New strategies for protecting group chemistry: Synthesis, reactivity, and indirect oxidative cleavage of para-siletanylbenzyl ethers

Article abstract of DOI:10.1021/jo802229p

Reported herein is a new entry in the growing arsenal of arylmethyl ether protecting groups. The parasiletanylbenzyl (PSB) ether is electronically similar to the benzyl ether. Cleavage of the PSB ether is accomplished under mild conditions-involving alkaline hydrogen peroxide - that are unique among cleavage protocols for arylmethyl ethers. Furthermore, the PSB group affords the user new flexibility in the implementation of protecting group strategies that revolve around multiple arylmethyl ether protecting groups. In addition to hydrogen peroxide-based cleavage protocols, conversion of a PSB ether into a para-methoxybenzyl (PMB) ether and assembly of a PSB ether from a pre-existing para-bromobenzyl (PBB) ether are described. Finally, a new reagent for installing PSB ethers under neutral "mix and heat" conditions is reported.

Full text of DOI:10.1021/jo802229p

New Strategies for Protecting Group Chemistry: Synthesis,
Reactivity, and Indirect Oxidative Cleavage of para-Siletanylbenzyl
Ethers
Sami F. Tlais, Hubert Lam,† Sarah E. House,‡ and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306-4390
gdudley@chem.fsu.edu
ReceiVed October 9, 2008
Reported herein is a new entry in the growing arsenal of arylmethyl ether protecting groups. The para-
siletanylbenzyl (PSB) ether is electronically similar to the benzyl ether. Cleavage of the PSB ether is
accomplished under mild conditionssinvolving alkaline hydrogen peroxidesthat are unique among
cleavage protocols for arylmethyl ethers. Furthermore, the PSB group affords the user new flexibility in
the implementation of protecting group strategies that revolve around multiple arylmethyl ether protecting
groups. In addition to hydrogen peroxide-based cleavage protocols, conversion of a PSB ether into a
para-methoxybenzyl (PMB) ether and assembly of a PSB ether from a pre-existing para-bromobenzyl
(PBB) ether are described. Finally, a new reagent for installing PSB ethers under neutral “mix and heat”
conditions is reported.
Protecting Group Strategies
protecting group must occur easily and in high yield; (2) the
installed protecting group must render inert an otherwise reactive
site during a synthetic sequence aimed at affecting other regions
of the molecular system; and (3) the removal (cleavage) of the
protecting group must occur easily and under mild conditions
at the appropriate point in the synthetic scheme. Orthogonal
reactivity with other common protecting groups is especially
valuable for highly functionalized systems.
Protecting group strategies1 are indispensable to the general
pursuit of synthetic polyketides,2 oligosaccharides,3 peptides,4
and other complex small molecule structures5 of potential
relevance to human health. A desirable protecting group satisfies
three main criteria: (1) the installation (formation) of the
† Current address: General Electric Company-GE Global Research, One
Research Circle, Niskayuna, NY.
‡ Current address: Department of Chemistry, Latimer Hall, University of
California, Berkeley, CA.
Arylmethyl Protecting Groups
(1) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in Organic
Synthesis; 4th ed.; John Wiley and Sons: Hoboken, NJ, 2007. Kocienski, P. J.
Protecting Groups, 3rd ed.; Thieme: Stuttgart, Germany, 2003.
(2) Mickel, et al, S. J. Large-Scale Synthesis of the Anti-Cancer Marine
Natural Product (+)-Discodermolide. Part 1: Synthetic Strategy and Preparation
of a Common Precursor. Org. Process Res. DeV. 2004, 8, 92–100. Part 2:
Synthesis of Fragments C1-6 and C9-14, 101-106. Part 3: Synthesis of
Fragment C15-21, 107-112. Part 4: Preparation of Fragment C7-24, 113-
121. Part 5: Linkage of Fragments C1-6 and C7-24 and finale, 122-130.
(3) (a) PreparatiVe Carbohydrate Chemistry; Hanessian, S. , Ed.; Marcel
Dekker: New York, 1997. (b) The Organic Chemistry of Sugars; Levy, D. E.,
Fu¨gedi, P., Eds.; Taylor & Francis: Boca Raton, FL, 2006.
Benzyl and modified benzyl ethers are among the most
common and important protecting groups in synthetic chemistry.
Benzyl ethers are robust, yet they provide cleavage mechanisms
unique among alkyl ethers, including hydrogenolysis, dissolving
metal reduction, electron-transfer oxidation (i.e., DDQ oxida-
tion), and acidic cleavage under a range of experimental
conditions. Electronic tuning of the aromatic ring provides an
expanded range of valuable properties, resulting in a series of
arylmethyl protecting groups that includes para-methoxybenzyl
(4) Bray, B. L. Large-Scale Manufacture of Peptide Therapeutics by Chemical
Synthesis. Nat. ReV. Drug DiscoVery 2003, 2, 587–593.
1876 J. Org. Chem. 2009, 74, 1876–1885
10.1021/jo802229p CCC: $40.75 2009 American Chemical Society
Published on Web 01/30/2009

para-Siletanylbenzyl Ethers
SCHEME 1. Tamao-type Oxidation of Organosiletanes
FIGURE 1. Benzyl transfer reagent 6 and related reagents.
siletane ring occurs rapidly under the mildest of Tamao oxidation
conditions,13 organosiletanes undergo carbosilane oxidations
without affecting a pendant silyl ether (Scheme 1) and at rates
comparable to even the most activated Tamao substrates.10
Notably, arylsiletanes provide convenient access to phenols
without requiring the separate “priming” step of the Tamao-
Fleming reaction, which often involves cleavage of an
aryl-silicon bond.14 When functionalized at the para-position
with an alkoxymethyl substituent, the arylsiletane oxidation
provides easy access to labile PHB ethers.15 From the perspec-
tive of protecting group strategies, the aforementioned para-
(alkoxymethyl)-arylsiletane is more appropriately referred to as
an alkyl PSB ether (PSB ) para-siletanylbenzyl).
(PMB), dimethoxybenzyl (DMB), napthylmethyl (NAP), para-
bromobenzyl (PBB),6 and many others.
