1994, 1405–1406. (e) Bader, A.; Salem, G.; Willis, A. C.; Wild, S. B. Tetrahedron: Asymmetry 1992, 3, 1227–1230.
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Scheme 6. Stereoselectivity in Pt-Catalyzed Alkylation of 1 (To Yield 3) and of 3 (To Yield 2)
Scheme 7. Synthesis and Pt-Catalyzed Asymmetric Alkylation of Secondary Phosphines 4-6a
Figure 5. ORTEP diagram of PHIs(CH2CH2OH) (7). Hydrogen atoms are not shown, except for the P-H, which was located and refined, and the O-H, which was placed in a calculated position. Scheme 8. Pt-Catalyzed Alkylation of Isityl(methyl)phosphinea
a
Legend: [Pt] = Pt((R,R)-Me-DuPhos), Ar = 2-naphthyl.
Table 2. Selectivity of Pt-Catalyzed Alkylation of PH(Is)(CH2)2X a Legend: [Pt] = Pt((R,R)-Me-DuPhos), Ar = 2-naphthyl. Alkylation of 4 gave 7 and 8, while 5 gave 8 and 6 gave 9.
observed ca. 2:1 selectivity in formation of intermediate 3 is more complicated; we cannot tell if selectivity of the first alkylation of 1 depends on the absolute configuration of the pendant PHIs group, as it does for the PIs(CH2Ar) group in 3. To investigate these effects in more detail, the secondary phosphines IsHP(CH2)2OR (R = SiMe3 (4), R = H (5), R = Si(i-Pr)3 (6)) were prepared (Scheme 7). Treatment of LiPHIs with Cl(CH2)2OSiMe3 gave 4, which on acid hydrolysis yielded the alcohol 5, whose crystal structure is shown in Figure 5. Silylation of 5 with Si(i-Pr)3Cl/imidazole gave 6. Pt-catalyzed alkylation of the triisopropylsilyl substrate 6 yielded 9 with an er value of 1.5:1 (Scheme 7). Pt-catalyzed alkylation of alcohol 5 gave 8 in about 2:1 er, but an unidentified byproduct (ca. 10%) also formed. A related reaction with trimethylsilyl ether 4 was slower than that of 5 and 6 and was also complicated by OSiMe3 hydrolysis, both during the reaction and the workup. Both silyl ether 7 (minor) and alcohol 8 (major) were formed with similar er values of 1.8:1. We cannot tell if Pt-catalyzed alkylation of 4 proceeded mostly via the original trimethylsilyl ether substrate or from alcohol 5, but the results for alkylation of pure 5 suggested that the selectivities were similar. In contrast to the results for these functionalized β-ethylphosphines, Pt-catalyzed alkylation of the methylphosphine PHMe(Is) with 2-bromomethylnaphthalene (Scheme 8) was both faster (complete in ca. 2 h; compare to 9 h for alcohol 5 and silyl ether 6) and more selective (er = 5.2). Substituent effects on selectivity of Pt-catalyzed P-alkylation of isitylphosphines are summarized in Table 2, using mole fractions for ease of comparison.
X (compd no.)
RP selectivity (mole fraction)
RP-P(Is)(CH2Ar) ((RP)-3) SP-P(Is)(CH2Ar) ((SP)-3) PH(Is) (1) OH (5) OSi(i-Pr)3 (6) PHMe(Is)a
0.27 0.87 0.65 0.66 0.60 0.84
a
The substrate was PHMe(Is) (see Scheme 8).
Conclusion Pt-catalyzed alkylation of the bis(secondary) phosphine 1 was meso-selective because the two diastereomers of IsHP(CH2)2PIs(CH22-naphthyl) (3), differing only in the absolute configuration of a pendant phosphine group three bonds away from the reactive site, were alkylated with reversed stereoselectivity. The R or S tertiary phosphine stereocenter in 3 favored alkylation of the secondary phosphine with opposite configuration (negative cooperativity). The selectivities of alkylation of the related substrates IsHP(CH2)2X (X = PHIs (1), OH (5), OSi(i-Pr)3 (6)) were similar, perhaps as a result of catalyst control; it is possible that only the very bulky β-ethyl substituents in 3 result in substrate control. What is the origin of this substrate control? The X group might affect the speciation and relative reactivity of the presumed Pt-phosphido intermediates in several ways. Tertiary phosphines are good ligands for platinum, so that chelation in five-coordinate 11 or formation of dinuclear
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Chart 3. Possible Role of X in Pt-Catalyzed Alkylation of IsHP(CH2)2Xa
a Legend: [Pt] = Pt((R,R)-Me-DuPhos), R = H, CH2Ar, Ar = 2-naphthyl, X = PHIs, P(CH2Ar)(Is), OR0 (R0 = SiMe3, Si(i-Pr)3, H).
