Phosphine-catalyzed reductions of alkyl silyl peroxides by titanium hydride reducing agents: Development of the method and mechanistic investigations

Article abstract of DOI:10.1021/jo1008367

(Figure presented) A method that allows for the reduction of protected hydroperoxides by employing catalytic amounts of phosphine is presented. The combination of a titanium(IV) alkoxide and a siloxane allowed for the chemoselective reduction of phosphine oxides in the presence of alkyl silyl peroxides. Subsequent reduction of the peroxide moiety by phosphine provided the corresponding silylated alcohols in useful yields. Mechanistic experiments, including crossover experiments, support a mechanism in which the peroxide group was reduced and the silyl group was transferred in a concerted step. Labeling studies with ¹⁷O-labeled peroxides demonstrate that the oxygen atom adjacent to the silicon atom is removed from the silyl peroxide.

Full text of DOI:10.1021/jo1008367

pubs.acs.org/joc
Phosphine-Catalyzed Reductions of Alkyl Silyl Peroxides by
Titanium Hydride Reducing Agents: Development of the Method and
Mechanistic Investigations
Jason R. Harris, M. Taylor Haynes II, Andrew M. Thomas, and K. A. Woerpel*
Department of Chemistry, University of California, Irvine, California 92697-2025
kwoerpel@uci.edu
Received April 28, 2010
A method that allows for the reduction of protected hydroperoxides by employing catalytic amounts of
phosphine is presented. The combination of a titanium(IV) alkoxide and a siloxane allowed for the
chemoselective reduction of phosphine oxides in the presence of alkyl silyl peroxides. Subsequent reduction
of the peroxide moiety by phosphine provided the corresponding silylated alcohols in useful yields.
Mechanistic experiments, including crossover experiments, support a mechanism in which the peroxide
group was reduced and the silyl group was transferred in a concerted step. Labeling studies with 17O-labeled
peroxidesdemonstratethattheoxygenatomadjacenttothesiliconatomisremovedfromthesilylperoxide.
Introduction
simplify isolation by reducing the amount of undesired
phosphine oxide byproduct.3
Reductions of the oxygen-oxygen bonds of peroxides
with phosphines provide useful methods for the synthesis
of alcohols, ethers, and carbonyl compounds.1 These reac-
tions require the use of stoichiometric quantities of the
phosphine, which generates an equivalent of a phosphine
oxide that must be separated from the desired products.
Phosphorus reagents attached to solid supports have been
developed to address the problems associated with the use of
stoichiometric quantities of phosphines.2 The development
of phosphine-catalyzed reductions of peroxides would also
The development of a phosphine-catalyzed reduction of
peroxides requires surmounting a challenge in selectivity.
Due to the mildness by which phosphines can reduce the
peroxide moiety in the presence of other functional groups,
we explored reaction conditions where only phosphine
would be the active peroxide reductant. A terminal reductant
is then needed to reduce a strong phosphorus-oxygen bond
(approximately 130 kcal/mol)4,5 in the presence of a weak
oxygen-oxygen bond (approximately 34-50 kcal/mol).5,6
Typical reducing agents used to convert phosphine oxides to
phosphines, such as metal hydrides and silanes,7 would be
(1) (a) Challenger, F.; Wilson, V. K. J. Chem. Soc. 1927, 209–213.
(b) Horner, L.; Jurgeleit, W. Liebigs Ann. Chem. 1955, 591, 138–152.
(c) Horner, L.; Winkler, H. Tetrahedron Lett. 1964, 5, 3275–3277.
(d) Gilchrist, T. L. In Comprehensive Organic Synthesis - Selectivity, Strategy,
and Efficiency in Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Elsevier: Oxford, UK, 1991; Vol. 8; Chapter 2, pp 381-402.
(4) Bedford, A. F.; Mortimer, C. T. J. Chem. Soc. 1960, 1622–1625.
(5) Luo, Y. R. Comprehensive Handbook of Chemical Bond Energies;
CRC: Boca Raton, 2007.
(6) Bach, R. D.; Ayala, P. Y.; Schlegel, H. B. J. Am. Chem. Soc. 1996, 118,
12758–12765.
(7) (a) Still, I. W. In Comprehensive Organic Synthesis - Selectivity,
Strategy, and Efficiency in Modern Organic Chemistry; Trost, B. M., Fleming,
I., Eds.; Elsevier: Oxford, UK, 1991; Vol. 8, Chapter 2, pp 403-415. (b) Honaker,
M. T.; Hovland, J. M.; Salvatore, R. N. Curr. Org. Synth. 2007, 4, 31–45.
(c) Allen, D. W. Organophosphorus Chem. 2008, 37, 13–53 and references
cited within.
(2) Relles, H. M.; Schluenz, R. W. J. Am. Chem. Soc. 1974, 96, 6469–6475
and references cited therein.
(3) For an example of a Wittig reaction with catalytic amounts of
phosphine, see: O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter,
A. L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A. Angew. Chem. Int. Ed.
2009, 48, 6836–6839.
DOI: 10.1021/jo1008367
r
Published on Web 07/06/2010
J. Org. Chem. 2010, 75, 5083–5091 5083
2010 American Chemical Society

Harris et al.
JOCArticle
SCHEME 1. Proposed Catalytic Reduction of a Protected
Peroxide with Phosphine
FIGURE 1. Substrates subjected to catalytic reduction conditions.
and ketal groups (1a and 1b, 1c, and 1d, respectively, Figure 1)
as masking groups due to their stability in reducing environ-
ments15,16 and their anticipated ease of removal after reduction.
Furthermore, reactivity between phosphines and these types of
peroxides has been previously documented. In general, silyl and
dialkyl peroxides undergo deoxygenation upon treatment with
phosphines and phosphites,17,18 but peroxy ketals can either
fragment19 or undergo deoxygenation20 when treated with
phosphines.21
Initial attempts to develop a phosphine-catalyzed reduc-
tion of peroxides were unsuccessful. The results with silyl-
protected peroxides are representative (Table 1). When
LiAlH4 was used as the terminal reductant, mixtures of silyl
ether 2a or 2b and alcohol 3 were observed (Table 1, entries 1
and 2). Alcohol 3 could be formed by reduction of the
oxygen-oxygen bond of peroxides 1a or 1b by LiAlH4,8 or
it could result from deprotection of silyl ethers 2a or 2b.22 We
surmise that direct reduction of the oxygen-oxygen bond by
LiAlH4 is more likely than deprotection because the sub-
strate with the more labile trimethylsilyl group (2a) proceeds
with less loss of the silyl group (Table 1, entry 1 vs entry 2).
When Cl3SiH was chosen as the stoichiometric reductant,
complete decomposition to an intractable mixture of pro-
ducts was observed (Table 1, entry 3). Decomposition of silyl
peroxide 1b could be due to the acidity of the chlorosilane
unsuitable because they decompose hydroperoxides to the
corresponding alcohols.1d,8,9 We hypothesized that the choice of
an appropriate protecting group for the hydroperoxide in
combination with a selective reducing agent could permit the
chemoselective reduction of the thermodynamically more stable
phosphine oxide in the presence of the fragile oxygen-oxygen
bond (Scheme 1). The catalytic cycle outlined in Scheme 1 differs
from typical metal-catalyzed oxygen transfer reactions because it
requires a phosphine oxide and not a peroxide to serve as an
oxygen transfer agent to the terminal reductant.10
In this paper, we present a phosphine-catalyzed reduction
of silyl-protected hydroperoxides using a titanium hydride11
as the terminal reducing agent. Electron paramagnetic re-
sonance (EPR) spectroscopy revealed the formation a spe-
cies consistent with decomposition of a titanium hydride
complex. Crossover experiments and the use of 17O-labeled
substrates indicate that the phosphine removes the oxygen
atom closest to the silyl group, and silyl transfer to the
remaining oxygen atom occurs concurrently with reduction.