Not included in this list is the relatively unstable para-
hydroxybenzyl (PHB) group, which decomposes to release the
unprotected substrate under very mild conditions.7 Jobron and
Hindsgaul recently drew attention to the advantage of employing
protected-PHB ethers in carbohydrate synthesis by introducing
para-acetoxybenzyl (PAB) and para-(tert-butyldimethylsilyl)-
oxybenzyl protecting groups, the cleavage of which is promoted
by first cleaving the acetate ester or silyl ether, respectively.8
The use of protected-PHB ethers is well suited to carbohydrate
synthesis. Arylmethyl protecting groups offer minimal electronic
impact on glycosyl donors, in contrast to the more electron-
withdrawing acetate esters and silyl ethers.9 Outside of glyco-
sylation reactions, however, it is unclear how much is gained
by employing protected-PHB protecting groups over direct use
of an acetyl or silyl moiety, especially as formation of protected-
PHB ethers has thus far only been demonstrated on primary
alcohols.8
Formation of Arylmethyl Ethers
Traditionally, preparation of arylmethyl ethers from alcohols
is accomplished by one of two strategies: Williamson ether
synthesis under basic conditions or under acidic conditions using
trichloroacetimidates.16 Neither strategy was found, generally,
to be appropriate for making the PSB ethers that are the subject
of this article.15 Upon exposure to alkali metal alkoxides, such
as are employed in the Williamson ether synthesis protocol,
siletanes undergo ring-opening polymerization to give rise to
carbosilane polymers.17 Under acidic conditions, arylsilanes are
subject to protiodesilylation.18
A new arylmethylation strategy had to be developed in order
to address these limitations, with an aim of eventually identifying
a general method for making PSB ethers. Because trichloro-
acetimidates require acidic conditions that were not compatible
with the aryl-silicon subunit, a search began for a reagent
analogous to benzyl trichloroacetimidate (BTCA, Figure 1) that
could be activated by N-alkylation rather than N-protonation.
Initial efforts, focusing on the preparation of simple benzyl
ethers,19 revealed that N-methylation of 2-benzyloxypyridine20
Arylsiletane Oxidations
Earlier methodology from these laboratories10 illustrated the
Tamao-type oxidation11 of silacyclobutanes (siletanes),12 in
which the strained organosiletane undergoes a rapid ring-opening
reaction promoted by aqueous fluoride to set the stage for
eventual oxidation of the carbon-silicon bonds. Organosiletanes
are stable to routine purification, handling, and even acidic
hydrolysis of silyl ethers. Because hydrolytic opening of the
(5) Seletsky, B. M.; Wang, Y.; Hawkins, L. D.; Palme, M. H.; Habgood,
G. J.; DiPietro, L. V.; Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.;
Kishi, Y.; Littlefield, B. A.; Yu, M. J. Structurally Simplified Macrolactone
Analogues of Halichondrin B. Bioorg. Med. Chem. Lett. 2004, 14, 5547–5550.
(6) Plante, O.; Buchwald, S. L.; Seeberger, P. H. Halobenzyl Ethers As
Protecting Groups for Organic Synthesis. J. Am. Chem. Soc. 2000, 122, 7148–
7149.
(7) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.; Murai, A. Convergent
Synthesis of the BCDE-Ring Part of Ciguatoxin. Synlett 2002, 1835–1838.
(8) Jobron, L.; Hindsgaul, O. Novel Para-Substituted Benzyl Ethers for
Hydroxyl Group Protection. J. Am. Chem. Soc. 1999, 121, 5835–5836.
(9) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. “Armed”
and “Disarmed” N-Pentenyl Glycosides in Saccharide Couplings Leading to
Oligosaccharides. J. Am. Chem. Soc. 1988, 110, 5583–5584.
(10) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Oxidation of Carbon-Silicon
Bonds: The Dramatic Advantage of Strained Siletanes. Org. Lett. 2003, 5, 4571–
4573.
(11) Tamao, K. Oxidative Cleavage of the Carbon-Silicon Bond: Develop-
ment, Mechanism, Scope, and Limitations. In AdVances in Silicon Chemistry;
Larson, G. L., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 3, pp 1-62. Jones,
G. R.; Landais, Y. The Oxidation of the Carbon-Silicon Bond. Tetrahedron 1996,
52, 7599–7662.
(13) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Nucleophilic Hydroxy-
methylation of Carbonyl Compounds: 1-(Hydroxymethyl)cyclohexanol. Org.
Synth. 1990, 69, 96–105.
(14) Fleming, I. Silyl-to-Hydroxy Conversion in Organic Synthesis.
Chemtracts: Org. Chem. 1996, 1–64.
(15) Lam, H.; House, S. E.; Dudley, G. B. the Para-Siletanylbenzyl (PSB)
Ether: A Peroxide-Cleavable Protecting Group for Alcohols and Phenols.
Tetrahedron Lett. 2005, 46, 3283–3285.
(16) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck, C. A Useful
Application of Benzyl Trichloroacetimidate for the Benzylation of Alcohols.
Tetrahedron 1993, 49, 1619–1624.
(17) Matsumoto, K.; Shimazu, H.; Deguchi, M.; Yamaoka, H. Anionic Ring-
Opening Polymerization of Silacyclobutane Derivatives. J. Polym. Sci., Part A:
Polym. Chem. 1997, 35, 3207–3216. Matsumoto, K.; Kage, S.; Matsuoka, H.
Synthesis of Water-Dispersible, Fluorinated Particles with Grafting Sulfonate
Chains by the Core Crosslinking of Block Copolymer Micelles. J. Polym. Sci.,
Part A: Polym. Chem. 2007, 45, 1316–1323. Sheikh, R. K.; Tharanikkarasu,
K.; Imae, I.; Kawakami, Y. Silacyclobutane As “Carbanion Pump” in Anionic
Polymerization. 2. Effective Trapping of the Initially Formed Carbanion by
Diphenylethylene. Macromolecules 2001, 34, 4384–4389.
(18) For a systematic study of protodesilylation of various arylsilanes, see:
Utimoto, K.; Otake, Y.; Yoshino, H.; Kuwahara, E.; Oshima, K.; Matsubara, S.
The Rate Enhancement Effect of Protodesilylation of Arylsilane Derivatives.
Bull. Chem. Soc. Jpn. 2001, 74, 753–754.
(12) For a review of the chemistry of organosiletanes see: Kozytska, M. V.;
Dudley, G. B. Four-Membered Rings with One Silicon, Germanium, Tin, or
Lead Atom. In ComprehensiVe Heterocyclic Chemistry III; Katritsky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford,
U.K., 2008; Vol 2, pp 513-554.