intermediates, such as 12, is possible (Chart 3). The pendant group might simply affect the conformations of the phosphinoethyl group and control Keq in the equilibrium of 13, as well as the relative reactivity of these diastereomers. Alternatively, developing positive charge at the phosphido P during nucleophilic attack on a benzyl bromide might be stabilized by donation from the pendant phosphine (14); such anchimeric assistance has been proposed in related systems.16 In future work, we will examine these possibilities with related bis(secondary) phosphines having varied linker lengths, to determine the structural requirements for substrate vs catalyst control and to investigate potential positive cooperativity via substrate control.17
Experimental Section General Experimental Details. Unless otherwise noted, all reactions and manipulations were performed in dry glassware under a nitrogen atmosphere at ambient temperature in a drybox or using standard Schlenk techniques. Petroleum ether (bp 38-53 °C), CH2Cl2, ether, THF, and toluene were dried over alumina columns similar to those described by Grubbs.18 NMR spectra were recorded by using a Varian 300 or 500 MHz spectrometer. 1H or 13C NMR chemical shifts are reported vs Me4Si and were determined by reference to the residual 1H or 13 C solvent peaks. 31P NMR chemical shifts are reported vs H3PO4 (85%) used as an external reference. Coupling constants are reported in Hz, as absolute values unless noted otherwise. Unless indicated, peaks in NMR spectra are singlets. IR spectra were recorded on KBr disks and are reported in cm-1. Quantitative Technologies Incorporated provided elemental analyses. Mass spectrometry was performed at the University of Illinois. Chiral HPLC was done on an Agilent Technologies 1200 series HPLC instrument using a ChiralPak AD-H column (4.6 mm inner diameter, 250 mm length, flow rate 1-1.2 mL/min) contained within a thermostated column compartment. Unless (16) (a) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928–12929. (b) Cairns, S. M.; McEwen, W. E. Phosphorus, Sulfur Silicon 1990, 48, 77–95. (c) McEwen, W. E.; Smith, J. H.; Woo, E. J. J. Am. Chem. Soc. 1980, 102, 2746–2751. (d) McEwen, W. E.; Janes, A. B.; Knapczyk, J. W.; Kyllingstad, V. L.; Shiau, W.-I.; Shore, S.; Smith, J. H. J. Am. Chem. Soc. 1978, 100, 7304–7311. (e) Keldsen, G. L.; McEwen, W. E. J. Am. Chem. Soc. 1978, 100, 7312–7317. (f) McEwen, W. E.; Fountaine, J. E.; Schulz, D. N.; Shau, W. J. Org. Chem. 1976, 10, 1684– 1690. (17) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, CA, 2009. (18) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520.
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otherwise noted, reagents were from commercial suppliers. Pt((R,R)-Me-Duphos)(Ph)(Cl),19 PH2Is,20 PHMe(Is),21 and (S)-{Pd[NMe2CH(Me)C6H4](μ-Cl)}222 were made by literature methods. PH(Is)(BH3)(CH2)2PH(Is)(BH3) (1-BH3). Under nitrogen, a Schlenk flask was loaded with Mg (Aldrich, 50 mesh powder, 730 mg, 30 mmol, 2 equiv), which was then slurried in THF (75 mL). To this was added dropwise a solution of 2-bromo1,3,5-triisopropylbenzene (8.50 g, 30 mmol, 2 equiv) in THF (25 mL) via cannula with stirring. Two drops of 1,2-dibromoethane were added to initiate the reaction. The mixture was gently refluxed for 1 h and then stirred for 14 h. The resulting dark gray solution was transferred via cannula to a cooled (-40 °C) solution of Cl2P(CH2)2PCl2 (3.48 g, 15 mmol, 1 equiv) in THF (100 mL). A solution of anhydrous ZnCl2 (8.17 g, 60 mmol, 4 equiv) in THF (100 mL) was then added via cannula; a white solid precipitated.6 The solution was stirred at -40 °C for 5 h and then warmed to room temperature. The mixture was transferred via wide-bore cannula to a filter frit with a Celite bed (3 cm high 6 cm wide) and