Mix-and-heat benzylation of alcohols using a bench-stable pyridinium salt

Article abstract of DOI:10.1021/jo0602773

2-Benzyloxy-1-methylpyridinium inflate (1) is a stable, neutral organic salt that converts alcohols into benzyl ethers upon warming. The synthesis and reactivity of 1 are described herein. Benzylation of a wide range of alcohols occurs in good to excellent yield.

Full text of DOI:10.1021/jo0602773

Mix-and-Heat Benzylation of Alcohols Using a Bench-Stable
Pyridinium Salt
Kevin W. C. Poon and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306-4390
gdudley@chem.fsu.edu
ReceiVed February 9, 2006
2-Benzyloxy-1-methylpyridinium triflate (1) is a stable, neutral organic salt that converts alcohols into
benzyl ethers upon warming. The synthesis and reactivity of 1 are described herein. Benzylation of a
wide range of alcohols occurs in good to excellent yield.
Introduction
Benzyl ethers are among the most common and important
protecting groups in organic synthesis.1 Like other alkyl ethers,
they are advantageous for their stability to a wide range of
reaction conditions and for the minimal electronic impact that
they impart on the oxygen atom to which they are attached.
For example, benzyl ethers are often employed to establish
chelation control during addition to chiral aldehydes, which
provides selectivity opposite that predicted by the acyclic
Felkin-Anh model and observed with bulky silyl ethers.2
Similarly, benzyl-protected glycosyl donors are “armed” relative
to acylated analogues.3 Among alkyl ethers, benzyl (and
modified arylmethyl) ethers are perhaps the most versatile with
respect to modes of cleavage, which include hydrogenolysis,
oxidation, and acidic decomposition under a range of experi-
mental protocols (Figure 1).4
FIGURE 1. Standard benzylation protocols and desired objective.
most popular protocols being (1) the Williamson ether synthesis,
an SN2-type reaction between alkali metal alkoxides and benzyl
bromide, and (2) coupling using benzyl trichloroacetimidate,5
which is generally promoted by trifluoromethanesulfonic acid
(triflic acid, TfOH).6 Typical benzylation reactions are thus
limited to substrates that tolerate either strongly acidic or basic
conditions.7 â-Hydroxy esters, for example, are subject to several
acid- or base-catalyzed reactions, including retro-Aldol, elimina-
tion, and epimerization of stereogenic centers R- to the carbonyl
group. Benzylation of these ubiquitous intermediates in the
Relatively harsh conditions are typically required for generat-
ing benzyl ethers from the corresponding alcohol, with the two
(1) (a) Greene, T. W., Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999. (b) Kocienski,
P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2003.
(2) Gawley, R. E.; Aube´, J. In Principles of Asymmetric Synthesis;
Baldwin, J. E., Magnus, P. D., Eds.; Tetrahedron Organic Chemistry Series
14; Pergamon: Tarrytown, NY, 1996; pp 121-134.
(3) (a) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997. (b) Mootoo, D. R.; Konradsson, P.; Udodong,
U.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 5583-5584. (c) Paulsen;
H.; Richter, A.; Sinnwell, V.; Stenzel, W. Carbohydr. Res. 1978, 64, 339-
362.
(4) Recent arylmethyl protecting groups that are cleaved under mild
conditions: (a) Jobron, L.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121,
5835-5836. (b) Plante, O.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem.
Soc. 2000, 122, 7148-7149. (c) Lam, H.; House, S. E.; Dudley, G. B.
Tetrahedron Lett. 2005, 46, 3283-3285.
(5) (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240-1241. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247-2250. (c) Eckenberg, P.; Groth, U.; Huhn, T.;
Richter, N.; Schmeck, C. Tetrahedron 1993, 49, 1619-1624.
(6) Boa, A. N.; Jenkins, P. R. Benzyl 2,2,2-Trichloroacetimidate. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley and Sons: New York, 1995; Vol. 1, pp 374-375.