(19) Poon, K. W. C.; House, S. E.; Dudley, G. B. A Bench-Stable Organic
Salt for the Benzylation of Alcohols. Synlett 2005, 3142–3144.
J. Org. Chem. Vol. 74, No. 5, 2009 1877

Tlais et al.
ethers are orthogonally compatible with other common protect-
ing groups, including MOM, TBS, PMB, and others.
Finally, the synthesis of PSB-OPT (1) is described in detail
as it is capable of delivering the PSB group onto the widest
range of alcohol substrates, including carbohydrates and second-
ary alcohols. The optimized synthesis of PSB-OPT features an
innovative technique for initiating the formation of Grignard
reagents.
FIGURE 2. Reagents for the synthesis of PSB ethers.
Results and Discussion
1. Formation of PSB Ethers. The first aspect of the develop-
ment of the para-siletanylbenzyl protecting group relates to the
synthesis of PSB ethers from a collection of representative
alcohols (Figure 3). This collection comprises primary and
secondary alcohols and phenols, which offers insight that can
be extrapolated to a wide range of potential substrates. Ad-
ditional specific substrates (carbohydrate and carboxylic acid)
are included as well.
1.1. Formation of Aryl PSB Ethers Using PSB-OH. Conver-
sion of phenols to the corresponding PSB ethers was best
accomplished under Mitsunobu conditions (Scheme 2) using
PSB-OH (9), providing ethers 17 (74%) and 18 (96%). Aryl-
methylation using PSB-Br under basic conditions was less
effective due to competing siletane polymerization.
1.2. Formation of PSB Ethers Using PSB-Br. Silver oxide-
mediated etherification protocols delivered PSB ethers with
limited efficiency (Table 1). Of the representative alcohols
screened, only the simple primary alcohol (13) gives rise to the
corresponding PSB ether in good yield (up to 83%). Aryl-
methylation of phenol 11 was reasonably efficient at best (70%),
whereas PSB ethers of secondary alcohols 20 and 21 were
obtained in only up to 50% and 38% yields, respectively.
Furthermore, these reactions were capricious, difficult to conduct
successfully, and required freshly prepared silver oxide for best
results. We concluded that PSB-Br 10 could not provide the
general solution that we sought for the synthesis of PSB ethers.
1.3. Formation of Secondary Alkyl PSB Ethers by Reduc-
tion of Dioxane Acetals. Regioselective reduction of benzylidene
acetals with DIBAL provides indirect access to secondary
arylmethyl ethers, including PSB ethers (Scheme 3).29 Con-
densation of 1,3-butanediol with acetal 8 provided 1,3-dioxane
23 (quantitative yield), the reduction of which with DIBAL
furnished PSB ether 24 in 97% yield. Glucopyranoside 25 was
readily protected as acetal 26 (Scheme 4). DIBAL reductive
ring opening of acetal 26 yielded a mixture of PSB ethers 27a
(81%) and 27b (15%).
1.4. Formation of Alkyl PSB Ethers from Alkyl PBB
Ethers. In light of difficulties associated with the direct
conversion of alcohols into PSB ethers using PSB-Br (section
1.1, above), a two-step process was developed to access PSB
ethers indirectly from para-bromobenzyl (PBB) ethers, which
are amenable to preparation using the Williamson ether syn-
thesis. First, the alcohol was treated with sodium hydride and
PBB-Br. With the PBB ether thus installed, conversion of the
aryl bromide moiety to the corresponding arylsiletane was
achieved under Barbier conditions to furnish the desired PSB
ethers (19-21, Scheme 5).
leads to a reagents2-benzyloxy-1-methylpyridinium triflate
(6)21sthat converts alcohols into benzyl ethers upon warming.23
Thus emerged a new benzyl ether synthesis, which has since
been extended to include reagents for the preparation of
PMB24-26 and halobenzyl ethers.27 Importantly, the new aryl-
methyl ether synthesis involves neutral conditions that are
applicable to the formation of PSB ethers (vide infra). This
methodology was inspired in part by Mukaiyama’s success with
acylation reactions using N-methylpyridinium salts as coupling
reagents.28
This article provides a detailed account of the development
of the PSB ether as an arylmethyl protecting group for alcohols
and phenols, with an emphasis on the synthesis of PSB ethers.
The direct formation of alkyl PSB ethers was not appropriately
addressed in previously reported studies,15,29 which instead
relied mostly on two-step protocols for preparing a limited range
of PSB ethers. Four different reagents with complementary
scope and limitations are now available for the synthesis of PSB
ethers (Figure 2): para-siletanylbenzaldehyde dimethyl acetal
8, para-siletanylbenzyl alcohol 9 (PSB-OH), para-siletanyl-
benzyl bromide 10 (PSB-Br), and para-siletanylbenzyl-oxypy-
ridinium triflate 1, referred to herein as PSB-OPT.
Two convenient peroxide oxidation methods for converting
PSB ethers into PHB ethers are outlined, along with relevant
applications of known protocols for cleaving PHB ethers.
Competition experiments illustrate the degree to which the PSB
(20) Serio Duggan, A. J.; Grabowski, E. J. J.; Russ, W. K. Phase-Transfer
Mediated Heteroaromatic Nucleophilic Substitution: Introduction of a ꢀ-Adr-
energic Blocking Moiety. Synthesis 1980, 573–575.
(21) Dudley, G. B. 2-Benzyloxy-1-Methylpyridinium Trifluoromethane-
sulfonate. In Electronic Encylopedia of Reagents for Organic Synthesis; Paquette,
L., Fuchs, P., Crich, D., Molander, G., Eds.; John Wiley & Sons: Chichester,
U.K., DOI: 10.1002/047084289X.rn00906.
(22) Poon, K. W. C.; Dudley, G. B. Mix-and-Heat Benzylation of Alcohols
Using a Bench-Stable Pyridinium Salt. J. Org. Chem. 2006, 71, 3923–3927.
Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Protection of Alcohols Using
2-Benzyloxy-1-Methylpyridinium Trifluoromethanesulfonate: Methyl (R)-(-)-
3-Benzyloxy-2-Methyl Propanoate. Org. Synth. 2007, 84, 295–305.