Results and Discussion
Exploration of Peroxide Protecting Group and Reducing
Conditions. Our investigation began by protecting a hydro-
peroxide with groups that could survive conditions com-
monly employed to reduce phosphine oxides.12-14 Typically,
a free hydroperoxide moiety is intolerant of many strongly
reducing conditions.8 We chose to examine the silyl, benzyl,
(15) For examples of the stability of alkyl, ketal, and silyl peroxides
toward hydride reduction, see: (a) Dussault, P.; Sahli, A.; Westermeyer, T.
J. Org. Chem. 1993, 58, 5469–5474. (b) Lowe, J. R.; Porter, N. A. J. Am.
Chem. Soc. 1997, 119, 11534–11535. (c) Porter, N. A.; Caldwell, S. E.; Lowe,
J. R. J. Org. Chem. 1998, 63, 5547–5554. (d) Jin, H.-X.; Liu, H.-H.; Zhang,
Q.; Wu, Y. J. Org. Chem. 2005, 70, 4240–4247 and references cited within.
(e) Murakami, M.; Sakita, K.; Igawa, K.; Tomooka, K. Org. Lett. 2006, 8,
4023–4026.
(8) For examples of reductions of peroxides by metal hydrides, see:
(a) Matic, M.; Sutton, D. A. J. Chem. Soc. 1952, 2679–2682. (b) Russell,
G. A. J. Am. Chem. Soc. 1953, 75, 5011–5013. (c) Davies, A. G.; Feld, R.
J. Chem. Soc. 1956, 665–670. (d) Baldwin, J. E.; Barton, D. H. R.;
Sutherland, J. K. J. Chem. Soc. 1964, 3312–3315.
(9) For an example of reductions of hydroperoxides by silanes and
stannanes, see: Nakamura, E.; Sato, K.-i.; Imanishi, Y. Synlett 1995,
525–526.
(10) The formation of a phosphine oxide from a phosphine and oxygen is
exothermic, so a phosphine oxide would not be expected to be a strong
oxygen atom donor. Conversely, the formation of peroxide from an alcohol
and oxygen is endothermic, so a peroxide would be more likely to serve as an
oxygen transfer agent. For examples and a discussion, see: Holm, R. H.
Chem. Rev. 1987, 87, 1401–1449.
(11) (a) Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1992, 57, 3751–3753.
(b) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1995, 60, 7884–7890.
(12) For examples of reductions of phosphine oxides by metal hydrides,
see: (a) Hein, F.; Issleib, K.; Rabold, H. Z. Anorg. Allg. Chem. 1956, 287,
208–213. (b) Horner, L.; Hoffmann, H.; Beck, P. Chem. Ber. 1958, 91, 1583–
1588. (c) Henson, P. D.; Naumann, K.; Mislow, K. J. Am. Chem. Soc. 1969,
91, 5645–5646. (d) Busacca, C. A.; Raju, R.; Grinberg, N.; Haddad, N.;
James-Jones, P.; Lee, H.; Lorenz, J. C.; Saha, A.; Senanayake, C. H. J. Org.
Chem. 2008, 73, 1524–1531.
(16) (a) Dussault, P.; Porter, N. A. J. Am. Chem. Soc. 1988, 110, 6276–
6277. (b) Dussault, P. Synlett 1995, 997–1003.
(17) (a) Brandes, D.; Blaschette, A. J. Organomet. Chem. 1975, 99, C33–
C35. (b) Jefford, C. W.; Rimbault, C. G. J. Am. Chem. Soc. 1978, 100, 6437–
6445. (c) Gorbatov, V. V.; Yablokova, N. V.; Aleksandrov, Y. A.; Ivanov,
V. I. Zh. Obsch. Khim. 1983, 53, 1752–1755. (d) Ando, W.; Kako, M.;
Akasaka, T.; Kabe, Y. Tetrahedron Lett. 1990, 31, 4177–4180. (e) Adam, W.;
Albert, R. Tetrahedron Lett. 1992, 33, 8015–8016. (f) Einaga, H.; Nojima,
M.; Abe, M. J. Chem. Soc., Perkin Trans. 1 1999, 2507–2512. (g) Terent’ev,
A. O.; Platonov, M. M.; Tursina, A. I.; Chernyshev, V. V.; Nikishin, G. I.
J. Org. Chem. 2009, 74, 1917–1922.
(18) For examples and studies of phosphines and phosphites reacting with
dialkyl peroxides, see: (a) Denney, D. B.; Relles, H. M. J. Am. Chem. Soc.
1964, 86, 3897–3898. (b) Adam, W.; Rios, A. J. Org. Chem. 1971, 36, 407–
411. (c) Bartlett, P. D.; Baumstark, A. L.; Landis, M. E. J. Am. Chem. Soc.
1973, 95, 6486–6487. (d) Balci, M. Chem. Rev. 1981, 81, 91–108 and
references cited therein. (e) Abe, M.; Sumida, Y.; Nojima, M. J. Org. Chem.
1997, 62, 752–754. (f) Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2004, 69,
2577–2579.
(19) (a) Gibson, D. H.; Wilson, H. L.; Joseph, J. T. Tetrahedron Lett.
1973, 14, 1289–1292. (b) Galal, A. M.; Ross, S. A.; ElSohly, M. A.; ElSohly,
H. N.; El-Feraly, F. S.; Ahmed, M. S.; McPhail, A. T. J. Nat. Prod. 2002, 65,
184–188.
(20) (a) Clough, R. L.; Yee, B. G.; Foote, C. S. J. Am. Chem. Soc. 1979,
101, 683–686. (b) Sugimoto, T.; Nakamura, N.; Nojima, M.; Kusabayashi, S.
J. Org. Chem. 1991, 56, 1672–1674.
(13) For examples of reductions of phosphine oxides by silanes, see:
(a) Fritzsche, H.; Hasserodt, U.; Korte, F. Chem. Ber. 1964, 97, 1988–1993.
(b) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 2788–
2789. (c) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91,
7012–7023.
(14) For examples of reductions of phosphine oxides by Ti(IV)/siloxane,
see: (a) Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahedron Lett.
ꢀ
1994, 35, 625–628. (b) Berthod, M.; Favre-Reguillon, A.; Mohamad, J.;
Mignani, G.; Docherty, G.; Lemaire, M. Synlett 2007, 1545–1548.
(21) Peroxyketals are stable to phosphines in the presence of ozonides at
low temperature: (a) Dussault, P.; Sahli, A. Tetrahedron Lett. 1990, 31,
5117–5120. (b) Dussault, P.; Lee, I. Q.; Kreifels, S. J. Org. Chem. 1991, 56,
4087–4089.
(22) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031–1069.
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TABLE 1. Investigation of Other Stoichiometric Reducing Agents
entry
substrate
R
conditions
2a,b:3a
conva (%)
yielda (%)
1
2
3
1a
1b
1b
Me
Et
Et
LiAlH4 (1.0 equiv), PPh3 (0.05 equiv), THF, rt, 24 h
LiAlH4 (1.0 equiv), PPh3 (0.05 equiv), THF, rt, 24 h
Cl3SiH (1.0 equiv), PPh3 (0.05 equiv), toluene, 110 °C, 19 h
52:48
2:98
N.A.
>98
51
>98
81b
29
0
aAs determined by GC analysis of the unpurified reaction mixture relative to internal standard (dodecane). bCombined yields of 2a and 3.
conv = conversion. RT = room temperature. N.A. = not applicable.
