New reagents for the synthesis of arylmethyl ethers and esters

Article abstract of DOI:10.1055/s-0029-1219531

This Account chronicles efforts leading up to the development of new arylmethyl transfer (benzylation) reagents for protecting oxygen functional groups under relatively mild and neutral conditions. It begins with an investigation of organosiletanes as surrogate hydroxyl groups, which inspired siletane-functionalized benzyl ethers and forced us to confront the difficulties associated with the synthesis of benzyl ethers. The end result is a new series of neutral oxypyridinium salts for the benzylation of various nucleophilic functional groups under mild conditions. 1 Introduction 2 Tamao-type Oxidation of Strained Organosiletanes 3 p-Siletanylbenzyl (PSB) Protecting Groups 4 2-Benzyloxy-1-methylpyridinium Triflate 5 Friedel-Crafts Reactions and Mechanistic Insights 6 Benzyl Ester Formation 7 Substituted Benzyl Transfer Reagents 8 Conclusions and Outlook. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219531

ACCOUNT
841
New Reagents for the Synthesis of Arylmethyl Ethers and Esters
A
rylmethyl
Tr
h
ansfer
R
eage
i
nts lip A. Albiniak,a Gregory B. Dudley*b
a
Department of Chemistry, Ball State University, Muncie, IN 47306-0445, USA
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850) 644-8281; E-mail: gdudley@chem.fsu.edu
b
Received 6 November 2009
viable if Stages 1 and 3 can be accomplished in high yield
and with minimal effort.
Abstract: This Account chronicles efforts leading up to the devel-
opment of new arylmethyl transfer (benzylation) reagents for pro-
tecting oxygen functional groups under relatively mild and neutral
conditions. It begins with an investigation of organosiletanes as sur-
rogate hydroxyl groups, which inspired siletane-functionalized ben-
zyl ethers and forced us to confront the difficulties associated with
the synthesis of benzyl ethers. The end result is a new series of neu-
tral oxypyridinium salts for the benzylation of various nucleophilic
functional groups under mild conditions.
This Account chronicles the development of separate but
related contributions to the chemistry of arylmethyl pro-
tecting groups (Figure 1). Strained organosilane-derived
protecting groups – namely, the p-siletanylbenzyl ethers
described herein – offer distinct advantages during Stage
3 (cleavage), but posed problems during Stage 1 (installa-
tion). A solution was identified in the form of neutral,
bench-stable oxypyridinium triflate reagents, which im-
pact Stage 1 by enabling the installation of benzyl and re-
lated functionality under mild conditions.
1
2
3
4
5
6
7
8
Introduction
Tamao-type Oxidation of Strained Organosiletanes
p-Siletanylbenzyl (PSB) Protecting Groups
2-Benzyloxy-1-methylpyridinium Triflate
Friedel–Crafts Reactions and Mechanistic Insights
Benzyl Ester Formation
Substituted Benzyl Transfer Reagents
Conclusions and Outlook
O
TfO–
+N
O
TfO–
+N
Me
Me
Key words: siletanes, benzyl, PMB, PSB
X
21
X = siletanyl, Cl, Br, I
2-benzyloxy-1-methyl-
pyridinium triflate
(18, 67–70)
Me
N
1
Introduction
O
Synthetic chemists enjoy a love/hate relationship with
protecting group strategies. Skilled practitioners generally
strive to minimize the need for protecting group manipu-
lation steps in the design and execution of complex mole-
cule synthesis. Nonetheless, protecting group strategies
are necessarily incorporated into most approaches to the
synthesis of natural products and other small molecule tar-
gets. Those involved in synthetic production of primary
metabolites such as carbohydrates and peptides rely even
more heavily on appropriate protecting group strategies.
MeO
75
2-(p-methoxybenzyloxy)lepidine
Figure 1 New reagents featured in this Account
Arylmethyl (e.g., benzyl) protecting groups withstand a
wide range of reaction conditions, putting them among the
most effective choices for Stage 2 (the constructive stage)
of protecting group strategies. However, or perhaps con-
sequently, installation and cleavage processes for arylme-
thyl protecting groups are more difficult than analogous
processes involving silyl, acyl, or acetal protecting
groups. Myriad variations of arylmethyl ether protecting
groups have emerged to suit myriad applications in syn-
thesis. Ideally, modifications to the arylmethyl group that
lead to improvements in installation and cleavage do not
compromise the ability of the protecting group to survive
other typical reaction conditions. Synthetic chemists can
often identify one or more appropriate choices, based
upon the popularity of arylmethyl protecting groups in or-
ganic synthesis.