(7) p-Methoxybenzyl (PMB) ethers may be formed under mild conditions
that do not extend to benzylation (ref 1).
10.1021/jo0602773 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/07/2006
J. Org. Chem. 2006, 71, 3923-3927
3923

Poon and Dudley
SCHEME 1. Synthesis of 2-Benzyloxy-1-methylpyridinium
Triflate (1)
synthesis of polyketides and other important compounds can
be problematic. Selective protection of polyol systems (e.g.,
carbohydrates) can also be complicated by base-catalyzed
migration of esters and silyl ethers and by acid-catalyzed
cleavage of silyl ethers and acetal linkages.
Benzylation of alcohols under mild and nearly neutral
conditions would constitute a significant advance in synthetic
chemistry. A recent review addresses the myriad options for
protecting alcohols using mild, convenient, and environmentally
friendly conditions, but no methods for the formation of benzyl
ethers are discussed.8 Silylation and acylation of alcohols can
be accomplished under effectively neutral conditions using
activated reagents that react with the free alcohol.1 Imidazole
and DMAP are frequently employed to activate silyl and acyl
chlorides; conveniently, they are also capable of scavenging any
acid that is produced during the course of the reaction.
Protonation of benzyl trichloroacetimidate provides an activated
reagent that reacts with free alcohols, but this mode of activation
precludes neutralization of free acid. In principle, irreversible
covalent activation (alkylation) of a trichloroacetimidate sur-
rogate would enable the formation of benzyl ethers in the
absence of external base or acid and in the presence of acid
scavengers (if desired).
We envisioned that 2-benzyloxypyridine9 could serve as an
imidate surrogate for benzylation of alcohols. Pyridinium salts
have been employed in esterification reactions, with Mukaiya-
ma’s 2-chloro-1-methylpyridinium iodide being perhaps the
most popular.10 Conversion of alcohols into thioesters and azides
using 2-fluoro-1-methylpyridinium tosylate has also been
demonstrated.11 The two pieces of prior knowledge that were
most influential in guiding the current work are as follows: (1)
certain 2-alkoxypyridinium bromides decompose to bromoal-
kanes and pyridones;12 (2) 2-alkoxypyridinium sulfonates do
not proceed spontaneously to alkyl sulfonates.13 We anticipated
that decomposition of 2-alkoxypyridinium sulfonates in the
presence of alcohols would give rise to alkyl ethers and
pyridones, and we reported preliminary data in support of this
hypothesis.14
TABLE 1. Initial Optimization
entry
acid scavenger
equiv of 1
yieldb,c (%)
1
2
3
4
5
6
7
2,6-lutidine
Hu¨nig’s base
K2CO3
MgO
none
MgO
1.0
1.0
1.0
1.0
1.0
2.0
3.0
43 (57)
29 (39)
68 (93)
78 (93)
53 (87)
76 (85)
87
MgO
a See the Supporting Information for details. b Values in parentheses refer
to the calculated yield based on recovered alcohol. c Estimated by 1H NMR
spectroscopy.
Results and Discussion
1. Synthesis and Isolation of Pyridinium Salt 1. The
synthesis of 1 is illustrated in Scheme 1. Benzyl alcohol was
coupled with 2-chloropyridine using a modification of a reported
procedure9a to afford 2-benzyloxypyridine (5) in high yield. We
then screened a range of alkylating agents and solvents in search
of optimal conditions for the irreversible covalent activation of
5. The current best protocol is to add methyl triflate (bp 94-
99 °C) to an ice-cold solution of 5 in toluene and allow the
mixture to warm to ambient temperature. A white microcrys-
talline solid (1) forms within minutes. Analytically pure 1 (mp
82-86 °C) can be isolated by filtration or by evaporation of
the supernatant under reduced pressure.15 This salt (1) is
remarkably stable. We store it under an argon atmosphere either
in the refrigerator or on the laboratory benchtop, and the white
crystals of 1 are routinely handled open to the air. No differences
have been observed between freshly prepared crystals and those
that were prepared 3 months prior.