(23) Dudley Benzylation Reagent. ChemFiles 2007, 7 (3), 3. Sigma-Aldrich
product number: 679674.
(24) Nwoye, E. O.; Dudley, G. B. A Method for the Synthesis of Para-
Methoxybenzyl (PMB) Ethers Under Effectively Neutral Conditions. Chem.
Commun. 2007, 1436–1437.
(25) Stewart, C. A.; Peng, X.; Paquette, L. A. An Efficient Means for
Generating P-Methoxybenzyl (PMB) Ethers under Mildly Acidic Conditions.
Synthesis 2008, 433–437.
(26) Also now commercially available: Sigma-Aldrich product number
701440.
(27) Albiniak, P. A.; Amisial, S. M.; Dudley, G. B.; Hernandez, J. P.; House,
S. E.; Matthews, M. E.; Nwoye, E. O.; Reilly, M. K.; Tlais, S. F. Stable
Oxypyridinium Triflate (OPT) Salts for the Synthesis of Halobenzyl Ethers. Synth.
Commun. 2008, 38, 656–665.
(28) Armstrong, A. 2-Chloro-1-Methylpyridinium Iodide. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley and Sons:
New York, New York, 1995; Vol. 2, pp 1174-1175. Mukaiyama, T. New
Synthetic Reactions Based on the Onium Salts of Aza-Arenes. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 707–721.
This approach provided the compounds needed to advance
our initial studies on the cleavage of PSB ethers.15 In a more
general context, this sequence represents conversion of a PBB
ether into a PSB ether on synthetic intermediates that can tolerate
the aforementioned Barbier conditions, which provides valuable
(29) House, S. E.; Poon, K. W. C.; Lam, H.; Dudley, G. B. P-Siletanylben-
zylidene Acetal: Oxidizable Protecting Group for Diols. J. Org. Chem. 2006,
71, 420–422.
1878 J. Org. Chem. Vol. 74, No. 5, 2009

para-Siletanylbenzyl Ethers
FIGURE 3. Representative alcohols employed as test substrates.
TABLE 1. Formation of PSB Ethers Using PSB-Bra
a Yield of individual experiments highly dependent on the quality of 10, silver oxide, and other reaction variables.
SCHEME 2. Synthesis of PSB Ethers Using the Mitsunobu
Reaction
SCHEME 4. Formation and Reductive Ring Opening of
Glucopyranoside Dioxane Acetal 26
SCHEME 3. Synthesis of a Secondary PSB Ether via a
1,3-Dioxane Acetal
SCHEME 5. Two-Step Assembly of PSB Ethers via PBB
Ethers
flexibility to arylmethyl protecting group strategies. For example,
Murai employed a conceptually similar sequence to remove a
PBB ether via an arylborane in a synthetic approach to
ciguatoxin.7 The corresponding arylsiletane could be cleaved
under similar conditions or advanced through unrelated synthetic
operations prior to releasing the free alcohol. Despite potential
value in such highly specialized applications, we continued to
work toward alternative, general methods for preparing PSB
ethers.
1.5. Formation of Alkyl PSB Ethers Using PSB-OPT. The
viability of PSB-OPT and its immediate precursor, PSB-OP 29,
as general reagents for the synthesis of PSB ethers is the key
finding of this article. Given the lability of siletanes to sodium
alkoxide nucleophiles and the general incompatibility of aryl-
siletanes to strong acid, the ideal method for preparing PSB
ethers involves neutral conditions. PSB-OPT and PSB-OP
enable such a method. Our findings using benzyl-transfer reagent
6 (Figure 1) guided the development of PSB-OPT.
A range of representative primary and secondary alcohols
give way to PSB ethers upon warming in the presence of PSB-
J. Org. Chem. Vol. 74, No. 5, 2009 1879

Tlais et al.
TABLE 2. Formation of Alkyl PSB Ethers Using PSB-OPT (1)a
b
a See Supporting Information for details. Unless otherwise indicated, 2.0 equiv of 28, MeOTf, and MgO employed relative to ROH. Estimated by H
1
NMR, unless otherwise noted; isolated material contaminated with varying amounts of di-PSB ether 41.
c Yield in parentheses refers to synthesis of the corresponding benzyl ether using benzyl reagent 6, as reported in the literature. d Isolated yield of pure
material judged to be >95% pure by 1H NMR. e For this experiment, triflate 1 was prepared and isolated prior to use, and 3.0 equiv of 28 and MgO
were employed relative to ROH. f Reported synthesis of the benzyl ether, included for the sake of comparison, using benzyl reagent 6 and MgO.
g Obtained as a mixture of mono- and dibenzylated products. No other benzylation protocols were more effective for this transformation, and the authors
ultimately changed their protecting group strategy.
OPT (Table 2, entries 1-5). Analogous benzylation reactions
are recounted for comparison (yields given in parentheses), along
with a few additional examples from the recent literature (entries
7-9). 3-Phenylpropanol, a simple primary alcohol, was con-
verted into the corresponding PSB ether in 90% by heating it
at 80 °C in the presence of 2 equiv of PSB-OPT (formed in
situ from PSB-OP and methyl triflate) and magnesium oxide
for 24 h (entry 1). PSB protection of secondary alcohols
1880 J. Org. Chem. Vol. 74, No. 5, 2009

para-Siletanylbenzyl Ethers
1-phenylethanol and menthol each proceeded in 88% yield
(entries 2 and 3). The Roche ester, which is susceptible to
ꢀ-elimination of its oxygen functionality, was protected as a
PSB ether (11 f 35, entry 4) in 71% yield. Additionally, glucose
derivative 30 was prepared in 91% yield using a slightly larger
excess (3.0 equiv) of preformed PSB-OPT 1 (entry 5).