TABLE 2. Screen of Protecting Groups using Titanium(IV) and HSiMe2OSiMe2H as Stoichiometric Reducing Agents
entry
1
substrate
R1
conditions
2a,c,d:3
conva (%)
80
yieldb (%)
2c: 0; 3: 31
1c
CH2Ph
Ti(O-i-Pr)4 (0.5 equiv), HSiMe2OSiMe2H (2.0 equiv),
PPh3 (0.05 equiv), toluene, 100 °C, 24 h
0:>98
2
3
1d
1a
CMe2(OMe)
SiMe3
Ti(O-i-Pr)4 (0.5 equiv), HSiMe2OSiMe2H (2.0 equiv),
PPh3 (0.05 equiv), toluene, 100 °C, 24 h
N.A.
100:0
>98
>98
2d: 0
Ti(O-i-Pr)4 (0.5 equiv), HSiMe2OSiMe2H (2.0 equiv),
PPh3 (0.05 equiv), toluene, 100 °C, 6 h
2a: 41 (98);c 3: 13
aAs determined by GC analysis of the unpurified reaction mixture relative to an internal standard (dodecane). bIsolated yield. cYield in parentheses is
yield determined by GC analysis of the unpurified reaction mixture relative to an internal standard (dodecane). conv = conversion. N.A. = not applicable.
(pKa in DMSO of 8.3),23 which might result in deprotection
to form the hydroperoxide, which would decompose at
elevated temperatures.
by the titanium reagent. Without protection, hydroperoxide 4
was cleanly converted to the alcohol 3 by Ti(O-i-Pr)4 and
HSiMe2OSiMe2H, as determined by NMR analysis (eq 2).25
Because the titanium(IV)-siloxane system can neither reduce
the silyl peroxide 1a nor deprotect it (eq 1), observation of silyl
ether 2a in Table 2 (entry 3) indicates that the phosphine, not
the titanium reagent, must reduce the silyl peroxide 1a.
The combination of a titanium(IV) alkoxide and a silox-
ane proved to be a useful terminal reductant for the phos-
phine-catalyzed reduction of protected hydroperoxides.11,14
When benzyl peroxide 1c was treated with catalytic amounts
of phosphine in the presence of titanium isopropoxide (Ti(O-
i-Pr)4) and HSiMe2OSiMe2H (1,1,3,3-tetramethyldisilox-
ane, TMDS), only alcohol 3 and unreacted starting material
1c were isolated from the reaction mixture (Table 2, entry 1).
Ketal 1d underwent decomposition to an unknown product
under the catalytic reducing conditions (Table 2, entry 2).24
Reduction was much cleaner when a silyl protecting group
was used for the peroxide (Table 2, entry 3). Silyl ether 2a was
obtained in >98% yield as determined by GC analysis of the
unpurified reaction mixture. The isolated yield of the silyl
ether 2a was significantly lower than the yield determined by
GC, however. We attribute the low isolated yield to depro-
tection of the labile trimethylsilyl group upon purification.
Control experiments indicated that the reductions of silyl
peroxides in Table 2 proceeded with reduction of the per-
oxide by the phosphine and reduction of the phosphine oxide
by a metal complex as envisioned in Scheme 1. In the absence
of a phosphine, silyl peroxide 1a did not react with the
titanium(IV)-siloxane reducing agent, as determined by
GC analysis (eq 1). On the other hand, protection with the
silyl group was necessary to prevent reduction of the peroxide
Scope of Catalytic Reduction. The phosphine-catalyzed
reduction of silyl peroxides proceeded in good yields for a
variety of triethylsilyl peroxides (Table 3). In addition to
tertiary peroxides, the phosphine-catalyzed reduction can be
applied to secondary silyl peroxides. Tertiary and secondary
alkyl triethylsilyl peroxides can be prepared in one step from
alkenes by acobalt-catalyzed peroxidationreactiondeveloped
by Mukaiyama and Isayama.26 Carbonyl compounds, readily
formed under mildly basic conditions by R-deprotonation of
(23) Fu, Y.; Liu, L.; Li, R.-Q.; Liu, R.; Guo, Q.-X. J. Am. Chem. Soc.
2004, 126, 814–822.
(24) Heating peroxy ketal 1d in the absence of reducing agents also
resulted in decomposition, presumably by homolytic decomposition of the
oxygen-oxygen bond. See: Helgorsky, C.; Bevilacqua, M.; Degueil-
Castaing, M.; Maillard, B. Thermochim. Acta 1997, 297, 93–100.
(25) It is unclear if peroxide reduction is occurring by a hydride equivalent
attacking the O-O bond or from decomposition of a TiIV-OOR complex.
For an example of decomposition of a TiIV-OOR complex, see: DiPasquale,
A. G.; Kaminsky, W.; Mayer, J. M. J. Am. Chem. Soc. 2002, 124, 14534–
14535.
(26) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 573–576.
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TABLE 3. Substrate Scope of Catalytic Reduction
isolate the silyl ethers.11 This workup precluded the use of
trimethylsilyl peroxides because they were too susceptible to
deprotection. In contrast, deprotection of the silyl group was
generally avoided when the triethylsilyl ether was employed as the
masking group; only one silyl peroxy ketal 5afforded appreciable
amounts (9%) of the free alcohol (Table 3, entry 2).
The phosphine-catalyzed reduction of chiral nonracemic silyl
peroxides occurs with retention of configuration. Treatment of
silyl peroxide (þ)-(R)-1b29 to the catalytic reductive conditions
formed the silyl ether (þ)-(R)-2b with retention of configuration
(eq 3).30 In addition, the optical purity of the starting material
was retained. These studies indicate that the titanium complexes
employed are not Lewis acidic enough to ionize either the start-
ing material or product to form tertiary carbocations.
Variation of the reaction conditions for the phosphine-cata-
lyzed reduction was tolerated.31 Phosphine oxides could be used
as a precatalyst for the reduction (eq 4). Additionally, these reac-
tions could be performed in THF as the solvent. As noted in
previous reports in the literature, these reactions could be per-
formed without rigorous exclusion of oxygen and moisture.11,14
EPR Spectroscopy of a Titanium(IV) Decomposition Pro-
duct. Because control experiments (eqs 1 and 2) suggested
that the silyl peroxide oxidized the phosphine to the phos-
phine oxide, attention turned to determining the titanium-
based reducing agent responsible for reduction of the phos-
phine oxide. The phosphine oxide could be reduced by a
titanium(IV) hydride produced from a siloxane and a tita-
nium alkoxide (Scheme 2).32 Although many titanium(IV)
hydrides with a variety of ligands have been reported,33,34
aYields reported are isolated yields.
secondary peroxides,27 were not observed in the reaction
mixture. A wide range of functional group tolerance in the
reduction of esters by a titanium(IV) alkoxide and a siloxane
has been demonstrated by Buchwald and co-workers,11 and this
functional group tolerance was also observed in the phosphine-
catalyzed reduction of alkyl silyl peroxides. For example, the
reaction conditions were also compatible with the presence of
protected ketones (entry 2), alkoxy groups (entry 6), and silyl
ethers (entries 1-8). In general, the yields determined by ana-
(29) Driver, T. G.; Harris, J. R.; Woerpel, K. A. J. Am. Chem. Soc. 2007,
129, 3836–3837.
(30) Davies, A. G.; Feld, R. J. Chem. Soc. 1958, 4637–4643.
(31) Although this study has focused on using triphenylphosphine as the
peroxide reductant, we have observed that other alkyl- and arylphosphines
behave with equal efficiency. For sterically hindered phosphines, e.g.,
tricyclohexylphosphine, the use of smaller alkyl trimethylsilyl peroxides is
required for efficient conversions.