2. Development and Analysis of the Optimal Benzylation
Protocol. At room temperature, the title reagent is freely soluble
in chlorinated solvents (dichloromethane, chloroform, dichlo-
roethane), partially soluble in ethereal solvents (THF and ether),
and insoluble in aromatic hydrocarbons (benzene, toluene).
Solutions of 1 and 3-phenylpropanol (2a) provided the desired
benzyl ether upon heating. Because of its ability to solvate 1
and its convenient boiling point (83 °C), the initial screening
of reaction conditions was conducted in dichloroethane (DCE).
The first issue that we endeavored to address was the
presumed mild acidity of hydroxypyridinium triflate 4 (Table
Herein we describe in detail our investigation into the
synthesis and reactivity of 2-benzyloxy-1-methyl-pyridinium
triflate (Bn-OPT, 1), which indeed provides benzyl ethers simply
upon warming in the presence of a free alcohol. The overall
balanced equation for the benzylation of alcohols (2 f 3) is
shown in eq 1. Oxypyridinium triflate 1 may eventually supplant
benzyl trichloroacetimidate for the synthesis of benzyl ethers
from alcohols.
(8) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P.
Chem. ReV. 2004, 104, 199-250.
(9) (a) Serio Duggan, A. J.; Grabowski, E. J. J.; Russ, W. K. Synthesis
1980, 573-575. (b) Cherng, Y.-J. Tetrahedron 2002, 58, 4931-4935.
(10) (a) Armstrong, A. 2-Chloro-1-methylpyridinium Iodide. In Ency-
clopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley
and Sons: New York, 1995; Vol. 2, pp 1174-1175. (b) Mukaiyama, T.
Angew. Chem., Int. Ed. Engl. 1979, 18, 707-808.
(12) Joshi, R. A.; Ravindranathan, T. Ind. J. Chem. Sect. B 1984, 23,
260-262.
(13) (a) Beattie, D. E.; Crossley, R.; Dickinson, K. H.; Dover: G. M.
Eur. J. Med. Chem. 1983, 18, 277-285. (b) Kornblum, N.; Coffey, G. P.
J. Org. Chem. 1966, 31, 3449-3451.
(14) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett 2005, 3142-
3144.
(11) See ref 10b and: (a) Hojo, K.; Yoshino, H.; Mukaiyama, T. Chem.
Lett. 1977, 437-440. (b) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.;
Mukaiyama, T. Chem. Lett. 1977, 635-636.
(15) Recrystallization of 1 from THF has no discernible effect on its
properties.
3924 J. Org. Chem., Vol. 71, No. 10, 2006

Mix-and-Heat Benzylation of Alcohols
SCHEME 2. SN1 vs SN2 Mechanistic Observations
FIGURE 2. Observed byproducts.
TABLE 2. Screening for Optimal Solvent
entry
solvent
yielda (%)
1
2
3
4
5
6
7
8
1,2-dichloroethane (DCE)
nitromethane
acetonitrile
N-methyl-2-pyrrolidinone (NMP)
toluene
benzene
67
low
-
-
91
93
>95
>95
chlorobenzene
benzotrifluoride (PhCF3)
1
a Estimated by HNMR spectroscopy.
1). Among the various acid scavengers that we evaluated,
heterogeneous inorganic salts were most compatible with the
desired benzylation reaction (entries 3-5). Soluble amines
seemed to interfere with the coupling reaction (entries 1 and
2), and it was not clear if external amine bases would present
any advantage in terms of moderating the potential acidity of
pyridinium 4. Based on these results and a quick cost analysis,
magnesium oxide (MgO) emerged as our preferred choice, and
so MgO was routinely included in all subsequent experiments.