Execution of an effective protecting group strategy con-
sists of three stages: (1) formation, in which a reactive
functional group is rendered inert by installation of the
protecting group; (2) transformations, during which time
the desired skeletal manipulations and additions are
achieved without undesired interference from the protect-
ed functionality; and (3) cleavage, at which point the pro-
tecting group is removed to restore the reactive
functionality to its original form. Considering that only
Stage 2 is constructive with respect to advancing towards
the synthetic target, protecting group strategies are only
Our Account begins with a discussion of how early inter-
est in the oxidation of siletanes under Tamao conditions
led to the development of the p-siletanylbenzyl (PSB) pro-
tecting group. Then, the emphasis shifts to the develop-
SYNLETT 2010, No. 6, pp 0841–0851
Advanced online publication: 18.02.2010
DOI: 10.1055/s-0029-1219531; Art ID: A55009ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

842
P. A. Albiniak, G. B. Dudley
ACCOUNT
ment of a new “mix-and-heat” reagent for the synthesis of
benzyl ethers. This methodology was originally undertak-
en to address difficulties in the synthesis of PSB ethers,
but the findings ended up having broader applications.
Recent and on-going efforts, in this lab and others, to ex-
tend the use of oxypyridinium salts to the synthesis of oth-
er arylmethyl ethers are described. Finally, we revisit the
original challenge of preparing PSB ethers using oxypyri-
dinium salts. Mukaiyama’s fruitful studies on the use of
halopyridinium salts in esterification (acylation) reactions
were influential in directing our attention to oxypyridini-
um salts for etherification (alkylation) reactions.
~90°
~109°
Si
Si
L–
Si–
L
Si
more ring strain
less ring strain
Figure 2 Strain-release Lewis acidity of siletanes
ditions (i.e., heteroatom-activated silanes) do not stand up
very well to routine laboratory handling and purification
techniques like aqueous workup and chromatography on
silica gel. More robust tetraalkylsilanes, on the other
hand, require a priming step as described by Fleming,6
which often involves cleavage of an aryl–silane bond.7
Arylsiletane substrates undergo oxidation to phenols di-
rectly under Tamao conditions, yet the siletanes withstand
a much wider range of conditions than traditional Tamao
substrates, including routine laboratory handling and pu-
rification.
2
Tamao-type Oxidation of Strained Organo-
siletanes
The research program featured in this Account began with
our discovery of the oxidation of alkyl- and arylsiletanes
under the mild conditions recommended by Tamao1 for
the oxidation of C–Si bonds in activated silyl halides. The
enhanced reactivity of siletanes relative to unstrained tet-
raalkylsilanes is attributable to strain-release Lewis acidi-
ty’ of siletanes as described by Denmark (Figure 2).2
Angle strain is relieved as the four-coordinate (tetrahe-
dral) silane species binds another ligand to produce a five-
coordinate (trigonal bypyramidal) silicate species. Den-
mark,3 Oshima,4 Myers,5 and others have successfully ex-
ploited this enhanced reactivity in C–C bond-forming
reactions; we extended this concept to the formation of C–
O bonds.
Siletanes (1) were easily prepared in high yield by Gri-
gnard transmetallation with chlorosiletanes.8 Various sub-
stituted arenes as well as alkyl and alkenyl functionalities
were incorporated by this method (Scheme 1).
30% H2O2
KF (2 equiv)
KHCO3 (2 equiv)
Si
Cl
Si
R
1
R
MgX
R
OH
THF–MeOH
(1:1), r.t.
Et2O
2
reflux , 18 h
Organosiletane oxidations offer important advantages, es-
pecially in the synthesis of phenols from arylsilanes. Most
silyl substrates that undergo oxidation under Tamao con-
R = aryl, alkyl, alkenyl
Scheme 1 Preparation and oxidation of organosiletanes
Biographical Sketches
Philip A. Albiniak was try under the direction of Ball State University in
born in Myrtle Beach, SC Martin F. Semmelhack. In Muncie, IN. Current re-
and received his B.S. de- the fall of 2006 he moved to search interests include the
grees in chemistry and bio- Florida State University to development of novel oxy-
chemistry from the College begin a postdoctoral associ- pyridinium reagents and or-
of Charleston in 2000. Later ation with Gregory B. Dud- ganometallic methodology
that fall, he moved to Princ- ley, and in 2009 began his for organic synthesis.
eton University to begin independent faculty career
graduate studies in chemis- as an Assistant Professor at
Gregory Dudley received a Institute for Cancer Re- cess
by
contributing
B.A. from FSU in 1995 and search, he returned to FSU fundamental new knowl-
a Ph.D. in 2000 under the di- as an Assistant Professor in edge to organic synthesis.
rection of Professor Rick 2002. Professor Dudley was Recent methodology has fo-
Danheiser at MIT. After promoted to Associate Pro- cused on novel C–C bond
completing an NIH Post- fessor with tenure in 2008. cleavage and rearrangement
doctoral Fellowship with The current mission of his reactions for target-oriented
Professor Samuel Danishef- research program is to im- synthesis.