(32) A strongly associated titanium/silane complex or a titanium-(η2)-
silane could also be the active reductant. For a discussion, see: (a) Reference
11b. (b) Crabtree, R. H. Angew. Chem. Int. Ed. Engl. 1993, 32, 789–805.
(c) Corey, J. Y.; Braddock-Wilking, J. Chem. Rev. 1999, 99, 175–292. (d) Lin, Z.
Chem. Soc. Rev. 2002, 31, 239–245.
1
lysis of the unpurified reaction mixture by GC or H NMR
spectroscopy were higher than the isolated yields. The lowered
isolated yields were attributed, in part, to volatility of the pro-
ducts (e.g., silyl ether 13, entry 3) and the challenge of separating
the silyl ethers from the silicone polymers formed by titanium-
catalyzed dehydrocoupling of the siloxane.28 Basic hydrolysis of
the reaction mixture was found to be the most reliable method to
(33) Titanium(IV) hydrides have been proposed in the reaction between
titanium(IV) alkoxides and silanes/siloxanes; see: (a) Albizzati, E.; Abis, L.;
Pettenati, E.; Giannetti, E. Inorg. Chim. Acta 1986,120, 197–203. (b) Reference 11.
(34) For examples of Ti(IV) hydrides without cyclopentyldienyl ligands,
see: (a) Cummins, C. C.; Schrock, R. R.; Davis, W. M. Organometallics 1992,
11, 1452–1454. (b) Bennett, J. L.; Wolczanski, P. T. J. Am. Chem. Soc. 1994,
€
116, 2179–2180. (c) Noth, H.; Schmidt, M. Organometallics 1995, 14, 4601–
4610. (d) Bennett, J. L.; Wolczanski, P. T. J. Am. Chem. Soc. 1997, 119,
10696–10719. (e) Liu, X.; Wu, Z.; Cai, H.; Yang, Y.; Chen, T.; Vallet, C. E.;
Zuhr, R. A.; Beach, D. B.; Peng, Z.-H.; Wu, Y.-D.; Concolino, T. E.;
Rheingold, A. L.; Xue, Z. J. Am. Chem. Soc. 2001, 123, 8011–8021.
(f) Turculet, L.; Tilley, T. D. Organometallics 2004, 23, 1542–1553.
(27) (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73,
880–881. (b) Buncel, E.; Davies, A. G. J. Chem. Soc. 1958, 1550–1556.
(28) (a) Aitken, C.; Harrod, J. F.; Samuel, E. J. Organomet. Chem. 1985,
279, C11–C13. (b) Harrod, J. F. Coord. Chem. Rev. 2000, 206-207, 493–531.
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SCHEME 2. Proposed Catalytic Cycle for Peroxide Reduction
Involving a Titanium Hydride
FIGURE 2. Unsymmetrical 17O-labeled peroxides synthesized for
oxygen atom transfer studies.
question regarding the reduction of silyl peroxides by
phosphines involves assigning which oxygen atom is trans-
ferred to the phosphine during the reaction. Previous
investigations of the deoxygenation of alkyl silyl peroxides
by phosphines and phosphites suggested the oxygen atom
adjacent to the silicon atom is removed.15e,17b Computa-
tional studies42 and the preferential deoxygenation of an
alkyl silyl peroxide in the presence of a dialkyl peroxide17g
also both suggest that the oxygen atom adjacent to the silicon
atom is transferred to heteroatom nucleophiles. A kinetic
study, however, concluded that the oxygen atom attached to
the carbon atom was transferred to trimethylphosphite.17c
We envisioned that experiments using an unsymmetri-
cally isotopically-labeled hydroperoxide15b,c would enable
the fate of each oxygen atom to be determined unambi-
guously.
direct evidence for a titanium(IV) hydride produced from a
titanium(IV) alkoxide and a silane has not been obtained.
We attempted to observe a titanium(IV) hydride directly by
mixing equimolar amounts of Ti(O-i-Pr)4, HSiMe2OSiMe2H,
and PPh3 in toluene-d8 (eq 5).34c Analysis of the reaction
mixture by 1H NMR spectroscopy did not provide any signals
consistent with a titanium(IV) hydride. When 1H NMR spec-
troscopy was used to monitor the reaction progress during the
catalytic reduction, slight line broadening of the resonances was
occasionally observed.33a,35b This line broadening could result
from the formation of a paramagnetic titanium(III) species.35
An 17O-labeled peroxide was prepared to determine which
oxygen atom was transferred during the reduction. The use
of the 17O isotope enabled the use of NMR spectroscopy to
analyze the products. The low natural abundance of 17O
(0.037%) ensured that the signal-to-noise ratio of all spectra
would be good, even with low enrichment of the heavier
isotope.43 Our use of 17O-labeled peroxides was inspired by
Porter and co-workers’ use of substrates with an 18O isotope
to determine which oxygen atom was transferred in the
reduction of hydroperoxides by phosphines.15b,c Because of
the nondestructive nature of 17O NMR spectroscopy, low
levels of enrichment in the 17O isotope (1%) can be used to
perform the analysis compared to use of the 18O label, which
often requires analytical methods such as mass spectrometry
or elemental analysis.44 Using the method of Porter,15b,c,45
hydroperoxide 19 and silyl peroxide 20 were prepared with
approximately 1% 17O enrichment (Figure 2).46
Evidence for the formation of a titanium(III) species was
obtained by EPR spectroscopy. When equimolar amounts of
Ti(O-i-Pr)4 and HSiMe2OSiMe2H were mixed in toluene, a dark
blue solution was formed. EPR spectroscopy of the resulting
solution at ambient temperature gave a complex line shape with
a center field resonance of g = 1.963,36 which is similar to the g
values of other titanium(III) alkoxides.37 A titanium(III) species
could be formed from a titanium(IV) hydride by bimetallic
reductive elimination to form H2 (eq 6).33a,34c,38 Alternatively,
reduction of the phosphine oxide could occur from a titanium-
(III) hydride,28b,39,40 or a titanium(IV) species may be serving as
a one-electron reductant.41 The EPR experiments do not differ-
entiate between these possibilities.
2 R3TiIV-H f 2 R3TiIII þ H2
ð6Þ
Examination of Oxygen-Atom Transfer in the Reduction of
Silyl Peroxides by Phosphines. An unresolved mechanistic
The use of the 17O-labeled peroxides and 17O NMR spec-
troscopy revealed that triphenylphosphine removed the oxy-
gen atom remote to the carbon atom from both hydroperoxide
19 and silyl peroxide 20. Treatment of hydroperoxide 19 and
silyl peroxide 20 with triphenylphosphine in CD2Cl2 gave
similar 17O NMR resonances at δ 47 ppm (eqs 7 and 8). An
independently synthesized sample of Ph3Pd17O (22) also dis-
played a 17O chemical shift of δ 47 ppm.47 The 17O chemical
shifts of the unpurified reaction mixtures did not correspond to
17O-labeled alcohol 24 (δ 56 ppm, Figure 3), which was
prepared independently.48 These results demonstrate that the
oxygen atom adjacent to hydrogen in hydroperoxide 19 or
(35) Treatment of cyclopentyldienyltitanium(IV) compounds with silanes
has resulted in EPR active products; see: (a) Samuel, E.; Harrod, J. F. J. Am.
Chem. Soc. 1984, 106, 1859–1860. (b) Aitken, C. T.; Harrod, J. F.; Samuel, E.