filtered under N2. The solid was washed with two 150 mL portions of Et2O, and the solvent was removed from the filtrate under reduced pressure to leave an oily off-white solid. The residue was redissolved in 250 mL of Et2O, and the solution with some white precipitate was transferred via filter cannula to a slurry of LiAlH4 (600 mg, 15 mmol, 1 equiv) in Et2O (20 mL) at 0 °C. The resulting mixture was stirred for 1 h, and then triethanolamine (2.0 mL, 15 mmol, 1 equiv)23 was injected via wide-bore syringe at 0 °C, producing some effervescence. The solution was warmed to room temperature and was stirred vigorously for 2 h, causing the residual gray solid to become very finely divided. To this was added degassed H2O (40 mL), generating minimal effervescence. The mixture was transferred via wide-bore cannula to a filter frit with a Celite bed (3 cm high 6 cm wide) and filtered under N2. The gray solid was washed with two 100 mL portions of Et2O, and the organic layer was separated from the aqueous layer via cannula and dried over MgSO4. After cannula filtration, the solvent was removed under reduced pressure to give 5.60 g (75% yield) of white solid. The solid was redissolved in petroleum ether (100 mL) and cooled to 0 °C, and BH3(SMe2) (20 mL, 2.0 M in THF, 40 mmol, 2.66 equiv) was added via cannula with stirring. Upon warming to room temperature, a white solid precipitated and the solvent was removed under reduced pressure. The solid was recrystallized from THF/ petroleum ether at -28 °C to give 4.59 g of fine white solid (58% overall yield). Anal. Calcd for C32H58P2B2: C, 73.02; H, 11.11. Found: C, 72.65; H, 11.19. HRMS (FAB) for C32H52P2B2 (M - 6H)þ: calcd m/z 520.3730, found m/z 520.3797.24 IR (KBr): 2964, 2927, 2867, 2433, 2399, 2367, 2344, 2250. 31P{1H} NMR (CDCl3): δ -21.2 (broad). 1H NMR (CDCl3): δ 7.07 (d, J = 3, 4H, Is), 5.82 (d of m, JPH = 371, 2H, P-H), 3.26 (apparent quint, J = 7, 4H, i-Pr CH), 2.89 (sep, J = 7, 2H, i-Pr CH), 2.32 (m, 2H, P-CH2), 2.02 (m, 2H, P-CH2), 1.28 (d, J = 7, 6H, i-Pr CH3), 1.25 (d, J = 7, 6H, CH3, i-Pr), 1.20 (d, J = 7, 6H, CH3, i-Pr). The BH3 signals (19) Brunker, T. J.; Blank, N. F.; Moncarz, J. R.; Scriban, C.; Anderson, B. J.; Glueck, D. S.; Zakharov, L. N.; Golen, J. A.; Sommer, R. D.; Incarvito, C. D.; Rheingold, A. L. Organometallics 2005, 24, 2730–2746. (20) van der Winkel, Y.; Bastiaans, H. M. M.; Bickelhaupt, F. J. Organomet. Chem. 1991, 405, 183–194. (21) Brauer, D. J.; Bitterer, F.; Dorrenbach, F.; Hessler, G.; Stelzer, O.; Kruger, C.; Lutz, F. Z. Naturforsch., B 1996, 51, 1183–1196. (22) Tani, K.; Brown, L. D.; Ahmed, J.; Ibers, J. A.; Nakamura, A.; Otsuka, S.; Yokota, M. J. Am. Chem. Soc. 1977, 99, 7876–7886. (23) Powell, J.; James, N.; Smith, S. J. Synthesis 1986, 338–340. (24) We have observed similar mass spectrometric behavior in other primary and secondary phosphine-boranes: (a) Brunker, T. J.; Anderson, B. J.; Blank, N. F.; Glueck, D. S.; Rheingold, A. L. Org. Lett. 2007, 9, 1109–1112. (b) Blank, N. F.; McBroom, K. C.; Glueck, D. S.; Kassel, W. S.; Rheingold, A. L. Organometallics 2006, 25, 1742–1748.
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were not observed. 13C{1H} NMR (CDCl3): δ 152.7 (quat o and p, Ar), 122.7 (CH, Ar), 117.9 (d, J = 53, quat, P-C), 34.3 (CH, iPr), 32.4 (CH, i-Pr), 24.5 (CH3, i-Pr), 24.3 (br, CH3, i-Pr), 23.6 (d, J = 6, CH3, i-Pr), 20.8 (d, J = 26, P-CH2). IsHP(CH2)2PH(Is) (1). Piperazinomethyl polystyrene (5.6 g, 2.7 mmol/g, 15 mmol, 4 equiv) and 1-BH3 (1.99 g, 3.75 mmol, 1 equiv) were slurried in toluene (200 mL) under N2.7 The mixture was stirred at 50 °C for 24 h, after which 31P NMR spectroscopy showed complete deprotection (δ -87.2, -88.6). The solution was transferred under N2 via filter cannula to a round-bottom Schlenk flask equipped with a stir bar. The remaining resin was washed with three 20 mL portions of toluene, and the extracts were combined with the filtrate. The toluene was removed under reduced pressure to leave 1.79 g of white solid (96% yield). Anal. Calcd. for C32H52P2: C, 77.07; H, 10.51. Found: C, 76.93; H, 10.65. HRMS (ESþ) for C32H53P2 (MHþ): calcd m/z 499.3623, found m/z 499.3609. 