sky at the Sloan–Kettering pact the drug discovery pro-
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

ACCOUNT
Arylmethyl Transfer Reagents
843
The diverging reactivity of silyloxyhexylsiletane 3 dem- Given the demonstrated stability of arylsiletanes to elec-
onstrates the utility of siletanes (Scheme 2).8 The TBS trophilic oxidants and mildly acidic conditions, we antic-
ether is inert to the siletane oxidation, whereas wet acetic ipate that PSB ethers will be of considerable utility in
acid cleaves the TBS ether without impacting the siletane carbohydrate synthesis. In preliminary studies, we dem-
moiety. These results show the significance of siletanes as onstrated regioselective installation of the PSB group onto
substrates for Tamao–Fleming oxidations and as latent the C4 hydroxy of glucopyranoside 9 via initial formation
hydroxyl groups. The unique reactivity of siletanes due to of the C4/C6 dioxane acetal 11, followed by reductive
their Lewis acidic strain-release’ allows for the use of sta- ring opening with DIBAL-H (Scheme 4).
ble, simple-to-handle siletanes with the reactivity of het-
eroatom-substituted silanes.
OMe
HO
CSA
HO
O
O
OMe
CH2Cl2
+
O
reflux, 3 h
94%
OH
OMe
30% H2O2
KF (2 equiv)
KHCO3 (2 equiv)
Si
Si
Si
AcOH–THF–
H2O (3:1:1)
10
9
88%
THF–MeOH (1:1)
85%
PSB
O
PSB
O
HO
PSP
O
O
TBSO
O
O
O
O
HO
O
O
HO
TBSO
DIBAL-H
4
3
5
–13 °C, 12 h
O
O
O
OMe
OMe
OMe
CH2Cl2
Scheme 2 Divergent reactivity of organosiletanes and silyl ethers
12
13
(15%)
11
(81%)
Scheme 4 Reductive ring opening of a siletanylbenzylidene acetal
3
p-Siletanylbenzyl (PSB) Protecting Groups
Advantages of the PSB group. One way to harness sile-
tane oxidations is through the use of PSB ethers in protect-
ing group strategies for organic synthesis (Scheme 3).
Silyl substituents have a negligible electronic effect on ar-
omatic rings, so the PSB group is electronically similar to
the benzyl group. Oxidation of the aryl–siletane s-bond
generates a phenol – in this case a p-hydroxybenzyl
(PHB) ether (8) – and dramatically changes the oxidation
potential of the aromatic ring. Cleavage of PHB ethers is
trivial, even in the presence of other arylmethyl ethers,
and sometimes occurs spontaneously under the conditions
required to generate them.
A unified synthetic sequence provides a series of standard
PSB-transfer reagents (Scheme 5). The dimethyl acetal of
p-bromobenzaldehyde (14) gives rise to 10 under Barbier
conditions; this reaction also demonstrates the stability to
arylsiletanes to organomagnesium reagents, even at ele-
vated temperatures. Hydrolysis and reduction produces
PSB–OH (16), which is useful for the protection of phe-
nols under Mitsunobu conditions. Finally, reaction of
PSB–OH under Appel’s conditions provides PSB–Br,
which was expected to furnish alkyl PSB ethers by means
of the Williamson ether synthesis.
OMe
OMe
Cl
Si
OMe
OMe
R–OH
, Mg
PHB–X
THF
86–91%
Si
X
6
10
Br
14
Si
cleavage
PSB–X
formation
1 M HCl
H2O–Et2O
>90%
X
R
8
R
7
CHO
O
O
H2O2, KF, K2CO3
siletane oxidation
1. DIBAL-H
Si
87–95%
Si
PHB–OR
HO
PSB–OR
Si
16 X = OH
17 X = Br
2. PH3, CBr4
95%
15
Scheme 3 Protection and deprotection of alcohols using PSB ethers
Scheme 5 Synthesis of PSB reagents
The PSB group complements other arylmethyl protecting
groups. For example, the PSB ether can be oxidized under
Tamao conditions, which do not affect PMB ethers.9 Al-
ternatively, oxidative cleavage of the PMB group with
DDQ, which occurs via a charge-transfer oxidation of the
aromatic ring, occurs without noticeable effect on the PSB
ether.9
Challenges associated with the PSB group. Formation
of alkyl PSB ethers using the Williamson ether synthesis
was problematic. The propensity of siletanes to undergo
anionic ring-opening polymerization in the presence of al-
kali metal alkoxides10 required that we take recourse to
silver-mediated etherification protocols. While successful
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

844
P. A. Albiniak, G. B. Dudley
ACCOUNT
for the synthesis of PSB ethers from primary alcohols, this idate with triflic acid,11 followed by trapping of the
method was sensitive to the quality of the silver oxide and resulting cation with an alcohol. This method requires that
was unsuitable for the protection of secondary alcohols. the other functionality in the molecule be stable to strong-
Attempts at the formation of PSB ethers using trichloro- ly acidic conditions. These methods limit the ability to
acetimidate 19 and an alcohol resulted only in decompo- benzylate alcohols in complicated systems.
sition of 19 with consumption of the alcohol substrate.