J. Am. Chem. Soc. 1986, 108, 4059–4066. (c) Woo, H. G.; Harrod, J. F.;
ꢀ
Henique, J.; Samuel, E. Organometallics 1993, 12, 2883–2885. (d) Lunzer, F.;
Marschner, C.; Landgraf, S. J. Organomet. Chem. 1998, 568, 253–255.
(e) Wang, Q.; Corey, J. Y. Can. J. Chem. 2000, 78, 1434–1440.
(36) The amount of paramagnetic species was not quantified.
(37) (a) Billiau, F.; Folcher, G.; Marquet-Ellis, H.; Rigny, P.; Saito, E.
J. Am. Chem. Soc. 1981, 103, 5603–5604. (b) Covert, K. J.; Wolczanski, P. T.;
Hill, S. A.; Krusic, P. J. Inorg. Chem. 1992, 31, 66–78.
(38) (a) Shiihara, I.; Kawai, W.; Ichihashi, T. J. Polym. Sci. 1962, 57, 837–
854. (b) Barber, J. J.; Willis, C.; Whitesides, G. M. J. Org. Chem. 1979, 44,
3603–3604. (c) Fischer, J. M.; Piers, W. E.; Pearce Batchilder, S. D. P.;
Zaworotko, M. J. J. Am. Chem. Soc. 1996, 118, 283–284. (d) Johnson, A. L.;
Davidson, M. G.; Mahon, M. F. Dalton Trans. 2007, 5405–5411.
(39) Hoskin, A. J.; Stephan, D. W. Coord. Chem. Rev. 2002, 233-234,
107–129 and references cited therein.
(40) (a) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 6784–6785. (b) Shu, R.; Harrod, J. F.; Lebuis,
A.-M. Can. J. Chem. 2002, 80, 489–495 and references cited therein.
(41) Based on a detailed mechanistic analysis on the reduction of phos-
phine oxides by titanium(IV) alkoxides and siloxanes, a titanium(IV) species
has been proposed to serve as a one-electron reductant: Petit, C.; Favre-
Reguillon, A.; Albela, B.; Bonneviot, L.; Mignani, G.; Lemaire, M. Orga-
nometallics 2009, 28, 6379–6382.
ꢀ
(42) Estevez, C. M.; Dmitrenko, O.; Winter, J. E.; Bach, R. D. J. Org.
Chem. 2000, 65, 8629–8639.
(43) Silver, B. L.; Luz, Z. Q. Rev. Chem. Soc. 1967, 21, 458–473.
(44) Jones, J. R. J. Labelled Compd. 1969, 5, 305–311.
(45) For earlier studies of O-O bond formation through alkoxy radicals,
see: Koenig, T.; Deinzer, M. J. Am. Chem. Soc. 1966, 88, 4518–4520 and
additional references cited in ref 15b,c.
(46) Details are provided as Supporting Information.
(47) Lapidot, A.; Irving, C. S. J. Chem. Soc., Dalton Trans. 1972, 668–670.
(48) Boykin, D. W. 17O NMR Spectroscopy in Organic Chemistry; CRC:
Boca Raton, 1991; pp 21-39.
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FIGURE 3. 17O NMR spectra of independently synthesized alcohol 24 and phosphine oxide 22 with unpurified reaction mixtures of labeled
peroxides 19 and 20.
adjacent to the silicon atom in silyl peroxide 20 is transferred
to triphenylphosphine.
connected to the silyl group of silyl peroxide 20 is transferred to
the phosphine requires that the silyl group be moved to the other
oxygen atom to account for the formation of the silyl ether 23
(eq 8). Two mechanisms to explain silyl-group transfer are
presented in Scheme 3. Both mechanisms would involve a
dialkoxyphosphorane intermediate (e.g., 25) formed by formal
oxidative addition of the phosphine into the oxygen-oxygen
bond of the silyl peroxide (Scheme 3).18a,b,49,50 Intermediate
25 could undergo concerted silyl transfer (e.g., 26, Scheme 3)
to give the silyl ether and phosphine oxide products. Alternativ-
ely, dialkoxyphosphorane 25 could undergo heterolysis18d,e to
form the ion pair 27 and 28, and the silylated phosphine oxide
28 could silylate the alkoxide ion 27 (Scheme 3).51 Because the
concerted and ionic and mechanisms involve intra- and inter-
molecular silyl group transfer, respectively, a crossover experi-
ment could distinguish between them.
Mechanism of Silyl Transfer in Peroxide Reduction. The
oxygen-transfer experiments raise the question of how the silyl
group is transferred from the starting materials to the products
during the reduction. The observation that the oxygen atom
The results of the crossover experiment are consistent with
a concerted intramolecular transfer of the silyl group from
(49) For observations of cyclic O-PV-O intermediates, see: (a) Denney,
D. B.; Gough, S. T. D. J. Am. Chem. Soc. 1965, 87, 138–139. (b) Adam, W.;
Ramırez, R. J.; Tsai, S.-C. J. Am. Chem. Soc. 1969, 91, 1254–1256.
´
(c) Reference 18c. (d) Bartlett, P. D.; Baumstark, A. L.; Landis, M. E.; Lerman,
C. L. J. Am. Chem. Soc. 1974, 96, 5267–5268. (e) Barlett, P. D.; Landis, M. E.;
Shapiro, M. J. J. Org. Chem. 1977, 42, 1661–1662. (f) Clennan, E. L.; Heah, P. C.
J. Org. Chem. 1981, 46, 4105–4107. (g) Clennan, E. L.; Heah, P. C. J. Org.
Chem. 1982, 47, 3329–3331. (h) Clennan, E. L.; Heah, P. C. J. Org. Chem. 1983,
48, 2621–2622.
(50) For indirect detections of acyclic O-PV-O intermediates, see:
(a) Greenbaum, M. A.; Denney, D. B.; Hoffmann, A. K. J. Am. Chem.
Soc. 1956, 78, 2563–2565. (b) Denney, D. B.; Greenbaum, M. A. J. Am.
Chem. Soc. 1957, 79, 979–981. (c) Denney, D. B.; Adin, N. G. Tetrahedron
Lett. 1966, 7, 2569–2572. (d) Denney, D. B.; Denney, D. Z.; Hall, C. D.;
Marsi, K. L. J. Am. Chem. Soc. 1972, 94, 245–249.
(51) Liu, X.; Verkade, J. G. Heteroat. Chem. 2001, 12, 21–26 and
references cited therein.
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TABLE 4. Crossover Experiment To Determine the Mechanism of Silyl Transfer
entry
conditions
2bþ30:31:32a
1
2
3
4
PPh3 (1.0 equiv), toluene, 100 °C
PPh3 (1.0 equiv), MeCN, 70 °C
PPh3 (1.0 equiv), neat, 100 °C
100:0:0
100:0:0
100:0:0
100:0:0
Ti(O-i-Pr)4 (0.5 equiv), HSiMe2OSiMe2H (2.0 equiv), PPh3 (0.05 equiv), toluene, 100 °C
aRelative ratios of silyl ethers 2bþ30 to crossover products 31 or 32 by GC analysis of the unpurified reaction mixtures. Some free alcohols of the silyl
ethers were observed; details are provided as Supporting Information.
SCHEME 3. Potential Silyl Group Transfer Pathways
Catalytic quantities of phosphine can be used because the
resulting phosphine oxide is subsequently reduced by a
secondary reducing system based on a Ti(IV) catalyst and
a siloxane. Control experiments demonstrate that the phos-
phine is responsible for fragmentation of the oxygen-oxy-
gen bond. Mechanistic investigations revealed that the
phosphine attacks the silyl peroxide at the oxygen atom
adjacent to the silicon atom, and the silyl group is transferred
in a concerted step to the forming alkoxide.
