Microwave-assisted benzyl-transfer reactions of commercially available 2-benzyloxy-1-methylpyridinium triflate

Article abstract of DOI:10.1039/c1ob06504a

Benzylation of alcohols and other substrates under thermal conditions translates smoothly from conventional heating into MW-assisted organic synthesis (MAOS). Reactions times are decreased from hours to minutes while good to excellent yields are maintained. MW heating should be considered for benzylation of high-value substrates using the title reagent.

Full text of DOI:10.1039/c1ob06504a

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Microwave-assisted benzyl-transfer reactions of commercially available
2-benzyloxy-1-methylpyridinium triflate†
Teng-wei Wang,‡ Tanit Intaranukulkit,‡ Michael R. Rosana, Rimantas Slegeris, Janet Simon and
Gregory B. Dudley*
Received 2nd September 2011, Accepted 10th October 2011
DOI: 10.1039/c1ob06504a
Benzylation of alcohols and other substrates under thermal
conditions translates smoothly from conventional heating
into MW-assisted organic synthesis (MAOS). Reactions times
are decreased from hours to minutes while good to excellent
yields are maintained. MW heating should be considered for
benzylation of high-value substrates using the title reagent.
Benzyl ethers and esters are ubiquitous for the protection of
alcohols and carboxylic acids in chemical synthesis.1 The benzyl
group is inert to most common reaction conditions, yet it is
susceptible to cleavage on command using a variety of mild
protocols. The synthesis of benzyl ethers from alcohols has
traditionally been accomplished under basic or acidic conditions
(using benzyl bromide or trichloroacetimidate, respectively). We
Fig. 1 2-Benzyloxy-1-methylpyridinium triflate (1), and benzyl ethers
recently offered 2-benzyloxy-1-methylpyridinium triflate (1) as a
(OBn) optimally or uniquely prepared using 1 (yield in parentheses).
complementary option using neutral, thermal conditions.2
¯
The advantage of using 13 for the benzylation of acid- and/or
base-sensitive alcohols is clear from literature reports in which
its unique effectiveness has been noted (Fig. 1).4 As this reagent
involving polar solvents and/or solutes, which convert incident
gains popularity, we considered it worthwhile to revisit our reagent
MW radiation into heat more effectively than nonpolar solutes
development efforts in order to minimize certain disadvantages.
Namely, the prolonged heating needed to activate the reagent
can be detrimental to sensitive substrates, and the standard use
of excess reagent increases costs and can increase the formation
owing to higher loss tangents (tan d) for polar molecules. Benzyl-
transfer reactions of 1 meet these criteria, so we investigated a
representative sample of diverse substrates using MW heating
that we had previously examined using conventional heating.
of by-products, most notably dibenzyl ether.3b We reasoned that
Specifically, we looked at primary and secondary alcohols, car-
these disadvantages could possibly by attenuated using rapid and
boxylic acids, and electron-rich aromatic systems, all of which
efficient microwave (MW) heating;5 reports of MW heating of ionic
are good substrates for benzylation using 1. We also tested the
benzylation of tertiary alcohols and phenols, which have been
problematic substrates. In all cases, MW-assisted benzylations
were accomplished in comparable yield with dramatic reductions
in reaction times, as described in the following paragraphs.
We first examined the benzylation of diethylene glycol,
monomethyl ether (DEGME, 2a, eqn (1)). Our original protocol,
developed for maximum generality, involves heating at ca. 83 ◦C
for 24 h in the presence of magnesium oxide (MgO, an acid
scavenger).3b The sealed vessel capabilities of dedicated MW
reactors make it convenient to heat reaction mixtures above the
boiling point of the solvent (PhCF3, b.p. 102 ◦C). After screening
multiple sets of conditions, we settled on heating at 120 ◦C for
20 min. DEGME, like other primary alcohols, is an excellent
substrate for benzylation, so one can reduce the stoichiometry
of 1 and omit MgO as shown in eqn (1).7
liquids6 fuelled our optimism with respect to reactions involving
1, an ionic reagent.
MW heating of organic reactions has been associated with
reduced reaction times and, in many cases, higher chemical yields
and fewer by-products, typically based on the ability of dedicated
MW reactors to produce (and reproduce) heating profiles that
are difficult to generate using conventional heating methods. The
benefits of MW heating are most commonly observed in systems
Department of Chemistry and Biochemistry, Florida State University,
Tallahassee, Florida, USA. E-mail: gdudley@chem.fsu.edu; Fax: +1-850-
644-8281; Tel: +1-850-644-2333
† Electronic supplementary information (ESI) available: Experimental
details and copies of NMR spectra. See DOI: 10.1039/c1ob06504a
‡ These two authors contributed equally to this work. TW and TI are 2011
summer undergraduate research students from the Department of Science,
Chulalongkorn University, Bangkok, Thailand.
248 | Org. Biomol. Chem., 2012, 10, 248–250
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Table 1 Benzyl-transfer reactions of 1 with various alcohols, carboxylic acids, and other substrates under MW heating
Entry
Substrate