RO–
Presumably, protiodesilylation of the arylsiletane is faster
acidic
basic
ROH
than transfer of the PSB group from the acid-activated
trichloroacetimidate intermediate.
CCl3
NH
O
Br
New hypothesis for the synthesis of arylmethyl ethers.
In considering our problems with the formation of PSB
ethers using PSB trichloroacetimidate (19, Figure 3), we
speculated that the issue was not a failure of the activated
imidate to transfer the PSB group, but rather the instability
of arylsiletane to the acidic condition required to activate
the imidate group. A guiding hypothesis thus emerged: in
the absence of acidic protons, an activated imidate-type
species will succeed in delivering intact the PSB group
onto an alcohol.
HOTf
protonated trichloroacetimidates
Williamson ether synthesis
R–OH
neutral
R2
R–OBn
R1
O
N +
Me
–OTf
Scheme 6 Strategies for benzylation of alcohols
CCl3
We opted to target a new reagent that would allow for the
benzylation of alcohols under milder conditions. Instruc-
tive precedence was found in Mukaiyama’s reagent, 2-
chloro-1-methylpyridinium iodide (20), which is a bench-
stable salt that is used as an acyl transfer reagent by in situ
formation of 2-acyloxypyridinium salts.12 2-Alkoxypyri-
dinium salts of sulfonates have been isolated, but they de-
compose in the presence of bromide ions to bromoalkanes
and pyridones.13,14 These points encouraged us to consider
2-benzyloxypyridinium sulfonates (e.g., 21, Figure 4) in
the search for a new benzylation reagent, which in the
presence of alcohols could decompose to give rise to ben-
zyl ethers and pyridones.
PSBO
NH
PSBO
OTf
+N
Me
vs.
(to be activated
with TfOH)
–
18
oxypyridinium triflate
19
trichloroacetimidate
Figure 3 Comparison of PSB-oxypyridinium triflate (18) with tri-
flic acid activated PSB-trichloroacetimidate
To test this hypothesis, we need to replace all exchange-
able protons with alkyl groups. As described, this objec-
tive was best met through the use of oxypyridinium
derivatives as imidate surrogates, with activation using
methyl triflate instead of triflic acid. Ultimately, a new
class of arylmethyl-transfer reagents emerged that is ef-
fective under neutral conditions and succeeds even when
challenged with highly acid- or base-sensitive substrates.
+
O
N+
Me
Cl
N
–I
–OTf
Me
21
20
Figure 4 Mukaiyama’s reagent (20) and benzyl-transfer reagent 21
4
2-Benzyloxy-1-methylpyridinium Triflate
The first objective was to synthesize 2-benzyloxy-1-
methylpyridinum triflate (21). This was accomplished by
coupling 2-chloropyridine with the potassium salt of ben-
zyl alcohol in refluxing toluene to yield 2-benzyloxypyri-
dine,15 followed by methylation (Scheme 7). The triflate
salt precipitates from the reaction mixture as a white, crys-
talline solid that is stable indefinitely to storage at room
temperature or below. Alternatively, 21 is now commer-
cially available.16
To begin the investigation of imidate surrogates as aryl-
methyl-transfer reagents, we focused on the synthesis of
benzyl ethers for the protection of alcohols. Benzyl ethers
are stable to a wide variety of reaction conditions and can
be removed under a variety of conditions. In addition, var-
ious substituted benzyl ethers alter reactivity and chemi-
cal differentiability.
The benzyl ether is a very useful protecting group; how-
ever, the methods for synthesizing benzyl ethers are lim-
ited. Benzyl ethers are typically generated by one of two
methods (Scheme 6). The first method is Williamson
etherification, which involves treating benzyl bromide
with an alkoxide salt to induce an SN2 reaction. This meth-
od of protection requires that the other functionality in the
molecule be stable to strongly basic conditions. The sec-
ond method involves activating benzyl trichloroacetim-
Cl
N
MeOTf
, KOH
BnOH
BnO
OTf–
+N
Me
toluene,
0 °C to r.t.
