A novel acid-catalyzed O-benzylating reagent with the smallest unit of imidate structure

Article abstract of DOI:10.1021/ol302222p

Formal trimerization of the smallest unit of benzyl imidate leads to 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT), which can be used as an acid-catalyzed O-benzylating reagent. The reaction of various functionalized alcohols with 0.4 equiv of TriBOT in the presence of trifluoromethanesulfonic acid afforded the benzyl ethers in good yields. TriBOT is an inexpensive stable crystalline solid with high atom economy.

Full text of DOI:10.1021/ol302222p

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5026–5029
A Novel Acid-Catalyzed O‑Benzylating
Reagent with the Smallest Unit of
Imidate Structure
Kohei Yamada, Hikaru Fujita, and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 Japan
kunisima@p.kanazawa-u.ac.jp
Received August 9, 2012
ABSTRACT
Formal trimerization of the smallest unit of benzyl imidate leads to 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT), which can be used as an acid-
catalyzed O-benzylating reagent. The reaction of various functionalized alcohols with 0.4 equiv of TriBOT in the presence of
trifluoromethanesulfonic acid afforded the benzyl ethers in good yields. TriBOT is an inexpensive stable crystalline solid with high atom economy.
The benzyl group is one of the most versatile protecting
groups for hydroxy groups in organic synthesis.1 Typically,
the benzylation of alcohols is carried out using benzyl halide
and a strong base such as NaH (Williamson ether synthesis);
however, this method tends to fail or give lower yields when
it is applied to alcohols possessing alkali-labile functional-
ities. Several methods2 for benzylation occurring under
acidic2aꢀi or nearly neutral conditions2jꢀn have been devel-
oped and can be applied to the benzylation of such alkali-
labile alcohols. The most frequently used acid-catalyzed
benzylating reagent is benzyl 2,2,2-trichloroacetimidate
(BTCAI), which is activated by trifluoromethanesulfonic
acid (TfOH) or trimethylsilyl trifluoromethanesulfonate
(TMSOTf).3 It can be used for the benzylation of β-hydroxy
esters to afford the corresponding benzyl ethers without
a retro-aldol reaction or β-elimination. However, there is
still room for improvement in terms of stability (sensitive
to moisture and heat),4 usability (liquid), atom economy
(additional trichloromethyl group), and cost. The develop-
ment of a practical acid-catalyzed benzylating reagent that
can solve the above-mentioned problems would be
advantageous.
The conversion of imidate structure to the stable amide
by protonation at the nitrogen of BTCAI seems to be a
main driving force in benzylation. In addition, the trichlor-
omethyl group as an electron-withdrawing group will
enhance the reactivity of the imidate as a leaving group.
(1) (a) Greene, T. W.; Wuts, P. G. M. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley-Interscience: New York, 2006. (b)
Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2003.
(2) (a) Onaka, M.; Kawai, M.; Izumi, Y. Bull. Chem. Soc. Jpn. 1986,
59, 1761. (b) Liotta, L. J.; Ganem, B. Tetrahedron Lett. 1989, 30, 4759.
(c) Hatakeyama, S.; Mori, S.; Kitano, K.; Yamada, H.; Nishizawa, M.
Tetrahedron Lett. 1994, 35, 4367. (d) Nakano, M.; Matsuo, J.;
Mukaiyama, T. Chem. Lett. 2000, 29, 1352. (e) Boyer, B.; Keramane, E.-
M.; Roque, J.-P.; Pavia, A. A. Tetrahedron Lett. 2000, 41, 2891. (f) Izumi,
M.; Fukase, K. Chem. Lett. 2005, 34, 594. (g) Aoki, H.; Mukaiyama, T.
Chem. Lett. 2005, 34, 1016. (h) Aoki, H.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 2006, 79, 1255. (i) Okada, Y.; Ohtsu, M.; Bando, M.; Yamada,
H. Chem. Lett. 2007, 36, 992. (j) Lemieux, R. U.; Kondo, T. Carbohydr.
Res. 1974, 35, C4. (k) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett
2005, 3142. (l) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71,
3923. (m) Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth.
2007, 84, 295. (n) Albiniak, P. A.; Dudley, G. B. Synlett 2010, 841.
(3) (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun.
1981, 1240. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247. (c) Widmer, U. Synthesis 1987, 568.
(d) Eckenberg, P.; Groth, U.; Huhn, T.; Richter, N.; Schmeck, C.
Tetrahedron 1993, 49, 1619.
(4) BTCAI can be stored at 5 °C as a solution in hexane for periods of
up to 2 months; see ref 3b.
r
10.1021/ol302222p
Published on Web 09/20/2012
2012 American Chemical Society