The experiments described in entries 1-4 mirror previously
reported findings on the synthesis of benzyl ethers using reagent
6, so limitations of the arylmethyl transfer method are alluded
to in entries 6 and 9. Recently reported transformations for which
benzyl reagent 6 was uniquely successful (entries 7 and 8) are
also recounted for reference. We suggest that one can extrapolate
from these representative results to predict with confidence the
likely reactivity of various alcohols toward PSB-OPT under
similar conditions.
various protocols designed to cleave one protecting group or
the other. The anisyl and phenyl tags are easily distinguishable
by NMR spectroscopy, and we assume that their n-propyl chains
provide essentially equivalent chemical platforms for studying
the cleavage of the respective ethers. Entries 1 and 2 describe
orthogonal reactivity of PSB and PMB ethers under oxidative
conditions. The alkaline nucleophilic peroxide oxidation affects
only PSB ether 19, whereas the charge-transfer oxidation of
DDQ occurs preferentially at the electron-rich aromatic ring of
the PMB ether. Similarly, MOM ether 47b withstands the
Tamao oxidation but succumbs to aqueous hydrochloric acid,
which does not affect the PSB ether (entries 3 and 4). As we
showed in our original siletane oxidation study,10 TBS ethers
survived the mild Tamao conditions, and they cleaved under
acidic hydrolysis conditions to which the PSB group is inert
(entries 5 and 6). Finally, PSB ether 19 was recovered
unchanged from a reaction mixture that cleaved the Troc
carbonate of 47d (entry 8), but Troc carbonate 47d partially
hydrolyzed on exposure to alkaline peroxide (entry 7).
Implicit in this study is the assumption that these other
protecting groups will equally survive removal of the intermedi-
ate PHB ethers. We consider this assumption to be quite sound
in general because each of these protecting groups (with the
obvious exception of the PMB ether) can withstand conditions
that cleave arylmethyl ethers. PMB ethers are known32 to be
stable to FeCl3 under the conditions that we used to cleave PHB
ethers, so we chose to look specifically at cleavage of the PHB
ether in the presence of the PMB ether using DDQ (Scheme
6). By controlling the reaction stoichiometry and temperature,
we quickly obtained evidence to validate our assumption: The
PHB ether was removed in 82% yield, whereas the PMB ether
(47a) was recovered 85% yield.
Although not directly related to this orthogonality study, it
is interesting to note that PSB ethers can be converted into PMB
ethers (eq 4) under mild conditions that would not impact most
other protected or unprotected alcohols. The ability to convert
a given protecting group into an orthogonal protecting group
during multistep synthesissas opposed to employing a depro-
tection/reprotection sequencesadds valuable flexibility to pro-
tecting group strategies based on the PSB ether.
1.5. Formation of Akyl PSB Esters Using PSB-OPT.
Benzyl reagent 6 gives rise to benzyl esters upon reaction with
carboxylic acids.30 Similar reactivity of oxypyridinium 1 is
illustrated by the PSB esterification of acetylsalicylic acid in
84% yield (eq 1.5).
2. Cleavage of PSB Ethers. The cleavage of PSB ethers
was described in detail in our preliminary account of this work.15
The salient features are recounted here. Tamao-type oxidation
of the arylsiletane generates an intermediate PHB ether. In the
cases of protected phenols, the alkaline oxidation conditions
promote expulsion of the free phenols. In cases of protected
aliphatic alcohols, the intermediate PHB ethers are sufficiently
stable to be isolated prior to cleavage. A separate step is then
employed to release the free alcohol from the PHB ether.
Conditions for cleaving PHB ethers have been reported
elsewhere7,8 and include DDQ, iron trichloride, sodium meth-
oxide, and others. Of these, we focused on the use of DDQ
(conditions D) and iron trichloride (conditions E).
The PSB ethers prepared in this study were thus cleaved in
one- or two-step protocols (Table 3) that involved standard
Tamao conditions (conditions A). Alternatively, Woerpel’s
method31 (conditions B) provided PHB ethers faster and in
higher yield (compare entries 3 and 6 with 4 and 7), so this
protocol is recommended for substrates that can withstand the
more forcing conditions. PHB ethers release the original alcohols
upon subsequent treatment with either iron trichloride or DDQ.
Finally, as seen in entry 5, catalytic hydrogenolysis (conditions
C) efficiently removed PSB ethers, as expected by analogy to
electronically similar benzyl ethers.
3. Orthogonality and Reactivity Experiments. In order to
determine orthogonality with other common protecting groups,
a series of competition experiments were performed (Table 4).
The PSB ether of 3-phenylpropanol (19) was mixed with
protected versions of 3-(p-anisyl)propanol (47) and treated under
4. Synthesis of PSB Reagents. The arylsiletanes employed
in this methodology were prepared by coupling 1-chloro-1-
methylsiletane (28) with the requisite aryl Grignard reagent or,
similarly, with the aryl halide under Barbier conditions. The
applicability of Barbier conditions illustrates that arylsiletanes
are stable to organomagnesium nucleophiles even at elevated
temperature (refluxing THF). In contrast, organolithium reagents
(32) Kayser-Bricker, K. J.; Jordan, P. A.; Miller, S. J. Catalyst-Dependent
Syntheses of Phosphatidylinositol-5-Phosphate-Dic8 and Its Enantiomer. Tet-
rahedron 2008, 64, 7015–7120.
(33) Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. Synthesis of Benzyl Esters
Using 2-Benzyloxy-1-Methylpyridinium Triflate. J. Org. Chem. 2007, 72, 8962–
8964.
(34) Smitrovich, J. H.; Woerpel, K. A. Oxidation of Sterically Hindered
Alkoxysilanes and Phenylsilanes under Basic Conditions. J. Org. Chem. 1996,
61, 6044–6046.
(30) Legeay, J.-C.; Langlois, L. Nitrone [2 + 3]-Cycloadditions in Stereo-
controlled Synthesis of a Potent Proteasome Inhibitor: (-)-Omuralide. J. Org.
Chem. 2007, 72, 10108–10113. Caubert, V.; Masse´, J.; Retailleau, P.; Langlois,
N. Stereoselective Formal Synthesis of the Potent Proteasome Inhibitor:
Salinosporamide A. Tetrahedron Lett. 2007, 48, 381–384.
(31) Schmidt, J. P.; Beltraˆn-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid,
M.; Taylor, R. J. K. The First Synthesis of the Abc-Ring System of ’Upenamide.
Org. Lett. 2007, 9, 4041–4044.
(35) Sharma, G. V. M.; Reddy, C. G.; Krishna, P. R. Zirconium(IV) Chloride
Catalyzed New and Efficient Protocol for the Selective Cleavage of P-
Methoxybenzyl Ethers. J. Org. Chem. 2003, 68, 4574–4575.
J. Org. Chem. Vol. 74, No. 5, 2009 1881

Tlais et al.