1 h, 99%
18-C-6, toluene
reflux, DS trap
1 h, 96%
BnO
N
22
21
Scheme 7 Synthesis of benzyloxypyridinium triflate 21
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

ACCOUNT
Arylmethyl Transfer Reagents
845
With pyridinium salt 21 in hand, we pursued conditions solvents, in which benzyl reagent 21 dissolves upon
for the benzylation of alcohols. Indeed, 21 provides ben- warming, were better suited to efficient benzylation. The
zyl ethers upon warming the reagent in the presence of an best conditions developed thus far involve stirring a mix-
alcohol (Table 1).17 Initial studies focused on chlorinated ture of alcohol and 21 in PhCF3 at 80 °C for 24 h
solvents in which 21 is soluble: namely, dichloromethane (Scheme 8). Manganese oxide is typically added to the re-
and dichloroethane.18 Later studies revealed that aromatic action mixture as an acid scavenger. Other aromatic sol-
Table 1 Synthesis of Benzyl Ethers Using 21
Entry
1
Alcohol
Ether
Yield (%)
93
O
O
MeO
OH
MeO
OBn
23
24
Me
Me
MeO
OH
MeO
OBn
2
3
85
88
O
O
25
26
OH
OBn
27
29
28
30
Me OH
Me
Me OBn
Me
4
5
44
65
OH
OBn
Ph
Ph
31
32
CO2Me
OH
CO2Me
OBn
619
75
96
N
O
N
O
H
H
33
34
OBn
OAc
OH
720
OAc
36
35
PivO
PivO
BnO
Ot-Bu
Ot-Bu
Ot-Bu
H
N
H
N
821
95
72
73
Ot-Bu
HO
TBDPSO
TBDPSO
37
38
O
O
O
O
922
TBDPSO
TBDPSO
O
O
BnO
HO
39
40
OBn
OBn
OPh
OPh
P
PhO
PhO
O
OH
O
OBn
P
1023
O
O
BnO
OBn
BnO
OBn
OH
OBn
41
42
OBn
OBn
MeO
MeO
1124
66
O
OH Me
O
OBn Me
43
44
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846
P. A. Albiniak, G. B. Dudley
ACCOUNT
1. 2.0 MeOTf
2.0 MgO
0 °C, PhCF3
vents gave suitable yields of benzyl ether products as well,
but PhCF3 was the favored choice due to its non-nucleo-
philic character. When the reaction is run in slightly
electron-rich aromatic solvents such as toluene, diaryl-
methane products are seen in NMR spectra of the crude
products. These products result from Friedel–Crafts-type
reactions of the solvent with the benzylating reagent, as
discussed in the following section.
ROH
+
R–OBn
+
2. 90 °C, 24 h
22
O
N
Me
BnO
N
Scheme 9 Benzylation via in situ methylation of 2-benzyloxypyri-
dine
After complete addition of MeOTf at 0 °C, the reaction is
warmed to 90 °C for arylmethyl transfer to take place.
Yields of benzyl ethers formed via direct treatment with
triflate salt 21 or in situ generation of 21 were generally
comparable.
PhCF3, MgO
BnO
TfO–
+N
Me
ROH
+
R OBn
80 °C, 24 h
21
Scheme 8 Benzylation of alcohols using 21
5
Friedel–Crafts Reactions and Mechanistic
Insights
Benzylation of primary and secondary alcohols generally
proceeds in high yield, whereas tertiary alcohols and phe-
nols are more challenging substrates (Table 1, entries 1–
5, results from the Dudley lab). Recent reports from inde-
pendent labs confirm our conclusions (entries 6–11) and
provide new insight into the unique effectiveness of ben-
zyl reagent 21. For example, hydroxymethyl lactam 33
was benzylated in 75% yield despite the presence of an-
other potentially reactive functionality (entry 6),19 and
monoacylated diol 35 was protected as benzyl ether 36
without acetate migration (entry 7).20 In each case, suc-
cessful benzylation was realized only with 21.
Chmielewski likewise reported that only 21 was suitable
for the benzylation of compound 37.21 More traditional
Williamson ether synthesis led to Hoffman degradation,
whereas acidic conditions utilizing benzyl 2,2,2-trichloro-
acetimidate led to removal of the acid labile groups.
Tamayo22 reported that treatment of alcohol 39 under
acidic or basic conditions led to a complicated mixture of
products, but treatment with 21 led smoothly to benzyl
ether 40 in 72% yield. Inositol 41 could be dibenzylated
without the formation of cyclic phosphates that occurred
under strongly basic conditions.23 These examples show
the diverse range of complicated molecules that can toler-
ate the benzylation conditions with 21, and demonstrate
the particular utility of 2-benzyloxy-1-methyl-pyridinum
triflate as an arylmethyl transfer reagent for late-stage
synthesis of complicated natural products.
Benzylation of alcohols using 21 is a nucleophilic substi-
tution reaction, which can be defined by two limiting
mechanistic pathways (Scheme 10). The first is an SN1 re-
action, with rate-limiting formation of a discrete benzyl
cation followed by rapid trapping by the alcohol moiety.
On the other end of the spectrum is the bimolecular SN2
reaction in which the alcohol displaces the oxypyridinium
leaving group with concerted formation of the product
benzyl ether.
We prepared and analyzed the reactivity of the analogous
methyl reagent, methoxypyridinium 47. Under similar re-
action conditions, pyridinium triflate 47 did not transfer a
methyl group (Scheme 11). If an SN2 pathway were acces-
sible, then one might expect methyl transfer to occur. We
interpret this data as evidence against the SN2 mechanism.