applications,5bꢀg but has not been investigated as a benzy-
lating reagent.6 In this paper, we describe the development
of TriBOT as a useful acid-catalyzed O-benzylating reagent.
Table 1. Comparison with BTCAI
TriBOT
42.0
BTCAI
MW of leaving
group per
161.4
benzyl group
contained halogen
atom
none
three chlorine
liquid
form
crystalline
solid
stability
stable in air
sensitive to moisture
and heat
Upon treatment of 3-phenylpropan-1-ol (1a) with Tri-
BOT (0.6 equiv) and TfOH (0.2 equiv) in CH2Cl2 at room
temperature, the benzylation of 1a proceeded smoothly to
form the corresponding benzyl ether 2a in 67% yield
(Table 2, entry 1). However, FriedelꢀCrafts benzylation
products7 and dibenzyl ether (Bn2O), which was probably
derived from residual moisture, were observed as bypro-
ducts. The use of 0.4 equiv of TriBOT marginally influ-
enced the yield of 2a (entry 2). While the reactions using
acetonitrile, DMF, DMSO, AcOEt, toluene, and R,R,R-
trifluorotoluene afforded 2a in poor to moderate yields
(entries 3ꢀ8), the reactions using ethereal solvents (diethyl
ether (Et2O), 1,2-dimethoxyethane (DME), and 1,4-diox-
ane, entries 9, 11, and 13) improved the yields, reducing the
FriedelꢀCrafts products compared with that using CH2Cl2.
When the reactions were conducted using 0.4 equiv of
TriBOT, the yields of 2a were greater than 90% when DME
and 1,4-dioxane were used, except for Et2O (entries 10, 12,
and 14). Among these ethereal solvents, 1,4-dioxane was
used for further examination because the solubility of
TriBOT in it (ca. 1.2 M) is higher than that in others
(Et2O, <100 mM; DME, ca. 0.5 M). Moreover, when
powdered molecular sieves 5A were added as a dehydrating
agent to remove residual moisture, the yield of 2a increased
and the formation of Bn2O decreased (entry 15). Among
these reactions, the formation of a small amount of
N-benzylisocyanuric acid (3)8 was observed as a byproduct
(30% yield based on TriBOT in the case of entry 15). Use
of 0.35 equiv of TriBOT and the same amount of TfOH were
effective for the suppression of the production of 3 (entry 16).
Upon treatment of 1a with 0.35 equiv of TriBOT and the
same amount of various acids, the reactions with TfOH and
TMSOTf gave good yields (Table 3, entries 1 and 2),
whereas the use of the other Brønsted and Lewis acids such
Figure 1. Design and synthesis of TriBOT.
For the development of a new acid-catalyzed benzylating
reagent by exploiting the characteristics of imidate, we
conceived the idea that the formal trimerization of the
smallest unit of benzyl imidate leads to 2,4,6-tris(benzyloxy)-
1,3,5-triazine (TriBOT, Figure 1a). This can be considered
as the smallest benzyl imidate structure without any attach-
ment. The π-electron-deficient triazine ring of TriBOT
would function as an electron-withdrawing group corre-
sponding to the trichloromethyl group of BTCAI. The
molecular weight of the leaving group per one benzyl
group of TriBOT is 3.8 times smaller than that of BTCAI
(Table 1). TriBOT does not contain any halogen atoms.
TriBOT is easily synthesized on a scale of several hundred
grams from benzyl alcohol and cyanuric chloride in the
presence of NaOH by the reported procedure5a as a stable,
crystalline solid material at a low cost (Figure 1b). We did
not observe any irritating or allergenic properties in our
laboratory. Further, the final concomitant leaving group iso-
cyanuric acid (vide infra) can be removed easily by filtration
because it is weakly soluble in many organic solvents (AcOEt,
ca. 0.13% (w/v); CH2Cl2, <0.1% (w/v)); and water, 0.2%
(w/v). These features classify it as an eco-, and user-friendly
reagent. TriBOT has been investigated for several
(5) (a) Hanada, S.; Tanaka, Y.; Nishihata, A.; Ueda, S.; Inamoto, Y.;
Tanimoto, F.; Kitano, H. U.S. Patent 4 074 052, 1978. (b) Srinivas, K.;
Sitha, S.; Rao, V. J.; Bhanuprakash, K.; Ravikumar, K. J. Mater. Chem.
2006, 16, 496. (c) Srinivas, K.; Srinivas, U.; Rao, V. J.; Bhanuprakash,
K.; Kishore, K. H.; Murty, U. S. N. Bioorg. Med. Chem. Lett. 2005, 15,
1121. (d) Spielman, M. A.; Close, W. J.; Wilk, I. J. J. Am. Chem. Soc.
1951, 73, 1775. (e) Sekiguchi, T.; Kurita, N.; Nakazawa, K. Jpn. Kokai
tokkyo koho, JP 54 004 949, 1979. (f) Sekiguchi, T.; Kurita, N.; Nakazawa,
K. Jpn. Kokai tokkyo koho, JP 54 004 950, 1979. (g) Hosoi, T.; Tsugawa, H.;
Mutsui, Y. Jpn. Kokai tokkyo koho, JP 02 293 181, 1990.
as H2SO4, TsOH, and BF3 OEt2 afforded only poor yields
(0ꢀ15%, entries 3ꢀ5). The recovered TriBOT indicates that
3
(7) FriedelꢀCrafts benzylation gave several compounds that could
not be identified because each product is not isolated. The yields were
calculated from integrated values of diarylmethylene peaks (3.92ꢀ4.10
ppm) of 1H NMR as assuming that FriedelꢀCrafts benzylation was
conducted only once on one substrate molecule.
(6) Intermolecular O- to N-rearrangement of benzyl group of TriBOT
catalyzed by tetrabutylammonium iodide was investigated. Reynolds,
G. F.; Nagel, C. J. M.; Larson, P. A. J. Chem. Res., Synop. 1982, 310.
(8) Akteries, B.; Jochims, J. C. Chem. Ber. 1986, 119, 83.
Org. Lett., Vol. 14, No. 19, 2012
5027