TABLE 3. One- and Two-Step Cleavage of PSB Ethers
a See Supporting Information for details. Conditions A: 30% aqueous H2O2, KF, K2CO3, THF/MeOH, 50 °C. Conditions B: t-BuOOH, TBAF, DMF,
70 °C. Conditions C: H2, 10% Pd/C, EtOH. Conditions D: DDQ, CH2Cl2; Conditions E: FeCl3, CH2Cl2. b Overall yield for two steps.
are not suitable for the preparation of arylsiletanes because even
substoichiometric amounts of most organolithium reagents
promote anionic ring-opening polymerization of organosilet-
anes.17
PSB-OPT 1, like other oxypyridinium triflate reagents
prepared in these laboratories, arises by N-methylation of
2-PSBO-pyridine (29). However, the standard method for
preparing 2-pyridyl ethersspotassium hydroxide-promoted nu-
cleophilic aromatic substitution of 2-chloropyridinesis not
compatible with the siletane ring. Therefore, alternative synthetic
protocols were developed (vide infra).
8, PSB-OH 9, and PSB-Br 10, as described previously (Scheme
7).29 para-Bromobenzaldehyde dimethyl acetal (50) undergoes
Barbier coupling with 28 to furnish para-siletanylbenzaldehyde
dimethyl acetal (8) in 86-91% yield. Hydrolysis of 8 and
reduction with DIBAL provides PSB-OH 9 in 87-95% yield
over two steps. Finally, PSB-Br is available in 95% yield by
treating PSB-OH with Appel’s conditions (Ph3P, CBr4,
CH2Cl2).36
4.2. Synthesis of PSB-OPT (1) from para-Iodobenzyl
Alcohol. The standard method employed in these laboratories
(36) Appel, R. Tertiary Phosphane/Tetrachloromethane, A Versatile Reagent
for Chlorination, Dehydration, And P-N Linkage. Angew. Chem., Int. Ed. Engl.
1975, 14, 801–811.
4.1. Synthesis of PSB-Br (10) via 8 and 9. A straightforward
series of reactions sequentially provided PSB dimethyl acetal
1882 J. Org. Chem. Vol. 74, No. 5, 2009

para-Siletanylbenzyl Ethers
TABLE 4. Orthogonality in the Cleavage of PSB Ethers with Other Common Protecting Groups
entry
PG (47)
conditions
recovered PSB 19 (%)
recovered PG 47 (%)
yield of PHB 44 (%)
yield of 48 (%)
1
2
3
4
5
6
7
8
PMB (47a)
PMB (47a)
MOM (47b)
MOM (47b)
TBS (47c)
TBS (47c)
Troc (47d)
Troc (47d)
H2O2, KF
DDQ
H2O2, KF
6N HCl
H2O2, KF
AcOH, H2O
H2O2, KF
Zn, AcOH
s
94
s
85
s
90
s
96 (47a)
s
90 (47b)
s
88 (47c)
s
82
s
85
s
72
s
N.D.
s
s
96
s
86
s
98
N.D.
90
92
s
SCHEME 6. DDQ Oxidation of PHB Ether 44 in the
Presence of a PMB Ether
SCHEME 9. Preparation of para-Halogenated
2-Benzyloxypyridines
SCHEME 10. Synthesis of PSB-OP 29 from Aryl Iodide 54
SCHEME 7. Synthesis of PSB Reagents 8-10
yield if the potassium hydroxide pellets are thoroughly ground
with a mortar and pestle prior to use. Aryl halides 53 and 54
were converted to the corresponding Grignard reagents for
trapping with chlorosiletane 28.
SCHEME 8. Nucleophilic Substitution of 2-Chloropyridine
Initial attempts to generate aryl Grignard reagent 55 were
unsuccessful using either aryl bromide 53 or iodide 54,37 but
magnesium-iodide exchange38 furnished 55 (Scheme 10).
Subsequent addition of chlorosiletane 28 afforded PSBO-
pyridine 29 in 72% yield.
4.3. Synthesis of PSB-OPT from para-Bromobenzyl
Alcohol. A weakness in the synthesis of 1, as outlined in Scheme
10, is that para-iodobenzyl alcohol is prohibitively expensive39
compared to para-bromobenzyl alcohol.40,41 Although standard
methods for preparing Grignard reagents42 failed for this
(37) Multiple attempts to prepare Grignard 55 using activated magnesium
turnings under standard conditions were unsuccessful. Insertion does not occur
at room temperature, and it appears as though magnesium insertion into the
benzylic carbon-oxygen bond occurs upon prolonged heating, based on recovery
of bis-siletane 56 from the crude reaction mixture.
for preparing 2-pyridyl ethers is to heat 2-chloropyridine with
the corresponding alcohol in the presence of potassium hydrox-
ide (Scheme 8). Siletanes do not withstand such conditions, so
for the synthesis of 2-PSBO-pyridine 29 the siletane moiety
must be introduced last.
Thus, nucleophilic aromatic substitution of 2-chloropyridine
with para-bromobenzyl alcohol (51) and para-iodobenzyl
alcohol (52) was employed to provide aryl bromide 53 (97%
yield) and aryl iodide 54 (92% yield), respectively (Scheme 9).
Inclusion of 18-crown-6 in the reaction mixture increases the
efficiency of this coupling process,20,22,27 but this additive can
be excluded without suffering a significant drop in the reaction
(38) Wang, X.-j.; Xu, Y.; Zhang, L.; Krishnamurthy, D.; Senanayake, C. H.
Mild Iodine-Magnesium Exchange of Iodoaromatics Bearing a Pyrimidine Ring
with Isopropylmagnesium Chloride. Org. Lett. 2006, 8, 3141–3144.
(39) Sigma-Aldrich list pricing: Catalog number: 523496-5g; List price:
$104.00 ($4.87/mmol); see http://www.sigmaaldrich.com.
J. Org. Chem. Vol. 74, No. 5, 2009 1883

Tlais et al.
SCHEME 11. Preferred Synthesis of PSB-OPT 1
guide optimal incorporation of the PSB group in protecting
group strategies for multistep synthesis.
Based on our recent review of the siletane literature12 and
studies from the Denmark,46 Oshima,47 and other17,48 research
laboratories as well as our own,10 we have outlined a chart of
siletane reactivity (Table 5). This table is an abridged version
of (and follows the same layout as) the reactivity profile chart
published in Greene’s ProtectiVe Groups in Organic Synthesis.1
The entries for benzyl and TBS are reproduced for comparison.