31P{1H} NMR (C6D6): δ -87.2, -88.6 (mixture of rac and meso, ∼1:1). 1H NMR (C6D6): δ 7.07 (4H, Ar), 4.43 (br d, JPH = 212, 2H, P-H), 3.71 (broad, 4H, CH, i-Pr), 2.74 (apparent quint, J = 7, 2H, CH, i-Pr), 1.89 (broad, 2H, P-CH2), 1.78 (broad, 2H, P-CH2), 1.20 (d, J = 7, 24H, CH3, i-Pr), 1.12 (broad, 12H, CH3, i-Pr). 13C{1H} NMR (C6D6): δ 153.2 (broad, quat, Ar), 149.7 (quat, Ar), 128.1 (d, J = 48, quat, Ar P-C), 121.6 (CH, Ar), 34.7 (CH, i-Pr), 32.9 (m, CH, i-Pr), 24.9 (CH3, i-Pr), 24.4 (broad, CH3, i-Pr), 24.1 (CH3, i-Pr), 23.1 (broad, P-CH2). (BH3)(Is)(CH2-2-naphthyl)P(CH2)2P(CH2-2-naphthyl)(Is)(BH3) (2-BH3). In a flask under nitrogen, bis(isitylphosphino)ethane (1; 499 mg, 1.0 mmol), NaOSiMe3 (224 mg, 2.0 mmol, 2 equiv), and Pt((R,R)-Me-Duphos)(Ph)(Cl) (61 mg, 0.1 mmol, 10 mol %) were dissolved in THF (150 mL) to give a yellow solution. To this was added a solution of 2-(bromomethyl)naphthalene (442 mg, 2.0 mmol, 2 equiv) in THF (20 mL). The mixture was stirred for 14 h, over which time a white solid precipitated. In situ 31P NMR spectroscopy showed two peaks (δ -23.3, -22.6) in a 3.6:1 ratio, indicating that the reaction was complete. The solvent was removed under reduced pressure to leave a yellow residue that was partially redissolved in 9:1 petroleum ether-THF (30 mL) and eluted over a silica plug (5.0 cm wide 3.5 cm high) with two 20 mL portions of 9:1 petroleum ether-THF and then two 50 mL portions of petroleum ether. The catalyst and the NaBr did not elute. The solvent was removed from the eluent under reduced pressure to leave 710 mg of white solid (91% yield). The solid was dissolved in 30 mL of a 1:1 THF-petroleum ether mixture, and BH3(SMe2) (2.0 mL, 2.0 M solution in THF, 4.0 mmol, 4 equiv) was added to the solution via cannula at 0 °C. The solution was warmed to room temperature and was stirred for 14 h. In situ 31P NMR spectroscopy in THF showed complete protection of the bis(tertiary) phosphine (δ 13.1). The solvent was removed under reduced pressure to give a white solid that was recrystallized under N2 from THF (3 mL) layered with petroleum ether (12 mL) at -28 °C to give 323 mg (44% yield) of the meso diastereomer as a white crystalline solid. A second and third recrystallization gave an additional 57 and 53 mg of white solid. Slow evaporation of a toluene solution of a sample from the third crop gave crystals of rac-2-BH3 suitable for X-ray crystallographic analysis. Anal. Calcd for C54H74B2P2: C, 80.40; H, 9.25. Found: C, 79.35; H, 8.95. These unsatisfactory results may be due to oxidation of the air-sensitive diphosphine (Anal. Calcd for C54H68O2P2: C, 79.97, H, 8.45) after loss of the labile borane (observed on workup with water or aqueous acid, suggesting sensitivity to moisture, and by mass spectrometry (see below)). HRMS (ESþ) for C54H69O2P2 (MO2Hþ): calcd m/z 811.4773, found m/z 811.4766. 31P{1H} NMR (CDCl3): δ 12.1 (broad). 1H NMR (CDCl3): δ 7.72-7.70 (m, 2H, Ar), 7.60-7.56 (m, 4H, Ar), 7.41-7.37 (m, 6H, Ar), 7.15 (dd, J = 10, 2, 2H, Ar), 7.07 (4H, Ar), 3.84 (sep, J = 7, 4H, CH, i-Pr), 3.70 (AB, JHH = 14,