Experimental Section
General experimental details are provided as Supporting
Information.
the peroxide to the hydroxyl group. The triethylsilyl and tri-n-
propylsilyl peroxides 1b and 29 (Table 4) were chosen for this
study because they undergo reduction of the peroxide at similar
rates. Under all conditions examined, crossover products 31
and 32 were not observed.52 Varying the solvent polarity (Table
4, entries 1 and 2) or reagent concentrations (Table 4, entry 3)
did not lead to scrambling of the silyl protecting groups.
Performing the double-labeling experiment under the catalytic
conditions also did not produce crossover products (Table 4,
entry 4). The concerted transfer of the silyl group from the
terminal oxygen of the peroxide to the internal oxygen atom
(Scheme 3) accounts for these results. This crossover experi-
ment, however, is also consistent with the formation of a short-
lived ion pair 27 and 28 (Scheme 3)18d,e that transfers the silyl
group before diffusion out of the solvent cage can occur.53 That
mechanism is less likely considering that no crossover was
observed even in more polar solvents.
Trimethylsilyl Peroxy Ether 1a. To a cooled (0 °C) solution of
hydroperoxide 429 (1.06 g, 5.88 mmol) in CH2Cl2 (20 mL) were
added Et3N (1.64 mL, 11.8 mmol) and Me3SiCl (0.82 mL, 6.5 mL).
The reaction mixture was warmed to ambient temperature over 1 h
and then partitioned between CH2Cl2 (20 mL) and H2O (30 mL).
The layers were separated, and the organic layer was washed with
brine (1 ꢀ 30 mL), passed through cotton, and concentrated under
reduced pressure. Purification by column chromatography (100%
hexanes) afforded the trimethylsilyl peroxy ether 1a (0.95 g, 64%) as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.7 Hz,
2H), 7.33 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 2.00 (sp, J =
6.9 Hz, 1H), 1.62 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0
Hz, 3H), 0.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 144.3, 127.5,
126.8, 88.1, 37.7, 18.8, 17.8, 17.7, -0.94; HRMS (ESI) m/z calcd for
C14H24O2SiNa (M þ Na)þ 275.1443, found 275.1443. Anal. Calcd
for C14H24O2Si: C, 66.61; H, 9.58. Found: C, 66.83; H, 9.59.
Triethylsilyl Peroxy Ether 1b. To a cooled (0 °C) solution of
hydroperoxide 429 (0.26 g, 1.4 mmol) in CH2Cl2 (5 mL) were added
Et3N (0.58 mL, 4.2 mmol) and Et3SiCl (0.35 mL, 2.1 mmol). The
reaction mixture was warmed to ambient temperature over 2 h and
then partitioned between EtOAc (20 mL) and H2O (30 mL). The
layers were separated, and the organic layer was washed with H2O
(2 ꢀ 20 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography (100%
hexanes) afforded triethylsilyl peroxy ether 1b (0.40 g, 95%) as a
colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.3 Hz,
2H), 7.32 (t, J = 7.6 Hz, 2H), 7.24 (m, 1H), 1.98 (sep, J = 6.9 Hz,
1H), 1.61 (s, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.86 (d, J = 6.9 Hz, 3H),
0.74 (d, J = 6.9 Hz, 3H), 0.68 (q, J = 7.6 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ144.4, 127.6, 126.9, 126.6, 88.2, 37.8, 19.3, 17.9, 7.0,
4.1; IR (thin film) 2957, 1236, 741 cm-1; HRMS (ESI) m/z calcd for
C17H30O2SiNa (M þ Na)þ 317.1913, found 317.1922. Anal. Calcd
for C17H30O2Si: C, 69.33; H, 10.27. Found: C, 69.34; H, 10.50.
Conclusions
A method to reduce silylated hydroperoxides with cata-
lytic quantities of phosphines has been demonstrated.54
(52) Authentic samples of the crossover products 31 and 32 were prepared
for comparison purposes. Details are provided as Supporting Information.
(53) (a) Winstein, S.; Klinedinst, P. E., Jr.; Robinson, G. C. J. Am. Chem.
Soc. 1961, 83, 885–895. (b) Loupy, A.; Tchoubar, B.; Astruc, D. Chem. Rev.
1992, 92, 1141–1165.
(54) Details on experimental procedures, handling, and purifying organic
peroxides are provided in the Supporting Information. Although no diffi-
culties were observed in handling and purifying organic peroxides in this
report, organic peroxides are potentially explosive: Zabicky, J. In The
Chemistry of Peroxides; Rappoport, Z., Ed.; Wiley: Chichester, UK, 2006;
Vol. 2, Chapter 7, pp 597-774.
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Harris et al.
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Benzyl Peroxy Ether 1c. The procedure of Moulines and co-
workers was used.55 To a cooled (0 °C) suspension of powdered
KOH pellets (0.058 g, 1.04 mmol) and tetrabutylammonium
bromide (0.030 g, 0.094 mmol) in CH2Cl2 (1 mL) were added
hydroperoxide 429 (0.170 g, 0.944 mmol) and benzyl bromide
(0.11 mL, 0.94 mmol) in CH2Cl2 (1 mL) by addition funnel. The
reaction mixture was warmed to ambient temperature over 4 h
and then decanted into H2O (2 mL). The layers were separated,
and the aqueous layer was extracted with pentane (3 ꢀ 2 mL).
The organic layers were combined, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by col-
umn chromatography afforded benzyl peroxy ether 1c as a
colorless oil (0.16 g, 61%): 1H NMR (400 MHz, CDCl3) δ
7.43 (m, 2H), 7.31 (m, 8H), 4.93 (m, 2H), 2.01 (sep, J = 6.9 Hz,
1H), 1.63 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 136.7, 129.3, 128.4,
128.2, 127.8, 126.9, 126.8, 87.9, 77.1, 37.3, 18.4, 17.9, 17.8; IR
(thin film) 2964, 1371, 1028, 756, 698 cm-1; HRMS (ESI) m/z
calcd for C18H22O2Na (M þ Na)þ 293.1518, found 293.1519.
Peroxy Ketal 1d. The procedure of Dussault and co-workers
was used.15a To a cooled (0 °C) solution of hydroperoxide 429
(0.111 g, 0.616 mmol) and pyridinium p-toluenesulfonate
(PPTS) (0.015 g, 0.062 mmol) in CH2Cl2 (20 mL) was added
2-methoxypropene (0.085 mL, 0.92 mmol). After 1 h at 0 °C, a
solution of saturated NaHCO3 (10 mL) was added. The layers
were separated, and the aqueous layer was extracted with CH2Cl2
(3 ꢀ 10 mL). The organic layers were combined, passed through
cotton, and concentrated under reduced pressure. Purification by
column chromatography (5-10% EtOAc/hexanes) afforded the
Silyl Ether 12 (Table 3, Entry 2). The general procedure was
followed using silyl peroxide 5 (0.123 g, 0.387 mmol), PPh3
(0.0051 g, 0.019 mmol), Ti(O-i-Pr)4 (0.057 mL, 0.19 mmol), and
TMDS (0.141 mL, 0.774 mmol). Purification by column chro-
matography (10% Et2O/hexanes) afforded silyl ether 12 (0.077
g, 79%) and the corresponding free alcohol (0.0068 g, 9%) as
colorless oils. Analytical data for silyl ether 12: 1H NMR (400
MHz, CDCl3) δ 3.94 (m, 4H), 1.63 (m, 2H), 1.44 (m, 4H), 1.32 (s,
3H), 1.19 (s, 6H), 0.94 (t, J = 7.9 Hz, 9H), 0.56 (q, J = 7.9 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 110.4, 73.6, 64.9, 45.4, 39.9,
30.1, 23.9, 19.3, 7.3, 7.0; IR (thin film) 2957, 1474, 1391, 1260,
1081, 761 cm-1; HRMS (CI) m/z calcd for C16H35O3Si (M þ
H)þ 303.2355, found 303.2368. Anal. Calcd for C16H34O3Si: C,
63.65; H, 11.33. Found: C, 63.56; H, 11.31.