In addition to the desired benzyl ether, two byproducts were
observed in the crude product mixture: 1-methyl-2-pyridone
(6) and dibenzyl ether (Bn2O, 7) (Figure 2). Pyridone 6, the
conjugate base of hydroxypyridinium 4, is the expected byprod-
uct of the benzylation reactions using 1. Pyridone 6 is freely
water-soluble and easily removed by aqueous extraction. The
source of Bn2O is not clear. It may derive from reaction of 1
with MgO, although small amounts of 7 were also observed
during control experiments that did not include MgO. Adventi-
tious moisture may be partly responsible for the formation of
7. Because dibenzyl ether is unlikely to interfere with most
benzylation reactions, we do not consider it to be a serious
concern. Nonetheless, it was difficult to separate 7 from many
of the alkyl benzyl ethers generated during the course of our
investigations.
epimerization detectable by chiral HPLC analysis.17 Benzyl ether
3e was easily separated from Bn2O by chromatography on silica
gel. A series of primary and secondary alcohols were benzylated
under similar conditions and with similar efficiencies (70-76%
yield), as described in our preliminary report.14
Despite limited solubility, mixtures of 1 in many solvents
became homogeneous upon warming, especially as the tem-
peratures approached the melting point of 1 (82-86 °C).
Toluene emerged as a promising choice in small-scale explor-
atory experiments. Therefore, we screened a range of aromatic
solvents (2b f 3b, Table 2). Yields improved significantly in
aromatic hydrocarbon solvents relative to dichloroethane (>90%
vs 67%).
Reactions conducted in toluene (and, to a lesser extent,
benzene and chlorobenzene) gave rise to trace amounts of
benzylated solvent molecules (Scheme 2, vide infra). No such
(16) Widmer, U. Synthesis 1987, 568-570.
(17) In response to a reviewer’s suggestion for documentation of the
advantage of 1 over benzyl trichloroacetimidate, an additional experiment
was conducted using trimethylsilylethanol (13) as a test substrate. Note that
13 is subject to Peterson elimination under acidic (or basic) conditions;
see: Ager, D. J. Org. React. 1990, 38, 1. Benzylation of trimethylsilylethanol
(13 f 14) has not been reported previously. Reaction of 13 with 1 proceeded
to complete conversion with no evidence of decomposition, whereas a
similar experiment using benzyl trichloroacetimidate yielded no evidence
A crucial efficacy test for 1 was the benzylation of chiral
â-hydroxy ester 2e (eq 2). Benzyl ethers derived from such
1
of the desired product (14). See the Supporting Information for H NMR
spectra of the crude product mixtures after aqueous workup.
chiral alcohols are difficult to obtain under Williamson ether
conditions because of the potential both for â-elimination and/
or for epimerization of the labile stereogenic center R- to the
ester. Attempts at effecting the benzylation of 2e under
Willamson ether conditions were unsuccessful.16 Benzylation
using 1 proceeded efficiently (2e f 3e) with no evidence of
J. Org. Chem, Vol. 71, No. 10, 2006 3925

Poon and Dudley
TABLE 3. Scope and Limitations
a Yields are estimated by 1H NMR spectroscopy, unless otherwise indicated. b Reagent 1 stored for 3 months at room temperature before use. c Not
determined; see ref 19. d Isolated yield of pure product. e Unreacted 2k also observed in the crude product mixture.
products were observed from reactions conducted in benzotri-
fluoride (R,R,R-trifluorotoluene, PhCF3).
Having identified our preferred solvent, acid scavenger, and
time and temperature, we were ready to probe the scope and
limitations of what we consider to be mild and effectively neutral
benzylation conditions. The tolerance of this protocol for
sensitive functionality will be determined in due course, but
for an initial data point we tested our benzylation reaction in
the presence of a primary silyl ether (eq 3).18 The desired benzyl
ether (3a) was obtained in excellent yield, and silyl ether 8 was
recovered unchanged.17
In addition to being an excellent solvent for the present
benzylation reactions, benzotrifluoride is low-cost, moderately
volatile (bp 100-103 °C), and highly regarded as an environ-
mentally friendly alternative to chlorinated solvents. Benzotri-
fluoride is our choice of solvent for the benzylation reactions,
although Table 2 indicates that other aromatic hydrocarbons are
also suitable.