Table 2. Screening of Solvent Conditions and Equivalents
of TriBOT
Table 4. Scope and Limitations of Various Alcohols for
Benzylation Using TriBOT
TriBOT
(equiv)
2aa FriedelꢀCraftsa Bn2Oa
entry solvent
(%)
(%)
(%)
1 CH2Cl2
2
0.6
0.4
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.4
0.6
0.4
0.6
0.4
0.4c
0.35c,d
67
60
13
0
33
21
0
6
3
3 CH3CN
4 DMF
5 DMSO
6 AcOEt
7 toluene
8 PhCF3
9 Et2O
10
0
0
0
0
0
0
43
53
71
87
79
92
92
93
91
94
96
2
6
69b
24
7
4
14
13
5
1
11 DME
12
0
16
5
1
13 1,4-dioxane
14
7
16
7
6
15
5
4
16
3
<1
a Yields (%) were determined by 1HNMRbasedon1a using an internal
standard. b Yield contains the benzylated solvent adducts yield. c Powdered
molecular sieves 5A were added. d TfOH (0.35 equiv) was used.
these acids are not sufficiently strong to activate TriBOT
efficiently.
Table 3. Benzylation of 1a with Various Acid Catalysts
recovered 1aa recovered TriBOTb
entry
acid
TfOH
2aa (%)
(%)
(%)
1
2
3
4
5
96
90
5
2
3
0
0
TMSOTf
H2SO4
52
74
76
86
60
91
BF3 OEt2
15
0
3
a Isolated yield unless otherwise indicated. b Yields were calculated
by 1H NMR analysis from a mixture of the product and Bn2O because a
small amount of Bn2O could not be removed from the product. c TfOH
(0.35 equiv) was used. d TfOH (1.2 equiv) was used.
TsOH
a Yields (%) were determined by 1H NMR based on 1a using an
internal standard. b Yields (%) were determined by 1H NMR based on
TriBOT using an internal standard.
(entries 5 and 6), which are prone to undergo an elimina-
tion reaction of the hydroxy group or the resulting benzy-
loxy group, provided good yields. Monoacetylated diol
1g (entry 7) and halohydrins 1h and 1i (entries 8 and 9),
which are not easily benzylated under standard basic
conditions, gave excellent yields. The benzylation of
β-hydroxy ester 1j (entry 10), which is subject to acid- or
The scope and limitations of the substrates for the
benzylation were investigated using TriBOT and a cataly-
tic amount of TfOH (Table 4). Simple alcohols such as
primary, secondary, and tertiary alcohols (1aꢀd, entries
1ꢀ4) provided the desired benzyl ethers 2aꢀd in excellent
yields. Tertiary alcohol 1e and secondary benzyl alcohol 1f
5028
Org. Lett., Vol. 14, No. 19, 2012