Deprotected Alcohol (Table 3, entry 2): 1H NMR (500 MHz,
CDCl3) δ 3.94 (m, 4H), 1.65 (m, 2H), 1.62 (br s, 1H), 1.48 (m,
4H), 1.33 (s, 3H), 1.22 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
110.3, 71.2, 64.8, 44.2, 39.8, 29.5, 24.0, 19.1; IR (thin film) 3403,
2968, 1377, 1189, 1060, 872 cm-1; HRMS (ESI) m/z calcd for
C10H20O3Na (M þ Na)þ 211.1310, found 211.1313.
Silyl Ether 13 (Table 3, Entry 3). The general procedure was
followed using silyl peroxide 6 (0.145 g, 0.594 mmol), PPh3
(0.0078 g, 0.029 mmol), Ti(-Oi-Pr)4 (0.088 mL, 0.29 mmol), and
TMDS (0.217 mL, 1.19 mmol). Purification by column chro-
matography (0-2% CH2Cl2/pentane) afforded silyl ether 13 as
a colorless oil (0.063 g, 46%). Spectroscopic data match those
reported in the literature:56 1HNMR(400MHz, CDCl3) δ1.65 (m,
2H), 1.54 (m, 2H), 1.46 (m, 1H), 1.35 (m, 4H), 1.26 (m, 1H), 1.20 (s,
3H), 0.95 (t, J = 7.9 Hz, 9H), 0.57 (q, J = 7.9 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 72.7, 40.8, 30.0, 26.1, 22.9, 7.4, 7.2; IR (thin
film) 2938, 1460, 1170, 1027, 742 cm-1; HRMS (CI) m/z calcd for
C13H29OSi (M þ H)þ 229.1988, found 229.1983. Anal. Calcd for
C13H28OSi: C, 68.35; H, 12.35. Found: C, 68.08; H, 12.18.
Silyl Ether 14 (Table 3, Entry 4). The general procedure was
followed using silyl peroxide 7 (0.174 g, 0.674 mmol), PPh3
(0.0088 g, 0.034 mmol), Ti(O-i-Pr)4 (0.10 mL, 0.34 mmol), and
TMDS (0.247 mL, 1.35 mmol). Purification by column chro-
matography (5-10% CH2Cl2/hexanes) afforded silyl ether 14 as
a colorless oil (0.107 g, 66%). A previous literature report does
not provide analytical data for the compound:57 1H NMR (500
MHz, CDCl3) δ 3.80 (m, 1H), 1.66 (m, 7H), 1.51 (td, J = 5.8,
11.7 Hz, 4H), 1.43 (m, 3H), 0.95 (t, J = 8.0 Hz, 9H), 0.58 (q, J =
8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 72.7, 35.7, 27.6,
25.6, 23.1, 7.1, 5.1; IR (thin film) 2925, 1465, 1238, 1068, 1027,
742 cm-1; HRMS (CI) m/z calcd for C14H34NOSi (M þ NH4)þ
260.2410, found 260.2405. Anal. Calcd for C14H30OSi: C, 69.35;
H, 12.47. Found: C, 69.15; H, 12.60.
1
peroxy ketal 1d as a colorless oil (0.13 g, 82%): H NMR (400
MHz, CDCl3) δ 7.41 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 3.24 (s,
3H), 2.01 (sp, J = 6.9 Hz, 1H), 1.63 (s, 3H), 1.39 (s, 3H), 1.29 (s,
3H), 0.93 (d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 144.8, 127.6, 126.8, 126.7, 104.0, 86.7, 49.4,
37.6, 23.9, 22.7, 18.6, 18.0, 17.9; IR (thin film) 2991, 1446, 1369,
1207, 1072, 854 cm-1; HRMS (ESI) m/z calcd for C15H24O3Na
(M þ Na)þ 275.1623, found 275.1625. Anal. Calcd for C15H24-
O3: C, 71.39; H, 9.59. Found: C, 71.68; H, 9.67.
General Procedure for Catalytic Reduction of Silyl Peroxides
1b and 5-11. To a solution of the silyl peroxide (1.0 equiv) in a
threaded screw-cap vial in toluene (0.3 M) were added PPh3
(0.05 equiv), Ti(O-i-Pr)4 (0.5 equiv), and 1,1,3,3-tetramethyldi-
siloxane (TMDS, 2.0 equiv). The vial was sealed, and the
solution was heated to 100 °C (oil bath) for 24 h. The reaction
mixture was then cooled to ambient temperature, transferred to
a separate flask with EtOAc, and hydrolyzed with an equal
volume of 1 N NaOH. After 10 h, the layers were separated, and
the aqueous layer was extracted with EtOAc. The organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
afforded the silyl ethers as colorless oils.
Silyl Ether 2b (Table 3, Entry 1). The general procedure was
followed using silyl peroxide 1b (0.110 g, 0.372 mmol), PPh3
(0.0048 g, 0.019 mmol), Ti(O-i-Pr)4 (0.055 mL, 0.19 mmol), and
TMDS (0.136 mL, 0.744 mmol). Purification by column chroma-
tography (5% CH2Cl2/hexanes) afforded silyl ether 2b as a color-
less oil (0.76 g, 73%): 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J =
7.4 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 1.86
(sp, J = 6.8 Hz, 1H), 1.56 (s, 3H), 0.90 (t, J = 8.0 Hz, 9H), 0.82 (d,
J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H), 0.52 (m, 6H); 13C NMR
(125 MHz, CDCl3) δ 148.5, 127.5, 126.3, 126.2, 79.4, 41.4, 24.5,
17.9, 17.8, 7.4, 7.0; IR (thin film) 2956, 1456, 1371, 1236, 1128, 802,
701 cm-1; HRMS (ESI) m/z calcd for C17H30OSiNa (M þ Na)þ
301.1964, found 301.1962. Anal. Calcd for C17H30OSi: C, 73.31;
H, 10.86. Found: C, 73.19; H, 10.80.
Silyl Ether 15 (Table 3, Entry 5). The general procedure was
followed using silyl peroxide 8 (0.107 g, 0.403 mmol), PPh3
(0.0053 g, 0.020 mmol), Ti(O-i-Pr)4 (0.059 mL, 0.20 mmol), and
TMDS (0.148 mL, 0.805 mmol). Purification by column chro-
matography (2-6% CH2Cl2/hexanes) afforded silyl ether 15 as
a colorless oil (0.074 g, 73%). Spectroscopic data match those
reported in the literature:58 1H NMR (400 MHz, CDCl3) δ 7.29
(m, 4H), 7.22 (m, 1H), 4.56 (t, J = 6.2 Hz, 1H), 1.69 (m, 2H),
0.87 (m, 12H), 0.52 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
145.8, 128.1, 127.0, 126.2, 76.4, 33.9, 10.3, 7.0, 5.1; IR (thin film)
2958, 2877, 1105, 1056, 1010 cm-1; HRMS (ESI) m/z calcd for
C15H26OSiNa (M þ Na)þ 273.1651, found 273.1658.
Silyl Ether 16 (Table 3, Entry 6). The general procedure was
followed using silyl peroxide 9 (0.161 g, 0.543 mmol), PPh3
(0.0071 g, 0.027 mmol), Ti(O-i-Pr)4 (0.080 mL, 0.27 mmol), and
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5090 J. Org. Chem. Vol. 75, No. 15, 2010

Harris et al.