Chapp et al. JPH = 5, 6, 2H, P-CH2), 3.37 (AB, JHH = 14, JPH = 5, 2H, P-CH2), 2.92 (sep, J = 7, 2H, CH, i-Pr), 2.65-2.61 (m, 2H, P-CH2), 2.02-1.96 (m, 2H, P-CH2), 1.30 (dd, J = 7, 2, 12H, CH3, i-Pr), 1.18 (d, J = 7, 12H, i-Pr-CH3), 1.05 (d, J = 7, 12H, CH3, i-Pr). The BH3 signals were not observed. 13C{1H} NMR (CDCl3): δ 155.8 (t, J = 5, quat Ar), 152.5 (quat, Ar), 133.1 (quat, Ar), 132.2 (quat, Ar), 130.6 (t, J = 2, quat, Ar), 128.7 (t, J = 3, CH, Ar), 128.2 (t, J = 2, CH, Ar), 127.6 (CH, Ar), 127.5 (CH, Ar), 127.4 (CH, Ar), 125.9 (CH, Ar), 125.6 (CH, Ar), 123.6 (t, J = 4, CH, Ar), 118.8 (d, J = 43, quat, Ar), 35.7 (filled-in doublet,25 J = 17, P-CH2), 34.0 (CH, i-Pr), 30.6 (t, J = 3, CH, i-Pr), 25.2 (CH3, i-Pr), 25.2 (CH3, i-Pr), 23.6 (d, J = 3, CH3, i-Pr), 23.3 (filled-in doublet,25 J = 17, P-CH2). (Is)(CH2-2-naphthyl)P(CH2)2P(CH2-2-naphthyl)(Is) (2). Piperazinomethyl polystyrene (1.2 g, 2.7 mmol/g, 3.2 mmol, 9.7 equiv) and meso-2-BH3 (264 mg, 0.33 mmol, 1 equiv) were slurried in toluene (20 mL) under N2.7 The mixture was stirred at room temperature for 13 days, after which 31P NMR spectroscopy showed almost complete deprotection (δ -23.0) with a trace of partially deprotected (Is)(2-naphthylCH2)P(CH2)2P(CH22naphthyl)(Is)(BH3) (δ -22.4, -22.6). The broad peak for the starting material was not observed. (In a similar experiment but on a smaller scale (ca. 150 mg, 0.19 mmol of 2-BH3), heating to 60 °C resulted in much faster deprotection that went to completion in less than 1 day.) The solution was transferred under N2 via filter cannula to a round-bottom Schlenk flask equipped with a stir bar. The remaining resin was washed with two 15 mL portions of toluene, and the extracts were combined with the filtrate. The toluene was removed under reduced pressure to leave 256 mg of oily white solid. The solid was washed with two 1 mL portions of petroleum ether to remove the trace impurities, giving 220 mg (86% yield) of meso-2. In a similar deprotection, crystals suitable for X-ray analysis were obtained after dissolving the sample in petroleum ether, eluting through a silica pipet filter (0.5 cm wide 3.0 cm high), and allowing the petroleum ether to slowly evaporate. Elemental analysis of the air-sensitive phosphine was consistent with oxidation. Anal. Calcd for C54H68O2P2: C, 79.97; H, 8.45. Found: C, 80.38; H, 8.52. HRMS (ESþ) for C54H69P2 (MHþ): calcd m/z 779.4875, found m/z 779.4843. 31P{1H} NMR (CDCl3): δ -22.7 (meso; the rac peak appears at δ -22.1). 1H NMR (CDCl3): δ 7.76-7.74 (m, 2H, Ar), 7.65 (d, J = 8, 2H, Ar), 7.63-7.61 (m, 2H, Ar), 7.44 (2H, Ar), 7.41-7.36 (m, 4H, Ar), 7.23 (dd, J = 9, 2, 2H, Ar), 6.97 (4H, Ar), 3.81 (broad, 4H, CH, i-Pr), 3.41 (AB pattern, J = 14, 2H, P-CH2), 3.32 (AB pattern, J = 14, 2H, P-CH2), 2.87 (sep, J = 7, 2H, CH, i-Pr), 2.12-2.07 (m, 2H, P-CH2), 1.99-1.94 (m, 2H, P-CH2), 1.27 (d, J = 7, 12H, CH3, i-Pr), 1.20 (d, J = 7, 12H, CH3, i-Pr), 1.00 (d, J = 7, 12H, CH3, i-Pr). 13C{1H} NMR (CDCl3): δ 155.4 (broad, Ar), 150.2 (Ar), 137.3 (t, J = 6, Ar), 133.5 (Ar), 131.8 (Ar), 127.9 (m, Ar), 127.5 (Ar), 127.3 (Ar), 126.8 (t, J = 4, Ar), 125.7 (Ar), 125.0 (Ar), 122.0 (Ar), 109.7 (Ar), 35.8-35.6 (m, P-CH2), 34.1 (CH, i-Pr), 31.4 (t, J = 11, CH, i-Pr), 26.0 (d, J = 5, P-CH2), 24.8 (CH3, i-Pr), 24.7 (CH3, i-Pr), 23.8 (CH3, i-Pr). Is(CH2-2-naphthyl)P(CH2)2PHIs (3). Under N2, a solution of IsHP(CH2)2PHIs (1; 124 mg, 0.25 mmol) in 5 mL of THF was cooled to -78 °C. To this was added s-BuLi (250 μL, 1.05 M in hexane, 0.26 mmol, 1.05 equiv) via microliter syringe, and the solution turned yellow. The solution was stirred for 1 h and then transferred dropwise via cannula over 15 min to a -78 °C solution of 2-(chloromethyl)naphthalene (46 mg, 0.26 mmol, 1.05 equiv, technical grade, 90% purity from Matrix Scientific) in 5 mL of THF. The solution was stirred for 1 h more and then warmed to room temperature to give a pale yellow solution. The solvent was removed under reduced pressure, and the white residue was partially redissolved in Et2O (15 mL) to give a cloudy white solution. To this was added 4 mL of a degassed (25) Redfield, D. A.; Cary, L. W.; Nelson, J. H. Inorg. Chem. 1975, 14, 50–59.