3926 J. Org. Chem., Vol. 71, No. 10, 2006

Mix-and-Heat Benzylation of Alcohols
mixture was then cooled to room temperature and partitioned
between ethyl acetate (20 mL) and water (10 mL). The organics
were washed (brine), dried (Na2SO4), filtered, concentrated under
vacuum, and purified on silica gel (elution with 100:1 hexane/
EtOAc) to provide 3.28 g of 5 (96% yield) as a yellow liquid.
2-Benzyloxy-1-methylpyridinium Triflate (1). To a cold (0 °C)
solution of 2-benzyloxypyridine (5) (100 mg, 0.54 mmol) in toluene
(0.540 mL) was added methyl trifluoromethanesulfonate (64 µL,
0.57 mmol). The mixture was allowed to warm to room temperature,
which resulted in the formation of a white crystalline precipitate.
After 40 min, the volatiles were removed in vacuo, providing 0.172
g (91% yield) of 1 as a white microcrystalline solid, mp 82-86
°C. A similar large-scale experiment afforded 6.52 g (86% yield)
of 1 as a white solid, which was collected by filtration of the crude
reaction mixture through a fritted glass funnel, followed by drying
under vacuum: 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J ) 7.8
Hz, 1H), 8.34 (apparent t, J ) 8.3 Hz, 1H), 7.59 (d, J ) 9.0 Hz,
1H), 7.53-7.42 (m, 6H), 5.58 (s, 2H), 4.13 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.6, 148.0, 143.8, 132.5, 129.6, 129.1, 128.5,
119.0, 112.1, 74.5, 42.0; HRMS (ESI+) found 200.1070 (M -
OTf)+ (calcd for C13H14NO+ 200.1075).
Standard Procedure for Benzylation of Alcohols (2 f 3). A
mixture of pyridinium triflate 1 (100 mg, 0.29 mmol), benzotri-
fluoride (PhCF3, 0.29 mL), MgO (11.5 mg, 0.29 mmol, vacuum-
dried), and alcohol 2 (0.14 mmol) was heated at 83 °C for 1 day.
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 benzyl ether 3 (see Table 3), admixed
with varying amounts of Bn2O.
Benzylation of Diethylene Glycol Monomethyl Ether (Monogly-
me, 2d). A mixture of pyridinium triflate 1 (581 mg, 1.67 mmol),
benzotrifluoride (PhCF3, 1.7 mL), MgO (67 mg, 1.7 mmol), and
2d (100 mg, 0.83 mmol) was subjected to the standard procedure
to afford 0.163 g (93%) of diethylene glycol benzyl methyl ether
(3d) as a pale yellow liquid, which exhibited spectroscopic
properties consistent with the reported data.23
3. Mix-and-Heat Benzylation of Alcohols: Scope and
Limitations. Table 3 illustrates the benzylation reactions of
representative alcohols under our preferred conditions. Primary
(entries 1-6) and secondary (entries 7-9) alcohols all provided
the desired benzyl ethers (3a-h) in good to excellent yield.
Among these substrates are an allylic alcohol (entry 4), a
homoallylic alcohol (entry 9), and a â-hydroxy ester (entry 6).
We saw no difference between freshly prepared reagent and a
sample of 1 that had been aged for three months (cf. entries 1
and 2).
Tertiary alcohols and phenols provided variable results
(entries 10-12). 1-Adamantanol (2i), which is not prone to
elimination, afforded benzyl ether 3i in good yield. Tertiary
benzylic alcohol 2j, which is highly prone to elimination,
provided only a moderate yield of ether 3j. These two substrates
may approximate the upper and lower limits of benzylation
efficiency for tertiary alcohol substrates using 1. Phenols (e.g.,
2k, entry 12) reacted sluggishly in our study, possibly due to a
decrease in nucleophilicity relative to aliphatic alcohols. Because
benzylation of phenols can be accomplished using Mitsunobu
conditions,20 this class of substrates was not investigated further.