In conclusion, we provide full details of the development of
the para-siletanylbenzyl (PSB) ether as a new protecting group
for alcohols. PSB ethers are conveniently prepared using the
“mix-and-heat” protocol that we reported previously for the
synthesis of benzyl and para-halobenzyl ethers. PSB ethers are
electronically similar to benzyl ethers, but cleavage occurs under
conditions that are unique among benzyl ether derivatives. The
methodology described herein broadens the utility of arylmethyl
ethers as protecting groups for alcohols.
substrate (53 f 55),37 we identified a new protocol for activating
magnesium turnings that enabled us to generate 55 from aryl
bromide 53.
The reaction protocol that provided reproducible amounts of
arylsiletane 29 from 53 involved premixing aryl bromide 53
with a large excess (10 equiv) of unactivated magnesium
turnings in THF43 and then injecting dibromoethane (2 equiv)
rapidly by syringe. Bubbles of gas emanated from the surface
of the magnesium metal for approximately 30 min, after which
time the formation of Grignard 55 was complete. Addition of
chlorosiletane 28 then provided arylsiletane 29 in 55% yield
(eq 3).
Experimental Section
2-(4-(1-Methyl-1-siletanyl)-benzyloxy)-pyridine (PSB-OP, 29).
A stirred solution of bis[2-(N,N-dimethylamino)ethyl] ether (2.66
mL, 14 mmol) in 15 mL of THF under nitrogen was cooled at 0
°C, and i-PrMgCl (1.0 M, 14 mL, 14 mmol) was added dropwise.
After 30 min, iodide 52 (1.22 g, 3.93 mmol) in 5 mL of THF was
added over 1.5 h at 0 °C. The solution was allowed to warm to rt
over 1 h. After recooling the mixture to 0 °C, 1-chloro-1-
methylsiletane (28, 1.7 mL, 14 mmol) was added, the reaction
mixture was warmed to room temperature and stirred for an
additional 4 h. The reaction mixture was diluted with 20 mL of
diethyl ether, extracted with 5 mL of H2O, and washed with brine.
The organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure. 2-Benzyloxypyridine (a byproduct of this
reaction) was removed by bulb-to-bulb distillation at reduced
pressure (0.1 mmHg, bath temp 100 °C), and the residual oil was
further purified using silica gel chromatography (elution with 10%
EtOAc in hexane) to give 760 mg (72%) of 29 as a white solid:
mp 30 °C. 1H NMR (300 MHz, CDCl3) δ 0.55 (s, 3H), 1.11-1.34
(m, 4H), 2.18 (m, 2H), 5.39 (s, 2H), 6.81 (d, 1H, J ) 8.36 Hz),
6.88 (m, 2H), 7.49 (apparent d, 2H, J ) 7.87 Hz), 7.65 (apparent
d, 2H, J ) 7.9 Hz), δ 8.18 (d-d, 1H, J ) 5.03, 1.36 Hz). 13C NMR
(300 MHz, CDCl3) δ -1.71, 14.3, 18.2, 67.3, 111.2, 116.8, 127.3,
133.6, 138.0, 138.5, 138.6, 146.7, 163. HRMS (ESI+) calcd for
C16H21NOSi+ 270.1314, found 270.1317.
This protocol may be successful because of localized heating
that occurs selectively at the magnesium surface promoting
Grignard formation, but not bimolecular reactions between
combinations of aryl species (53 and 55). The localized heat
then dissipates to the solvent and eventually to external cooling
elements (water bath and reflux condenser).44 Such a procedure
is likely scale-dependent and would have to be monitored and
optimized carefully prior to preparing larger quantities of
material, but in our hands it provided 29 reproducibly on a ca.
1 mmol scale.45
5. Generation and Recrystallization of PSB-OPT. Pyridyl
ether 29 was dissolved in trifluorotoluene and treated with
methyl triflate. After 30 min, the volatiles were removed in
vacuo to leave crude PSB-OPT 1 as an oily residue. The residue
was dissolved in trifluorotoluene and left standing in the freezer
at -20 °C to provide crystalline 1 (mp 65 °C) in 95% yield
(Scheme 11). Alternatively, as outlined above in Table 2, the
activation of PSB-OP 29 with methyl triflate can be performed
in situ, thus obviating the need to isolate PSB-OPT 1.
1-Phenylethanol, PSB Ether (20): Typical Procedure for
the Synthesis of Alkyl PSB Ethers. An ice-cold mixture of PSB-
OP 29 (211 mg, 0.78 mmol), PhCF3 (2 mL), MgO (32 mg, 0.6
mmol, dried in an oven), and alcohol 13 (48 mg, 0.39 mmol) was
treated dropwise with methyl triflate (89 µL, 0.6 mmol). After 30
min, the reaction mixture was warmed to room temperature and
then stirred at 80-85 °C for 12 h until TLC analysis showed
5. Conclusion
Electronically, PSB ethers are similar to benzyl ethers. What
differentiates PSB ethers from benzyl ethers is the siletane ring.
Therefore, a thorough understanding of siletane reactivity will
TABLE 5. Reactivity of PSB, Bn, and TBS Ethers under Various Reaction Conditionsa
conditions
Bn
PSB
TBS
conditions
Bn
PSB
TBS
conditions
Bn
PSB
TBS
pH 1, H2O
NaOMe
R3N
RLi
RMgX
H2/Pd
L
L
L
L
L
H
L
R
L
R
L
H
H
L
L
Zn/AcOH
Na/NH3
LiAlH4
DIBAL-H
NaBH4
L
H
L
L
L
L
L
H
R
L
R
L
L
L
L
L
L
L
AlCl3, rt
Br2
H2O2, pH 10
Quinone
150 °C
H
M
L
L
L
H
M
Rc
L
L
R
M
L
L
L
L
L
L
L
Hb
Zn(BH4)2
N2CHCO2R, Cu
L
a Key: L: Low reactivity; protecting group is stable under the reaction conditions. M: Marginal reactivity; depends on exact reaction parameters. H:
Protecting group is removed. R: Protecting group reacts, but the original functionality is not necessarily restored. Letters in italics are based on direct
experimental evidence. Letters not in italics are based on circumstantial evidence. b In reference 1, TBS ethers are estimated to be highly reactive toward
H2/Pd. We transcribed this estimation to remain true to the source but consider TBS ethers to be stable to these conditions. c These conditions, along
with potassium fluoride, are recommended for converting PSB ethers into PHB ethers for ensuing cleavage.