Article saturated solution of NH4Cl in distilled H2O, and the solution turned colorless. The organic layer was removed via cannula, and the aqueous layer was extracted with two 15 mL portions of ether and dried over MgSO4. The solvent was removed under reduced pressure, and the white residue was brought into the drybox for column chromatography. The sample was dissolved in 1 mL of 98:2 petroleum ether-THF and loaded onto a silica column (14.0 cm high, 1.3 cm wide). The column was eluted with the same solvent mixture and 20 5 mL fractions were collected. The desired product was collected over fractions 2-4 (the most was in fraction 3) to give 54 mg (34% yield) of a white solid as a 1:1 mixture of diastereomers that also contained 2% of IsHP(CH2)2PHIs (1) and 1% of Is(CH2-2-naphthyl)P(CH2)2P(CH22-naphthyl)Is (2) as determined by 31P NMR spectroscopy. In a subsequent preparation of a different sample, all impurities were removed through purification by column chromatography, as ascertained by 31P NMR spectroscopy. The mass spectrum was consistent with oxidation at both P centers. HRMS (ESþ) for C43H61O2P2 (MO2Hþ): calcd m/z 671.4147, found m/z 671.4137. 31P{1H} NMR (C6D6): δ -23.6 (d, J = 30), -23.9 (d, J = 30), -88.6 (d, J = 30), -89.6 (d, J = 30). 1H NMR (C6D6): δ 7.59-7.53 (m, 4H, Ar), 7.38-7.34 (m, 1H, Ar), 7.25-7.18 (m, 2H, Ar), 7.10 (apparent t, J = 3, 2H, Is), 7.05 (d, J = 2, 2H, Is), 4.44 (dt, JPH = 211, JHH = 7, 0.5 H, 1 diastereomer), 4.40 (dt, JPH = 212, JHH = 7, 0.5H, 1 diastereomer), 4.11 (broad, 2H, CH, i-Pr), 3.74-3.65 (m, 2H, CH, iPr), 3.42 (AB pattern, JHH = 13, JPH = 12, 1H, 1 diastereomer), 3.41 (AB pattern, JHH = 13, JPH = 20, 1H, 1 diastereomer), 2.76-2.69 (m, 2H, CH, i-Pr), 2.35-2.25 (m, 1H, P-CH2), 2.212.12 (m, 1H, P-CH2), 2.05-1.98 (m, 0.5H, P-CH2), 1.921.86 (m, 0.5H, P-CH2), 1.82-1.68 (m, 1H, P-CH2), 1.31 (d, J = 7, 3H, CH3, i-Pr), 1.30 (d, J = 7, 3H, CH3, i-Pr), 1.23 (d, J = 7, 3H, CH3, i-Pr), 1.20-1.17 (m, 15H, CH3, i-Pr), 1.15-1.12 (m, 9H, CH3, i-Pr), 1.08 (d, J = 7, 3H, CH3, i-Pr). 13C{1H} NMR (C6D6): δ 156.2 (broad, quat, Ar), 156.1 (broad, quat, Ar), 153.3 (d, J = 11, quat, Ar), 153.2 (d, J = 11, quat, Ar), 150.8 (quat, Ar), 150.7 (quat, Ar), 149.8 (quat, Ar), 149.7 (quat, Ar), 137.6 (d, J = 4, quat, Ar), 137.5 (d, J = 4, quat, Ar), 134.21 (quat, Ar), 134.20 (quat, Ar), 132.5 (quat, Ar), 129.3 (d, J = 8, quat, Ar), 129.2 (d, J = 8, quat, Ar), 128.4-128.3 (m, CH, Ar), 128.3 (CH, Ar), 127.9 (CH, Ar), 127.7 (CH, Ar), 127.42 (d, J = 2, CH, Ar), 127.36 (d, J = 2, CH, Ar), 126.2 (CH, Ar), 126.1 (CH, Ar), 125.4 (CH, Ar), 122.3 (d, J = 3, CH, Ar), 121.6 (d, J = 3, CH, Ar), 36.3 (d, J = 20, P-CH2-Nap), 34.7 (CH), 34.6 (CH), 32.91 (d, J = 14, CH), 32.89 (d, J = 14, CH), 31.9 (CH), 31.7 (CH), 26.9-26.4 (m, P-CH2), 25.2 (CH3), 25.0 (CH3), 24.9 (CH3), 24.5 (CH3), 24.4 (CH3), 24.1-24.0 (m, CH3), 23.1-22.6 (m, P-CH2). One set of quaternary aryl carbons was not found. The number of H atoms reported is for one compound. A signal for one isomer is 0.5 H. Preparation of (Is)(2-naphthylCH2)P(O)(CH2)2P(O)(CH22naphthyl)(Is) (2-O) for er and dr Analysis. This general procedure was used to prepare 2-O from either IsHP(CH2)2PHIs (1) or Is(CH2-2-naphthyl)P(CH2)2PHIs (3) using either enantiomer of the Pt catalyst. Reactions were run on the same scale relative to the starting diphosphine. One or two equiv of NaOSiMe3 and 2bromomethylnaphthalene was used, depending on how many P centers were alkylated. IsHP(CH2)2PHIs (1; 25 mg, 0.05 mmol) was dissolved in 7 mL of THF, and the solution was transferred to a vial containing NaOSiMe3 (12 mg, 0.1 mmol, 2 equiv). The resulting solution was transferred to another vial containing Pt((R,R)-Me-Duphos)(Ph)(Cl) (3 mg, 0.005 mmol, 10 mol %) to give a yellow solution. To this was added 2-bromomethylnaphthalene (22 mg, 0.1 mmol, 2 equiv) and the solution was stirred for 12 h, over which time a white solid precipitated. The solvent was removed under reduced pressure, and the product was extracted and eluted over a silica pipet filter (0.5 cm wide 3.0 cm high) with three 2 mL portions of 9:1 petroleum ether-THF. The product was checked by 31P NMR spectroscopy before and after oxidation to ensure that the dr was not