strates with BTCAI could not be conducted3b,9 because
the reaction is generally performed in nonpolar solvents
(CH2Cl2/cyclohexane) to prevent rearrangement of BTCAI
to N-benzyltrichloroacetamide. The benzylation of a sugar
triol with BTCAI in DMSO resulted in a poor yield.9
When we conducted benzylation using pentamethylben-
zene (4), which is used as a non-Lewis-basic cation scav-
enger,10 benzylpentamethylbenzene (5) was obtained in a
good yield (Figure 2a). This result indicates that a benzyl
cation would be generated when the electron-deficient tria-
zine ring of TriBOT is activated by protonation. On the other
hand, 2,4,6-trimethoxy-1,3,5-triazine (6) was inert to 1a
under similar acidic conditions (Figure 2b), which indicates
that the SN2 reaction of alcohols to benzyl groups of activated
TriBOT is unlikely to proceed because even the methyl group
that generally undergoes SN2 reaction faster than the benzyl
group did not react.11 These results can be rationalized by the
following plausible mechanism (Figure 2c); TriBOT is pro-
tonated to form the benzyl cation which reacts with coexisting
alcohols via an SN1 mechanism to form benzyl ethers. The
remaining two benzyl groups similarly react to form ethers.
In conclusion, regarding the 1,3,5-triazine as a trimeric
structure of the smallest benzyl imidate unit, we have
successfully found that TriBOT is a novel practical and
useful acid-catalyzed O-benzylating reagent. Several ad-
vantages of TriBOT are as follows: (1) It can be easily
synthesized on a large scale from inexpensive, commer-
cially available benzyl alcohol and cyanuric chloride in one
step. (2) It is a nonhygroscopic, stable, crystalline solid. It
can be stored for 6 months at room temperature and
handled in open to the air without any detectable decom-
position. (3) The atom economy12 of TriBOT is better than
that of other traditional benzylating reagents13 because the
atoms of the leaving group per one benzyl group have only
one carbon, nitrogen, and oxygen atom.
Scheme 1. Benzylation of Methyl R-D-Glucoside
We now focus attention on the application of this
concept to p-methoxybenzyl group and other alkyl groups.
The results will be reported in due course.
Figure 2. Reaction mechanism for benzylation using TriBOT.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Young Scientists (B)
(23790009) from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan.
base-catalyzed β-elimination, retro-aldol reaction, and
racemization at the R-position to the carbonyl group,
achieved a good yield without loss of enantiomeric purity.
No racemization occurred during the benzylation of ethyl
lactate 1k (entry 11). The benzylation of phenol 1l (entry 12)
resulted in a moderate yield because competing Friedelꢀ
Crafts benzylation occurred at both the substrate and the
product. The selective O-benzylation of amino alcohol 1m
(entry 13) was achieved using 1.2 equiv of TfOH to suppress
the benzylation of amine by the formation of an ammonium
salt.
Supporting Information Available. Experimental de-
tails and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) (a) Yoshino, H.; Tsuchiya, Y.; Saito, I.; Tsujii, M. Chem. Pharm.
Bull. 1987, 35, 3438. (b) Yoshino, H.; Tsujii, M.; Kodama, M.; Komeda,
K.; Niikawa, N.; Tanase, T.; Asakawa, N.; Nose, K.; Yamatsu, K.
Chem. Pharm. Bull. 1990, 38, 1735. (c) Okano, K.; Okuyama, K.;
Fukuyama, T.; Tokuyama, H. Synlett 2008, 13, 1977.
(11) Streitwieser, A., Jr. Chem. Rev. 1956, 56, 571.
(12) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259.
(13) Total molecular weight of reagents for introduction of 1 mol of
benzyl group: 1/3 ꢁ TriBOT (399.44) þ 0.2 ꢁ TfOH (150.08) = 163.16,
BTCAI (252.52) þ 0.2 ꢁ TfOH (150.08) = 282.54, BnBr (171.03) þ
Ag2O (231.74) = 402.77, BnBr (171.03) þ NaH (24.00) = 195.03.
It is worth noting that the reaction of methyl R-D-
glucoside 1n as a highly polar substrate afforded corre-
sponding tetrabenzylated methyl R-D-glucoside 2n in 74%
yield (Scheme 1). The benzylation of highly polar sub-
(9) Bovin, N. V.; Musina, L. Y.; Khorlin, A. Y. Bull. Acad. Sci.
USSR, Div. Chem. Sci. 1986, 35, 614.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5029