Evidence in support of the SN1 mechanism is found in the
formation of diarylmethane byproducts during the benzy-
lation of alcohols in certain aromatic solvents; we inter-
pret these products as arising by reaction of electrophilic
phenylcarbenium (45) with the aromatic solvent.
The formation of diarylmethane byproducts during the re-
action of 21 with alcohols when toluene was used as a sol-
vent led us to investigate this reaction in detail. We heated
21 in the presence of electron-rich aromatics and in the ab-
sence of other nucleophiles, expecting to observe Friedel–
Crafts products. Such reactions typically are thought to
proceed by Lewis acid activation of an alkyl halide to gen-
erate a carbocation, which is trapped by the aromatic ring.
The electrophilic aromatic substitution process generates
an equivalent of strong acid in addition to the substituted
arene product.
The reaction yields two products other than the desired
benzyl ether. The first is N-methylpyridone, the expected
byproduct of benzyl transfer from oxypyridinium 21 in
the presence of an acid scavenger (MgO). The second
byproduct is dibenzyl ether (Bn2O), which presumably
arises as a result of interference from MgO and/or adven-
titious water. For complex molecules, this trace byproduct
should not be a concern; however, purification of simple,
non-polar benzyl ethers can be difficult with Bn2O con-
taminating the sample.
Benzylation of electron-rich arenes such as anisole occurs
readily (93% yield), and unactivated arenes such as ben-
zene are also subject to benzylation (43% yield).26 Reac-
tions were completed by stirring 21 neat in 5–10
equivalents of arene at 80 °C (Scheme 12). These
Friedel–Crafts reactions proceed even in the presence of
an acid scavenger (MgO). Reactions conducted at 1 M
The reaction conditions have been expanded to include in
situ activation of 2-benzyloxypyridine 22 to generate tri-
flate salt 21 in the presence of an alcohol (Scheme 9).25
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

ACCOUNT
Arylmethyl Transfer Reagents
847
opportunity to utilize benzyltransfer reagents 21 for gen-
+CH2
erating benzyl esters under mild conditions.27
The benzylation conditions optimized for alcohols were
evaluated for the benzylation of carboxylic acids, but
MgO proved to be a poor acid scavenger. In fact, trials run
with no external base gave better results (higher conver-
sion to the benzyl ester with fewer byproducts) than those
with MgO added. After a brief screening of alternative
bases, we found that inclusion of triethylamine (Et3N)
provided complete conversion to benzyl esters, and the
formation of the Bn2O byproduct was completely sup-
pressed (Scheme 13).
SN1
R
OH
45
OR
BnO
TfO–
21
+N
Me
R
OH
SN2
O
+N
Me
21 (2 equiv)
TfO–
Et3N (2 equiv)
RCO2H
RCO2Bn
PhCF3, 80 °C, 24 h
81–99%
R = 1°, 2° 3°, alkenyl, alkynyl, aryl
46
Scheme 10 Limiting mechanistic pathways for the substitution
reaction
Scheme 13 Benzylation of carboxylic acids
Using optimized conditions (carboxylic acid in PhCF3
with 2.0 equiv 21 and Et3N at 80 °C for 24 h), carboxylic
acids are actually better benzylation substrates than alco-
hols (Table 2). High yields were seen for diverse carbox-
ylic acid benzyl esters. Alcohols (!), phenols, amides, and
PhCF3, MgO
MeO
TfO–
+N
Me
ROH
HO
+
+ N
+
R
OMe
–OTf
Me
80 °C, 24 h
48
47
Scheme 11 Lack of reactivity in the putative methyl-transfer
reagent
Table 2 Synthesis of Benzyl Esters using 21.
Entry Carboxylic Acid
Ester
Yield (%)
92
concentration in PhCF3 provide yields comparable to
those run neat in arene.
CO2H
CO2Bn
CO2Bn
1
2
Ph
52
Ph
Ph
53
Ph
The success of the Friedel–Crafts reactions indicates that
the SN1-like pathway may be favored, as Friedel–Crafts
reactions are typically assumed to involve cationic inter-
mediates.
CO2H
94
91
54
55
MeO
MeO
CO2H
CO2Bn
3
4
HO
HO
56
57
6
Benzyl Ester Formation
CO2H
CO2Bn
81
91
Conversion of carboxylic acids to esters is commonly em-
ployed as part of protecting group strategies in chemical
synthesis. Carboxylic acids can be difficult compounds to
handle and purify. This difficulty is typically overcome by
protecting the acid as an ester until revealing the free acid
late in the synthesis of complex targets. Diazomethane is
one commonly used reagent to generate methyl esters.