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altered. It was redissolved in 5 mL of THF and oxidized in the air using excess H2O2 (0.2 mL, 30% in H2O). After the mixture was stirred for 1 h, the solvent was removed under reduced pressure and the residue was dried in a vacuum desiccator for 12 h to yield a white solid with typical yields ranging from 90 to 96%. Evaporation of a solution in hexanes/isopropyl alcohol gave X-ray-quality crystals. HRMS (ESþ) for C54H69O2P2 (MHþ): calcd m/z 811.4773, found m/z 811.4767. 31P{1H} NMR (CD2Cl2): δ 47.6. 31P{1H} NMR (CDCl3): δ 44.6 (meso), 44.1 (rac). 1H NMR (CD2Cl2): δ 7.79-7.76 (m, 2H, Ar), 7.71-7.69 (m, 4H, Ar), 7.58 (2H, Ar), 7.46-7.42 (m, 4H, Ar), 7.27 (d, J = 8, 2H, Ar), 7.06 (t, J = 2, 2H, Is), 3.71-3.56 (m, 8H, CH, i-Pr, P-CH2-Nap), 2.86 (sep, J = 7, CH, i-Pr), 2.46-2.39 (broad m, 4H, P-CH2), 1.23 (d, J = 7, 6H, CH3, i-Pr), 1.22 (d, J = 7, 6H, CH3, i-Pr), 1.18 (d, J = 7, 12H, CH3, i-Pr), 0.84 (d, J = 7, 12H, CH3, i-Pr). 13C{1H} NMR (CD2Cl2): δ 154.6 (broad, Ar), 153.3 (Ar), 133.7 (Ar), 132.7 (Ar), 129.4 (t, J = 4, Ar), 129.1 (t, J = 3, Ar), 128.4 (Ar), 128.3 (Ar), 127.84 (Ar), 127.82 (Ar), 126.5 (Ar), 126.1 (Ar), 123.6 (t, J = 6, Ar), 120.8 (m, Ar), 40.7 (m, P-CH2), 34.5 (CH, i-Pr), 30.4 (CH, i-Pr), 26.0 (m, P-CH2), 25.2 (CH3, i-Pr), 24.5 (CH3, i-Pr), 23.6 (d, J = 8, CH3, i-Pr). To provide a reference sample of 2-O for the assays below, an enriched sample of diphosphine 2, prepared on the same scale, was heated to epimerize the P stereocenters and then oxidized. Solid 2 was heated under N2 in an oil bath for 3 days at 165 °C. A 31 P NMR spectrum of this material in THF revealed an approximate 1.2:1 rac:meso ratio, confirming that the sample had been epimerized. It also contained some of the phosphine oxide 2-O. The residue was oxidized completely with H2O2 (0.2 mL, 30% in H2O). The residual H2O2 was removed under reduced pressure, and the sample was dried for 12 h in a vacuum desiccator to yield 36 mg (89% yield) of white solid, which contained a trace of an unidentified impurity (31P NMR (THF): δ 40.7). 31 P NMR Analysis of 2-O. This general procedure was used for measuring the dr and er of 2-O by 31P NMR spectroscopy following catalytic alkylation, subsequent oxidation, and treatment with the shift reagent L-FmocTrp(Boc)-OH (Novabiochem).11 The NMR solvents C6D6, CD2Cl2, and CDCl3 were tested, but CDCl3 gave the best chemical shift dispersion for accurate integration. A sample of 2-O (10 mg, 0.01 mmol) was dissolved in 1 mL of CDCl3. To this was added FmocTrp(Boc)OH (13 mg, 0.025 mmol, 2.5 equiv). Integration of the peaks in the 31P NMR spectrum (Figure S4, Supporting Information) gave the er and dr of the diphosphine oxide. 