1884 J. Org. Chem. Vol. 74, No. 5, 2009

para-Siletanylbenzyl Ethers
consumption of alcohol 13. The reaction mixture was cooled to
room temperature and filtered through Celite. The filtrate was
concentrated under vacuum and purified on silica gel to yield 140
mg of a light yellow oil, which based on 1H NMR analysis
comprises 102 mg (88%) of 29 and 38 mg (PSB)2O of (41).
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifica-
tion by column chromatography on silica gel (EtOAc/hexanes) gave
the corresponding alcohols. Spectroscopic data matched with the
commercially available samples. See Table 3 for yields.
Menthol, PMB Ether (49): Conversion of a PHB Ether into
a PMB Ether. PHB-menthol 46 (39 mg, 0.14 mmol) was dissolved
in 0.3 mL of methanol at 0 °C. TMSCHN2 (2 M in Et2O, 0.34 mL,
0.68 mmol) was added to the solution, which was then stirred at
room temperature for 24 h. After the solvent was evaporated under
reduced pressure, the residue was purified by column chromatog-
raphy on silica gel (5% EtOAc/hexanes) to give 38 mg (93%) of
PMB-menthol 49.
1
Characterization data for 29: H NMR (300 MHz, CDCl3) δ 0.56
(s, 3H), 1.14-1.31 (m, 4H), 1.48 (d, 3H, J ) 6.6 Hz), 4.52 (q, 1H,
J ) 6.4 Hz), 4.48 (d, 1 H, J ) 12.0 Hz), 4.32 (d, 1H, J ) 12.0
Hz), 7.30-7.42 (m, 7H), 7.62 (apparent d, 2H, J ) 7.8 Hz). 13C
NMR (75 MHz, CDCl3) δ -1.5, 14.5, 18.5, 24.4, 70.4, 126.6, 127.4,
127.7, 127.9, 128.7, 133.8, 138.0, 140.2, 143.9. IR (neat) 2971,
2928, 2864, 1451. HRMS (ESI+) calcd for C19H24OSi+ 296.1596,
found 296.1601.
Standard Procedure for the Oxidation of Alkyl PSB Ethers
(Conditions A).10,15 KF·2H2O (2.5 equiv) and K2CO3 (2.5 equiv)
were added to a 0.12 M solution of PSB ether (1 equiv) in THF/
CH3OH (1:1). The resulting mixture was cooled in an ice bath,
and H2O2 (30% in H2O, 25 equiv) was added dropwise. The reaction
mixture was stirred at 0 °C for 10 min and at 50 °C for 2 h. The
reaction mixture then was extracted with CH2Cl2. The combined
organic phases were sequentially washed with a 1.0 M aqueous
Na2S2O3 and brine. The combined aqueous phases were extracted
with CH2Cl2 (3x). The combined organic phases were dried over
MgSO4, filtered, and concentrated. Purification by flash column
chromatography on silica gel (EtOAc/hexanes) provided the PHB
ether. See Table 3 for yields, and see Supporting Information for
characterization data.
Standard Procedure for the Cleavage of Alkyl PHB Ethers
(Conditions E).8 A 0.35 M solution of PHB ether (1 equiv) in
Et2O was added to a 0.2 M solution of FeCl3 (1.5 equiv) in CH2Cl2
dropwise over 5 min under argon. The reaction was stirred from
0.5-3 h and then extracted with 1 M HCl. The aqueous layer was
extracted with CH2Cl2 (2x). The combined organic phases were
Acknowledgment. We thank the FSU Department of
Chemistry and Biochemistry, the FSU Research Foundation
(GAP Award) for support of this work, the NMR Facility
for spectroscopic support, the Krafft laboratory for the use
of their IR spectrometer, and Dr. Umesh Goli for assistance
with mass spectrometry. We thank the Brauchledt Foundation
for a summer undergraduate research fellowship (S.E.H.) and
the MDS Research Foundation for a postdoctoral fellowship
(H.L.). Dr. Kevin W. C. Poon (Chemica Technologies) and
James D. Sunderhaus (University of Texas, Austin) are
gratefully acknowledged for their seminal contributions to
this effort. We thank Cecelia C. O’Leary for providing
independent confirmation of the new protocol and for
preparing the Grignard derivative of aryl bromide 53.
Note Added in Proof. Additional data recently appeared
regarding the utility of oxypyridinium reagent 6 for addressing
difficulties associated with the synthesis of benzyl ethers.49 By
extension, such information is relevant to making the appropriate
choice of reagent for making PSB ethers.
(40) Sigma-Aldrich list pricing: Catalog number: 187054-50g; List price:
$151.50 ($0.57/mmol); see http://www.sigmaaldrich.com.
(41) Note that the Sigma-Aldrich list price of siletane 28 (catalog number:
411582-5g, list price: $145.50, $3.54/mmol) is comparable to that of TBS-OTf
(catalog number: 226149-5g, list price: $52.60, $2.78/mmol); see http://
www.sigmaaldrich.com.
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(42) Garst, J. F.; Easton Lawrence, K.; Batlaw, R.; Boone, J. R.; Ungva´ry,
F. Magnesium Bromide in Grignard Reagent Formation. Inorg. Chim. Acta 1994,
222, 365–375. Jing, L.; Xiangjun, L.; Hua, L.; Qinglan, X.; Zhun, L.; Xilin, H.
a New Way to Prepare Grignard Reagent from Rx (X)Cl, Br) Using the Mixture
of Brch2Ch2Br and I2 As an Initiator. Synth. Commun. 1999, 29, 1037–1039.
Bogdanovic, B.; Schwickardi, M. Transition Metal Catalyzed Preparation of
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(43) Grignard formation does not initiate spontaneously even when using
magnesium turnings that were preactivated with iodine and/or dibromoethane.
(44) A reflux condenser was included in the experimental setup as a
precaution; solvent reflux was never definitively observed in this experiment.
(45) The authors thank Ms. Cecelia C. O’Leary, an undergraduate research
student in the Dudley Lab, for providing independent verification of this new
and unusual procedure for making Grignard reagents. Further exploration of this
protocol is underway and will be reported in due course.
(46) Denmark, S. E.; Sweis, R. F. Design and Implementation of New,
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