JOCArticle
TMDS (0.20 mL, 1.1 mmol). Purification by column chroma-
tography (2.5-5% Et2O/hexanes) afforded silyl ether 16 as a
colorless oil (0.12 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.35
(m, 4H), 7.30 (m, 1H), 4.56 (m, 2H), 4.00 (m, 1H), 3.43 (dd, J =
5.7, 9.4 Hz, 1H), 3.31 (dd, J = 5.8, 9.4 Hz, 1H), 1.19 (d, J = 6.2
were combined, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by column chromatogra-
phy (2-8% CH2Cl2/hexanes) afforded recovered silyl peroxy
ether 1b (0.019 g, 40%) and reduced silyl ether 2b (0.021 g, 42%)
as colorless oils. Deprotection of silyl peroxy ether 1b with
TBAF (0.210 mL, 0.210 mmol, 1 M) in THF (1 mL) gave
(þ)-(R)-hydroperoxide 4 with a 97% ee as determined by chiral
HPLC [Chiracel OD-H column (250 mm ꢀ 4.6 mm i.d) with
Hz, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.61 (q, J = 7.9 Hz, 6H); 13
C
NMR (100 MHz, CDCl3) δ 138.8, 128.5, 127.8, 127.7, 76.4, 73.5,
67.7, 21.3, 7.0, 5.1; IR (thin film) 2955, 1457, 1111, 1018, 741
cm-1; HRMS (CI) m/z calcd for C16H32NO2Si (M þ NH4)þ
298.2202, found 298.2196. Anal. Calcd for C16H28O2Si: C,
68.52; H, 10.06. Found: C, 68.34; H, 10.01.
i-PrOH/hexanes (5:95 v/v), flow rate 1.0 mL min-1, detection
3
by UV absorbance at 220 nm, tR major: 9.342 min, tR minor:
15.583 min]. Deprotection of silyl ether 2b with TBAF (0.200 mL,
0.200 mmol, 1 M) in THF (1 mL) gave (þ)-(R)-alcohol 3 with a
97% ee as determined by chiral HPLC [Chiracel OD-H column
(250 mm ꢀ 4.6 mm i.d.) with i-PrOH/hexanes (5:95 v/v), flow
Silyl Ether 17 (Table 3, Entry 7). The general procedure was
followed using silyl peroxide 10 (0.110 g, 0.543 mmol), PPh3
(0.0054 g, 0.021 mmol), Ti(O-i-Pr)4 (0.061 mL, 0.21 mmol), and
TMDS (0.151 mL, 0.823 mmol). Purification by column chro-
matography (0-5% Et2O/pentane) afforded silyl ether 17 as a
colorless oil (0.071 g, 69%): 1H NMR (500 MHz, CDCl3) δ 7.26
(m, 2H), 7.18 (m, 3H), 3.98 (sext, J = 6.1 Hz, 1H), 2.78 (dd, J =
13.2, 6.6 Hz, 1H), 2.65 (dd, J = 13.2, 6.3 Hz, 1H), 1.15 (d, J =
6.1 Hz, 3H), 0.89 (t, J = 8.0 Hz, 9H), 0.49 (m, 6H); 13C NMR
(125 MHz, CDCl3) δ 139.6, 129.8, 128.3, 126.2, 70.1, 46.7, 23.8,
rate 1.0 mL min-1, detection by UV absorbance at 220 nm, tR
3
major: 6.917 min, tR minor: 5.725 min].
Labeled Phosphine Oxide 22 (eq 7). To a cooled (0 °C) solution
of labeled hydroperoxide 19 (0.049 g, 0.37 mmol) in CDCl3
(0.80 mL) was added PPh3 (0.098 g, 0.37 mmol). After 6 h,
analysis of the unpurified reaction mixture by 17O NMR
spectroscopy indicated a broad resonance at δ 47 ppm, which
corresponds to labeled Ph3Pd17O (22)47 (Figure 3). No other
visible 17O resonances were observed.
Labeled Phosphine Oxide 22 (eq 8). To a solution of the
labeled silyl peroxide 20 (0.067 g, 0.33 mmol) in CDCl3 (0.80
mL) was added PPh3 (0.087 g, 0.33 mmol). The reaction mixture
was heated to 50 °C (oil bath) for 8 h. Analysis of the unpurified
reaction mixture by 17O NMR spectroscopy indicated a broad
resonance at δ 47 ppm, which corresponds to labeled Ph3Pd17O
(22)47 (Figure 3). No other visible 17O resonances were observed.
7.0, 5.0; IR (thin film) 2958, 2877, 1259, 1088, 1029, 800 cm-1
;
HRMS (CI) m/z calcd for C15H30NOSi (M þ NH4)þ 268.2097,
found 268.2093. Anal. Calcd for C15H26OSi: C, 71.93; H, 10.46.
Found: C, 71.81; H, 10.45.
Silyl Ether 18 (Table 3, Entry 8). The general procedure was
followed using silyl peroxide 11 (0.125 g, 0.399 mmol), PPh3
(0.0052 g, 0.020 mmol), Ti(O-i-Pr)4 (0.059 mL, 0.20 mmol), and
TMDS (0.150 mL, 0.797 mmol). Purification by column chro-
matography (5% CH2Cl2/hexanes) afforded silyl ether 18 as a
colorless oil (0.093 g, 79%): 1H NMR (500 MHz, CDCl3) δ 3.81
(m, 1H), 1.62 (m, 2H), 1.37 (m, 20H), 0.96 (t, J = 8.0 Hz, 9H),
0.59 (q, J = 8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 69.9,
32.8, 24.8, 24.4, 23.5, 23.4, 21.1, 7.2, 5.2; IR (thin film) 2938,
1469, 1096, 1060, 724 cm-1; HRMS (CI) m/z calcd for C18H39-
OSi (M þ H)þ 299.2770, found 299.2765. Anal. Calcd for
C18H38OSi: C, 72.41; H, 12.83. Found: C, 72.62; H, 13.03.
(þ)-(R)-Silyl Peroxide 1b. To a solution of enantiomerically
enriched (þ)-(R)-silyl peroxide 1b29 (0.049 g, 0.17 mmol)
in toluene (0.6 mL) were added PPh3 (0.002 g, 0.008 mmol),
Ti(O-i-Pr)4 (0.024 mL, 0.084 mmol), and TMDS (0.061 mL, 0.33
mmol). The reaction mixture was heated to 100 °C (oil bath) for
8 h. GC analysis of the unpurified reaction mixture showed a
51:49 ratio of starting silyl peroxide 1b (GC tR = 10.530 min)
and silyl ether 2b (GC tR = 10.109 min). The reaction mixture
was poured into EtOAc (5 mL) and hydrolyzed with 1 N NaOH
(2 mL). After 8 h, the layers were separated, and the aqueous
layer was extracted with EtOAc (3 ꢀ 5 mL). The organic layers
Acknowledgment. This research was supported by the
National Science Foundation (CHE-0848121). J.R.H. thanks
Eli Lilly for a graduate fellowship. M.T.H. thanks Allergan
Pharmaceuticals for an undergraduate fellowship and the
Undergraduate Research Opportunities Program (UCI) for
support. K.A.W. thanks Amgen and Eli Lilly for awards to
support research. We thank Professor Alan Heyduk (UCI)
for helpful discussions, Dr. Phil Dennison (UCI) for assis-
tance with NMR spectrometry, Dr. John Greaves and
Ms. Shirin Sorooshian (UCI) for mass spectrometry, and
Dr. Evgeny Fadeev (UCI) for EPR spectroscopy.
Supporting Information Available: Complete experimental
procedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5091