4. Insights into the Potential Reaction Mechanism. The
mechanistic course of benzylation reactions using 1 undoubtedly
falls along the continuum between SN1 and SN2 pathways
(Scheme 2). Although we have not performed detailed kinetic
studies, two key observations are more consistent with an SN1-
type mechanism. Benzylation reactions conducted in toluene
afforded trace amounts of o-12 and p-12. We assume that these
compounds derive from Friedel-Crafts alkylation of toluene,
which suggests the presence of a highly electrophilic benzylating
species (e.g., benzyl cation 9) in the reaction mixture and argues
in favor of a more SN1-like pathway. Methoxypyridinium salt
1021 was completely inert under similar conditions, which argues
against an SN2-type pathway. We therefore surmise that the
actual benzylation event using 1 is better approximated by the
SN1 mechanism. This conclusion is consistent with behavior
observed in trichloroacetimidate reactions.22
Benzylation of 1-Adamantanol (2i). A mixture of pyridinium
triflate 1 (100 mg, 0.29 mmol), benzotrifluoride (PhCF3, 0.29 mL),
MgO (11.5 mg, 0.29 mmol), and 2i (21.8 mg, 0.14 mmol) was
subjected to the standard procedure to afford 0.0363 g of a yellow
1
oil, which was determined by H NMR analysis to consist of 8.7
mg of Bn2O and 0.0276 g (80%) of 1-benzyloxyadamantane (3i).
Spectroscopic analysis was consistent with the data reported
previously for 3i.24
Acknowledgment. We thank the FSU Department of
Chemistry and Biochemistry for support of this work, the NMR
Facility for spectroscopic support, the Krafft laboratory for the
use of their IR spectrometer and melting point apparatus, and
Dr. Umesh Goli for assistance with mass spectrometry.
Supporting Information Available: Characterization data and
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Conclusion
JO0602773
We report the synthesis and reactivity of 2-benzyloxy-1-methyl-
pyridinium triflate (1), a novel benzylation reagent for alcohols.
Salt 1 is easy to prepare, bench-stable, and preactivated. No
acidic or basic promoters are needed for benzyl transfer, which
occurs simply upon warming in the presence of the alcohol
substrate. Work on this and related reagents is in progress.
(18) Silyl ether 8 was prepared in quantitative yield by treating a solution
of 4-(4-methoxyphenyl)butan-1-ol in CH2Cl2 with DMAP (0.10 equiv), Et3N
(2.0 equiv), and TBSCl (1.1 equiv). See the Supporting Information for
characterization data.
(19) The mass balance exceeded the theoretical yield of 3, and dibenzyl
ether (7) was observed by TLC and/or 1H NMR analysis. The amount of 7
1
could not be estimated with any precision based on the H NMR spectra
because the diagnostic benzylic singlets were coincident.
(20) Hughes, D. L. Org. React. 1992, 42, 335-656.
Experimental Section
(21) Methoxypyridinium triflate 10 was prepared in 85% yield (unop-
timized) by a procedure similar to that used for the preparation of 1. See
the Supporting Information for characterization data.
(22) Cramer, F.; Hennrich, N. Chem. Ber. 1961, 94, 976-989.
(23) Grobelny, Z.; Stolarzewicz, A.; Maercker, A.; Krompiec, S.;
Kasperczyk, J.; Rzepa, J. J. Organomet. Chem. 2004, 689, 1580-1585.
(24) Hartz, N.; Prakash, G. K. S.; Olah, G. A. Synlett 1992, 569-572.
2-Benzyloxypyridine (5). The following is a modification of a
reported procedure.9a A mixture of benzyl alcohol (2.00 g, 18.5
mmol), 2-chloropyridine (3.46 g, 30.5 mmol), KOH (3.42 g, 61.0
mmol, ground with a mortar and pestle), toluene (37 mL), and 18-
crown-6 (24.4 mg, 0.925 mmol) was heated at reflux for 1 h with
azeotropic removal of water (Dean-Stark trap). The reaction
J. Org. Chem, Vol. 71, No. 10, 2006 3927