A bench-stable organic salt for the benzylation of alcohols

Article abstract of DOI:10.1055/s-2005-921898

2-Benzyloxy-1-methylpyridinium inflate (Bn-OPT) effects the benzylation of alcohols in the absence of acidic or basic promoters. Solutions of Bn-OPT and primary, secondary, or tertiary alcohols give rise to the corresponding benzyl ethers upon mild heating. Acid scavengers are generally included in the reaction mixture. Bn-OPT is crystalline and bench-stable. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921898

3142
LETTER
A Bench-Stable Organic Salt for the Benzylation of Alcohols
B
enzylation of Alc
e
ohols vin W. C. Poon, Sarah E. House, Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: gdudley@chem.fsu.edu
Received 21 September 2005
and potentially useful. Triflate salt 2 is a white, micro-
crystalline solid that is typically stored in a vial at room
temperature until needed.
Abstract: 2-Benzyloxy-1-methylpyridinium triflate (Bn–OPT) ef-
fects the benzylation of alcohols in the absence of acidic or basic
promoters. Solutions of Bn–OPT and primary, secondary, or tertia-
ry alcohols give rise to the corresponding benzyl ethers upon mild
heating. Acid scavengers are generally included in the reaction mix-
ture. Bn–OPT is crystalline and bench-stable.
Table 1 lists representative examples from our initial
screening of the reaction between 3-phenylpropanol (3a)
and Bn–OPT 2. Dichloroethane (DCE), in which 2 readily
dissolves, is a convenient reaction solvent. MgO may be
employed as an acid scavenger, although the reasonable
yield achieved in the absence of an acid scavenger sug-
gests that it is not critical (Table 1, entry 5). The presumed
by-product of the reaction, 1-methyl-2-pyridone (5), is
highly polar, water soluble, and easy to separate from
most benzyl ethers. A small amount of Bn2O is typically
formed, possibly as a consequence of adventitious
moisture.
Key words: synthesis, benzyl ethers, protecting groups, alcohols
Benzyl ethers play an important role in synthetic chemis-
try as protecting groups for sensitive alcohol functional-
ity.1 Most benzyl ethers are formed using one of two
standard protocols: (1) benzyl halide and base or (2) ben-
zyl trichloroacetimidate and acid2 (Figure 1). Herein we
report a third option.
Table 1 Initial Screening of Benzylation Conditions
standard benzylation protocols:
this report:
ROH
RO
Ph
M
ROH
CCl3
NH
R'
OTf
Ph
OBn
additive
4a
Ph
O
Br
Ph
O
NR"
MeOTf
Ph
OH
BnO
N
DCE
reflux
18–24 h
O
Me
HOTf
M = Na, K, etc. trichloroacetimidates
TfOH +
3a
2
(basic)
(acidic)
(neutral)
covalent activation
MeN
5
Figure 1 Synthesis of benzyl ethers from alcohols.
Entry
Additive
Equivalents of 2
Yielda
1
2
3
4
5
6
7
2,6-lutidine
Hünig’s base
K2CO3
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%
The need for acid or base activation limits benzylation
reactions to substrates that tolerate such conditions. A pre-
activated benzylation reagent – that is, one that provides
the ether simply upon mixing with the alcohol substrate –
would be ideal. Towards this end, we envision covalent
activation of an acetimidate surrogate as a means of
preparing benzyl ethers under neutral conditions
(Figure 1).3–6
none
MgO
MgO
KOH,
18-crown-6
BnOH
Cl
OTf
MeOTf
a Estimated by 1H NMR spectroscopy. Value in parenthesis refers to
calculated yield based on recovered alcohol.
O
N
BnO
N
PhMe, reflux
PhMe
91%
N
Me
1
2
95%
Scheme 1 Synthesis of benzyloxypyridinium triflate 2 (Bn–OPT).
The conditions described in Table 1, entry 6 [2 (2.0
equiv), MgO] were chosen for further screening of prima-
ry, secondary, and tertiary alcohols (Table 2). Phenol 3g
reacted sluggishly (Table 2, entry 7), presumably because
it is less nucleophilic than an aliphatic alcohol. The chiral
ester (Table 2, entry 4) showed no evidence of epimeriza-
tion, which is important due to the propensity of other
benzylation protocols to epimerize labile chiral centers.8
This Letter describes fruitful efforts aimed at reducing this
idea to practice using 2-benzyloxypyridine (1)7 as the ace-
timidate surrogate and benzyloxypyridinium triflate 2
(Bn–OPT, Scheme 1) as the covalently activated reagent.
The benzylation of alcohols using Bn–OPT is general
As outlined above, a wide range of benzyl ethers are
formed simply upon heating the alcohol substrates in the
presence of 2. The avoidance of strongly basic reaction
SYNLETT 2005, No. 20, pp 3142–3144
Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921898; Art ID: S08705ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