Unfortunately, diazomethane is unstable, can be explo-
sive, and is not suitable for large-scale preparation of me-
thyl esters. In addition, methyl esters can be difficult to
remove under mild conditions. On the other hand, benzyl
esters can be deprotected via hydrogenolysis. We saw an
N
N
58
59
H
H
N
CO2H
OH
N
CO2Bn
OH
Boc
Boc
5
6
60
61
CO2H
CO2Bn
O
O
O
O
O
O
99
O
O
O
O
62
63
H
Bn
+
80 °C
Bn2O
+
H
+
24 h
43–100% yield
6 examples
O
+ N
Me
BnO
+ N
Me
21
ED
ED
50
–OTf
48
–OTf
49
51
Scheme 12 Friedel–Crafts benzylation reactions
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

848
P. A. Albiniak, G. B. Dudley
ACCOUNT
esters were unaffected during the course of the reaction. an analogous route to the synthesis of benzyl reagent 21.29
Protecting groups such as N-Boc, acetonide, and acetate Yields varied from 88% to 95% for the two-step process
were all left untouched by the reaction conditions. In to generate the triflate salts.
short, these reactions are extremely flexible and efficient-
The new halobenzyl salts were tested for their reactivity
ly produce benzyl esters in high yield with no Bn2O
as transfer reagents with alcohols. Due to the similar elec-
byproduct.
tronics to the simple benzyl ether, we expected effective
decomposition to yield the corresponding arylmethyl cat-
ion. In fact, heating these salts in the presence of alcohols
gave good yields of a variety of 1°, 2°, and 3° substituted
benzyl ethers (79–95% yield). For optimum yields, these
reactions were heated at 100 °C, as opposed to 80 °C for
21. Presumably, this was necessary due to the modest in-
ductive deactivating effect of the halogen substituents.
+
CH2
O
N+
Δ
O
N
–OTf
Me
TfO–
Me
21
64
O
65
NEt3
H
O
PIB group
PBB group
R
O
+
–OTf
+
–OTf
NEt3
NEt3
R
OBn
H
Bn
66
fast
O
+N
Me
O
+N
Me
excess Et3N
TfO–
I
TfO–
Br
67
68
Scheme 14 Proposed mechanism for the formation of benzyl esters
OBB group
Br
PCB group
The enhanced reactivity of acids and the complete ab-
sence of Bn2O led us to postulate a revised mechanism,
particularly with respect to the role of Et3N. Presumably,
21 undergoes thermal decomposition to yield a charge-
separated benzyl cation as stated previously (Scheme 14).
The first equivalent of Et3N activates the carboxylic acid
as an acid–base pair. This explains how the acid outcom-
petes free alcohols. The second equivalent of Et3N traps
excess benzyl cation before other nucleophiles, which ex-
plains the selectivity for benzylation of the carboxylic
acid in the presence of alcohols.
O
+N
Me
O
+N
Me
TfO–
Cl
TfO–
69
70
Figure 5 Halobenzyl oxypyridinium salts
PMB reagent. Re-engineering was required in the design
and development of a p-methoxybenzyl (PMB) transfer
reagent (Figure 6).30 The direct PMB analog (71) was un-
stable at room temperature and insoluble in PhCF3. How-
ever, the more hydrophobic lepidine salt 72 was soluble in
PhCF3 at room temperature. The p-methoxy group can
stabilize the resultant carbocation formed from the de-
composition of the salt; therefore, the decomposition oc-
curs readily at significantly lower temperatures.
7
Substituted Benzyl Transfer Reagents
The success of 21 as a reagent for benzylating various nu-
cleophiles led us to investigate ways to expand the scope
of this reactivity to install protecting groups beyond sim-
ple benzyl groups. Early experiments showed that 2-meth-
oxy-1-methylpyidinium triflate (47) was ineffective for
transferring methyl groups to alcohols to yield methyl
ethers. This result was consistent with the postulated SN1
mechanism in that the methyl cation is too unstable for the
decomposition of 47 to occur readily. However, this result
reminds us that the stability of the carbocation formed
upon thermal decomposition is an essential consideration
for designing these reagents.
O
TfO–
+N
Me
O
+ N
Me
TfO–
MeO
MeO
72
71
*unstable at r.t.
*insoluble in PhCF3
*unstable at r.t.