31P{1H} NMR (CDCl3): δ 47.6 (rac, minor), 47.5 (rac, major), 47.3 (AB pattern, J = 50, meso) for a sample prepared with Pt((R,R)-MeDuPhos)(Ph)(Cl). HPLC Analysis of 2-O. A sample of 2-O (4 mg, 0.005 mmol) was dissolved in 0.4 mL of HPLC grade isopropyl alcohol. An additional 0.6 mL of HPLC grade hexanes was added, and the sample was loaded into the autosampler. The column (Daicel Chiralpak AD-H, 4.6 mm inner diameter, 250 mm length) was equilibrated for 30 min at 36 °C with 98:2 hexanes-isopropyl alcohol. The sample was injected using the autosampler. The meso isomer eluted at 18 min, and the rac isomers eluted at 27 and 34 min, respectively (1.0-1.2 mL/min, 36 °C). The peaks were identified by isolation of the pure meso compound and also by changing the hand of the catalyst to observe the change in the rac product ratios. Each enantiomer’s peak was well-resolved from the others, but the peak widths were large and resulted in a broad elution window for each isomer. IsHP(CH2)2OSiMe3 (4). To a solution of PH2Is (390 mg, 73% purity, 26% 1,3,5-triisopropylbenzene according to 1H NMR integration, 1.34 mmol of PH2Is) in 5 mL of THF at -78 °C was added s-BuLi (1260 μL, 1.1 M in cyclohexane, 1.4 mmol, 1.05 equiv), and the solution turned yellow. The solution was stirred at -78 °C for 1 h, and then a solution of Cl(CH2)2OSiMe3 (229 mg, 1.5 mmol, 1.1 equiv) was added dropwise via cannula. The solution was stirred an additional
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1 h at -78 °C and then warmed to room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in 15 mL of Et2O to give a cloudy white solution. To this was added 5 mL of a degassed saturated aqueous solution of NaHCO3. The aqueous layer was extracted with three 15 mL portions of Et2O, dried over MgSO4, and filtered, and the solvent was removed under reduced pressure to leave a clear oil (466 mg, 76% purity, containing 24% 1,3,5-triisopropylbenzene according to 1H NMR spectroscopy). Note that a similar workup at this point using degassed distilled H2O instead of NaHCO3 resulted in hydrolysis of the OSiMe3 group to give 5. The oil was dissolved in 1 mL of petroleum ether and loaded onto a silica plug (2.5 cm wide 4.0 cm high). The plug was eluted with 15 mL of petroleum ether and then two 15 mL portions of 9:1 petroleum ether-THF. The second of the mixed solvent fractions contained 224 mg (47% yield based on PH2Is) of the desired phosphine as an oil free from 1,3,5-triisopropylbenzene, as determined by 1H NMR spectroscopy. Anal. Calcd for C20H37OPSi: C, 68.13; H, 10.58. Found: C, 68.60; H, 10.30. The mass spectrum was consistent with hydrolysis of the silyl ether. HRMS (ESþ) for C17H30OP (MH2þSiMe3): calcd m/z 281.2034, found m/z 281.2028. 31P{1H} NMR (CDCl3): δ -106.1. 1H NMR (CDCl3): δ 7.03 (d, J = 3, 2H, Is), 4.32 (dt, JPH = 218, JHH = 7, 1H, P-H), 3.77-3.69 (m, 2H, CH2), 3.69-3.61 (m, 2H, CH, i-Pr), 2.88 (sep, J = 7, 1H, CH, iPr), 2.12-2.05 (m, 1H, CH2), 1.89-1.81 (m, 1H, CH2), 1.30 (d, J = 7, 6H, CH3, i-Pr), 1.26 (d, J = 7, 6H, CH3, i-Pr), 1.23 (d, J = 7, 6H, CH3, i-Pr), 0.11 (9H, OSi(CH3)3). 13C{1H} NMR (CDCl3): δ 152.7 (d, J = 11, quat, Ar), 149.4 (quat, Ar), 127.3 (d, J = 14, quat, Ar), 121.3 (d, J = 4, CH, Ar), 61.4 (d, J = 14, CH2), 34.2 (CH, i-Pr), 32.6 (d, J = 14, CH, i-Pr), 27.5 (d, J = 14, CH2), 24.9 (CH3, i-Pr), 24.2 (CH3, i-Pr), 23.8 (d, J = 4, CH3, i-Pr), -0.5 (OSi(CH3)3). IsHP(CH2)2OH (5). IsHP(CH2)2OSiMe3 (4; 95 mg, 0.11 mmol) was dissolved in 5 mL of degassed 5% v/v concentrated HCl in MeOH, and the mixture was stirred for 1 h. The solvent was removed under reduced pressure, and the oily residue was redissolved in Et2O. Residual HCl was neutralized with the addition of 5 mL of saturated aqueous NaHCO3. The organic layer was removed via cannula, and the aqueous layer was extracted with two additional 15 mL portions of Et2O. The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the remaining oil was eluted over a silica pipet filter (0.5 cm wide 3.0 high) with 5 mL of Et2O. The solvent was removed under reduced pressure to give a cloudy white oil that solidified and became a waxy white solid upon standing (69 mg, 92% yield). This material was ∼97% pure by 31P NMR spectroscopy (CDCl3); it contained an unidentified trace impurity (δ -94.2, 1.5%), PH2Is (δ -157.0,