LETTER
Benzylation of Alcohols
3143
In summary, we have disclosed initial findings on the syn-
thesis and utility of Bn–OPT (2), which may in time
emerge as a choice reagent for the protection of alcohols.
Further optimization is in progress. The benzylation reac-
tions cover a broad spectrum of primary, secondary, and
tertiary alcohol substrates without the need for acidic or
basic promoters, and the reaction mixture can be buffered
using acid scavengers. Results from our ongoing develop-
ment of this and related reagents will be reported in due
course.
Table 2 Benzylation of Representative Alcohols
OTf
2.0 equiv MgO
ROBn + Bn2O
ROH
BnO
N
DCE, reflux, 21–23 h
Me
3
2
4
6
Entry
1
ROH 3
ROBn 4
Yielda
76%
Ph
OH
Ph
4a
Me
OBn
3a
2
3
73%
70%
Me
Ph
OH
Ph
OBn
3b
4b
Bn–OPT (2)
OH
MeOTf (1.05 equiv) was added to an ice-cold solution of 17 in tol-
uene (1.0 M) under argon. The ice-bath was removed and 2 precip-
itated from the reaction mixture. After 40 min at r.t., the volatiles
were removed in vacuo to yield 2 as a white, microcrystalline solid;
mp 82–86 °C.
OBn
3c
4c
4
5
6
7
72%b
84%
54%
45%c
Me
Me
OH
OBn
MeO2C
MeO2C
1H NMR (300 MHz, CDCl3): d = 8.49 (d, J = 4.8 Hz, 1 H), 8.33
(apparent t, 1 H, J = 8.3 Hz), 7.61 (d, J = 9.0 Hz, 1 H), 7.51–7.40
(m, 6 H), 5.56 (s, 2 H), 4.11 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 148.0, 143.8, 132.5, 129.6,
129.1, 128.5, 119.0, 112.1, 74.5, 42.0.
HRMS (ESI+): m/z calcd for C13H14NO+: 200.1070; found:
200.10704.
3d
4d
OH
OBn
OBn
3e
4e
Me
OH
Me
3f
4f
Benzylation of Alcohols Using Bn–OPT (2)
A mixture of Bn–OPT 2 (2.0 equiv), MgO (2.0 equiv), and alcohol
3 (1.0 equiv) in DCE (ca. 0.5 M) was heated in an oil bath at 83 °C
for 21–23 h. The reaction mixture was filtered through Celite, and
the filtrate was concentrated under reduced pressure. Silica gel
chromatography afforded 4 and small amounts of Bn2O, the source
of which is under investigation.
Ph
OH
Ph
OBn
3g
4g
a Estimated yield of 4 unless otherwise indicated; product and Bn2O
by-product (ca. 10% by weight) were difficult to separate by silica gel
chromatography.
b Isolated yield of pure product, determined by chiral HPLC to be
>99% ee.
Acknowledgment
c Alcohol 3g was also recovered in 46% yield.
This research was supported by the FSU Department of Chemistry
and Biochemistry. S.E.H. received the Brautlecht Fellowship for
undergraduate research (2004). We thank Dr. Joseph Vaughn for
assistance with the NMR facilities, Dr. Umesh Goli for providing
the mass spectrometry data, and the Krafft Lab for the use of their
FT-IR instrument.
conditions permits the benzylation of chiral, epimerizable
alcohols with no apparent loss of enantiomeric purity.
The active reagent, Bn–OPT 2, is prepared by treating 2-
benzyloxypyridine7 in toluene with a slight excess of
methyl triflate. The material thus obtained is analytically
pure; recrystallization of 2 from THF–hexanes had no
discernable effect on its properties.
References
(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) TfOH is generally required, whereas milder acids will
promote the formation of p-methoxybenzyl ethers; see ref. 1.
(3) Scattered literature reports provided the foundation for this
work. In particular, alkoxypyridinium bromides decompose
to pyridones and alkyl bromides via nucleophilic attack of
the bromide ion (ref. 4), whereas alkoxypyridinium
sulfonates are isolable (ref. 5). Note that Mukaiyama’s
reagent (ref. 6) has been employed to convert alcohols into
thioesters and azides.
MeOTf, MgO
r.t. to reflux
Ph
OH
Ph
OBn
24 h, DCE
56% (unoptimized)
BnO
N
3a
4a
1
Scheme 2 One-pot benzylation using in situ covalent activation
of 1.
Alternatively, in situ activation of 2-benzyloxypyridine
(1) can be accomplished by selective methylation of 1 in
the presence of an alcohol [Scheme 2, 1 (2 equiv), MgO
(2 equiv), and MeOTf (2 equiv)]. This one-pot procedure
eliminates the need to isolate the activate reagent.
(4) Joshi, R. A.; Ravindranathan, T. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1984, 23, 260.
(5) (a) Beattie, D. E.; Crossley, R.; Dickinson, K. H.; Dover, G.
M. Eur. J. Med. Chem. 1983, 18, 277. (b) See also:
Kornblum, N.; Coffey, G. P. J. Org. Chem. 1966, 31, 3449.
Synlett 2005, No. 20, 3142–3144 © Thieme Stuttgart · New York

3144
K. W. C. Poon et al.
LETTER
solution of benzyl alcohol (0.5 M, 1.0 equiv), 2-chloro-
pyridine (1.2 equiv), KOH (3.2 equiv, powdered with a
mortar and pestle), and 18-crown-6 (0.05 equiv) was heated
at reflux for 1 h with azeotropic removal of water. Routine
aqueous workup and purification on silica gel afforded 1 in
96% yield.
(6) For leading references, see: (a) Hojo, K.; Yoshino, H.;
Mukaiyama, T. Chem. Lett. 1977, 437. (b) Hojo, K.;
Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem.
Lett. 1977, 635.
(7) (a) Serio, A. J.; Duggan, E.; Grabowski, J. J.; Russ, W. K.
Synthesis 1980, 573. (b) Cherng, Y.-J. Tetrahedron 2002,
58, 4931. (c) We prepared 1 by the following procedure,
which is a modification of that reported in ref. 7a: A toluene
(8) Widmer, U. Synthesis 1987, 568.
Synlett 2005, No. 20, 3142–3144 © Thieme Stuttgart · New York