*soluble in PhCF3
Figure 6 Pyridine- and lepidine-derived PMB-transfer reagents
Halobenzyl reagents. We set out to generate a series of
halobenzyl oxypyridinium triflate reagents. Halobenzyl
ethers have emerged recently as a class of flexible protect-
ing groups for carbohydrate synthesis.28 Palladium cross-
coupling reactions can yield amino or hydroxyl arenes
that can then be removed under mild conditions similar to
PMB groups. In particular, p-bromobenzyl (PBB), p-chlo-
robenzyl (PCB), p-iodobenzyl (PIB), and o-bromobenzyl
(OBB) oxypyridinium salts (Figure 5) were prepared by
To overcome the limited stability of the PMBO-lepidine
salt, the reagent is best generated in situ. A solution of al-
cohol, PMB lepidine ether 75, and MgO in PhCF3 was
stirred at 0 °C (Scheme 15). MeOTf was added, and upon
complete addition the reaction mixture was warmed to
room temperature. The quinoline ring nitrogen atom is
more nucleophilic than the neutral hydroxy of the alcohol
substrate, methyl triflate reacts chemoselectively with 75
to generate the active reagent (72). Once formed, the salt
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

ACCOUNT
Arylmethyl Transfer Reagents
849
decomposes with release of an electrophilic PMB group,
which is trapped by the free alcohol. These conditions
provided PMB ethers in high yield from a variety of 1°
and 2° alcohols. More hindered 2° and 3° alcohols gave
lower yields of products, typically around 60–70%. These
conditions provide a new, milder method to the traditional
trichloroacetamide route to generating PMB ethers.31
Table 3 Synthesis of PMB Ethers Using 75 and CSA
Entry Alcohol
Ether
Yield (%)
O
O
O
1
85
OH
OPMB
O
O
O
78
79
(2 equiv)
TMS
OH
TMS
OPMB
OH
OPMB
O
O
O
N
H
H
H
H
75
O
MeO
O
MeOTf (2 equiv), MgO (2 equiv)
PhCF3, 0 °C to r.t., 80%
2
3
4
95
91
79
O
O
74
76
Ph
Ph
Scheme 15 Alkylation of a b-hydroxysilane
80
81
TBDPSO
One striking demonstration of the utility of this method is
described in Scheme 15; alcohol 74 is subject to Peterson
elimination under either acidic or basic conditions. How-
ever, smooth transfer of the PMB occurs in this instance
with no evidence of 4-phenyl-1-butene, providing a
unique example of b-hydroxysilane alkylation. As in the
reactions using pre-formed oxypyridinium triflate re-
agents, MgO is included in the reaction mixture as a ter-
minal acid scavenger to maintain acid/base neutrality.
TBDPSO
O
O
OMe
OMe
OH
OPMB
82
83
HO
PMBO
In-situ generation of the methyl triflate salt of 75 solved
the initial problems — instability and insolubility — asso-
ciated with the synthesis of PMB ethers using neutral oxy-
pyridinium salts. However, this solution introduces a new
complication, which is that the user must stock and handle
the highly reactive (and expensive) activator, methyl tri-
flate. The Paquette lab developed an alternative protocol
that addresses this concern by substituting an acid catalyst
in place of methyl triflate for activating the PMBO-lepi-
dine reagent as shown in Scheme 16.32
H
H
84
85
PSB reagent. With general success in the arylmethylation
of alcohols using oxypyridinium salts, we returned to the
original challenges associated with the synthesis of PSB
ethers. p-Siletanylbenzyloxypyridinium triflate 18 can be
synthesized according to Scheme 17,34 and research quan-
tities of 18 can be obtained commercially.35 Initial attach-
ment of the pyridyl ring followed by Grignard formation
was the preferred order of addition. Alkylation of the pyr-
idyl nitrogen via MeOTf addition completes the synthesis
of 18.
75, cat. CSA
R
OH
R
OPMB
CH2Cl2, r.t.
73–95%
Scheme 16 Acid-catalyzed conversion of alcohols to PMB ethers
OH
Although the Paquette protocol involves acidic condi-
tions, the substrate scope includes several potentially
acid-sensitive compounds (Table 3). The authors point
out inherent and general advantages to using PMBO-lepi-
dine 75 instead of PMB trichloroacetimidate: PMBO-
lepidine is easier to prepare and handle, it shows no sign
of decomposition upon prolonged storage, and the main
byproduct of the reaction (either lepidone or N-methyl-
lepidone, depending on the activation protocol) is easily
removed during aqueous workup and/or chromatographic
purification. Trichloroacetamide is a notoriously prob-
lematic byproduct of trichloroacetimidate reactions.
PMBO-lepidine (75) is now commercially available.33
1. 2-Cl-pyridine
KOH, 97%
O
TfO–
N+
2. Mg metal,
Me
Si
BrCH2CH2Br
18
Br
Si
55%
Cl
3. MeOTf, 95%
Scheme 17 Synthesis of PSB-transfer reagent
Oxypyridinium salt 18 has similar reactivity to that of
benzyloxypyridinium salt 21, and converts alcohols into
PSB ethers readily (Table 4).
Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York

850
P. A. Albiniak, G. B. Dudley
ACCOUNT
Table 4 Synthesis of PSB Ethers Using 18
and Cece O’Leary for developing an improved procedure for the
synthesis of PMB reagent 75, which enabled commercialization of
this reagent to move forward.
Entry Alcohol
Ether
Yield (%)
90
OH
OPSB
1
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Acknowledgment
We thank the FSU Department of Chemistry and Biochemistry and
the FSU Research Foundation (GAP Award) for support of this
work. Prof. Leo Paquette (Ohio State University) and Dr. Nate Wal-
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Synlett 2010, No. 6, 841–851 © Thieme Stuttgart · New York