Conditionsa
Product
Yieldb,h
1c
2c
2a
A
A
3a
98% (93%)
98% (85%)
3
4
A
A
70%d (83%)
70%d
82%d,e (88%)
5f
6f
A
A
56%d (65%)
48%d
7f
8
A
B
B
59%
94% (93%)
98% (91%)
9
10
C
91%g (90%)
a Conditions A: 2.0 equiv 1, 120 ◦C (MW), 20 min. Conditions B: 2.0 equiv 1, 2.0 equiv Et3N, 120 ◦C (MW), 20 min. Conditions C: 5.0 equiv 2j, 1.0
equiv 1, 120 ◦C (MW), 20 min. b Refers to isolated yield of pure products, unless otherwise indicated. c 1.2 equiv of 1. d Yield estimated by H NMR
1
spectroscopy; product could not be separated from Bn2O by-product. e 1.0 equiv of diethylene glycol, dimethyl ether (diglyme) added. f 2.0 equiv of MgO
added. g ca. 60 : 40 mixture of regioisomers. h Yields in parentheses refer to benzylation using conditions reported earlier (ref. 2).
Thus, MW-promoted benzylation of other substrate types—
secondary and tertiary alcohol, phenol, carboxylic acid,2c and
arene2d—occurred with yields comparable to previous reports
but all within the shortened reaction time (entries 3–10). Note
(1)
the selectivity for benzylation of a carboxylic acid in the pres-
ence of an alcohol (entry 9), as reported previously.2c Selective
esterification using 1 provides a convenient alternative to the
use of diazomethane for making alkyl esters. Non-polar benzyl
ethers 3a–f could not be separated from dibenzyl ether (Bn2O, a
common by-product in these reactions2), so the reaction yields are
MW benzylation of diverse substrates is recounted in Table 1.
Primary alcohols DEGME (2a) and the Roche ester (2b, a core
building block for polypropionate synthesis) are shown in entries
1 and 2. Roche esters 2b and 3b are prone to elimination under
non-neutral conditions, so the high yield in entry 2 is noteworthy.
For substrates other than primary alcohols, it was necessary to use
two equivalents of 1 to achieve full conversion (entries 3–9).
1
estimated by analysis of the H NMR spectrum after silica gel
chromatography (entries 3–6). Interestingly, the yield of 3d was
improved by including 1.0 equiv of diethylene glycol, dimethyl
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ether (entry 4). This additive had no effect on other experiments;
the rationale behind the improved yield in entry 4 is unclear.
Considering the cost and high molecular weight of 1 compared
to, for example, benzyl bromide, 1 is perhaps most attractive
for the benzylation of complex, high-value substrates, such as
key intermediates in multi-step synthesis research (cf. Fig. 1).
Such efforts typically involve lab-scale experimentation, which
coincidentally is also the arena in which MAOS has had the
most impact (as opposed to chemical process or manufacturing-
scale activities). Thus, MW heating protocols should be widely
applicable for activating the title reagent (1).
2 (a) K. W. C. Poon, S. E. House and G. B. Dudley, Synlett, 2005, 3142;
(b) K. W. C. Poon and G. B. Dudley, J. Org. Chem., 2006, 71, 3923; (c) J.
Tummatorn, P. A. Albiniak and G. B. Dudley, J. Org. Chem., 2007, 72,
8962; (d) P. A. Albiniak and G. B. Dudley, Tetrahedron Lett., 2007, 48,
8097.
3 (a) Dudley Benzylation Reagent, In ChemFiles, 2007, 7, p. 3; (b) K. W.
C. Poon, P. A. Albiniak and G. B. Dudley, Org. Synth., 2007, 84, 295;
(c) G. B. Dudley, 2-Benzyloxy-1-methylpyridinium trifluoromethane-
sulfonate, In Electronic Encylopedia of Reagents for Organic Synthesis,
ed. L. Paquette, P. Fuchs, D. Crich, G. Molander, Wiley: Chich-
ester10.1002/047084289X.rn00906, Posting Date: Sept. 15, 2008; (d) P.
A. Albiniak and G. B. Dudley, Synlett, 2010, 841.
4 (a) V. Caubert, J. Masse´, P. Retailleau and N. Langlois, Tetrahedron
Lett., 2007, 48, 381; (b) J. P. Schmidt, S. Beltra´n-Rodil, R. J. Cox, G. D.
McAllister, M. Reid and R. J. K. Taylor, Org. Lett., 2007, 9, 4041; (c) S.
Stecko, J. Solecka and M. Chmielewski, Carbohydr. Res., 2009, 344, 167;
(d) C. M. Longo, Y. Wei, M. F. Roberts and S. J. Miller, Angew. Chem.,
Int. Ed., 2009, 48, 4158; (e) D. Lo Re, F. Franco, F. Sa´nchez-Cantalejo
and J. A. Tamayo, Eur. J. Org. Chem., 2009, 1984; (f) M. Binanzer, G.
Y. Fang and V. K. Aggarwal, Angew. Chem., Int. Ed., 2010, 49, 4264;
(g) M. A. McGowan, C. P. Stevenson, M. A. Schiffler and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2010, 49, 6147; (h) G. M. Chinigo, A. Breder and
E. M. Carreira, Org. Lett., 2011, 13, 78; (i) D. F. Taber and C. G. Nelson,
J. Org. Chem., 2011, 76, 1874; (j) T. Tomioka, Y. Yabe, T. Takahashi and
T. K. Simmons, J. Org. Chem., 2011, 76, 4669.
Conclusions
MW-assisted benzylation reactions using 2-benzyloxy-1-methyl-
pyridinium triflate (1) are reported. Representative substrates are
benzylated upon heating either in an oil bath2 or MW reactor,
but MW experiments can be conducted conveniently at higher
temperatures and at dramatically reduced reaction times. For those
considering installing benzyl ethers onto high-value alcohols or
carboxylic acids, we recommend using MW technology in the
development of the optimal protocol.
5 C. O. Kappe, D. Dallinger and S. S. Murphree, Practical Microwave
Synthesis for Organic Chemists. Strategies, Instruments, and Protocols,
Wiley-VCH, Weinheim, 2009.
6 R. Mart´ınez-Palou, Mol. Divers., 2010, 14, 3.
7 One can reproduce these conditions under conventional heating by
immersing a resealable reaction vessel in a pre-heated oil bath, but this
protocol provides lower yield (89%) and is less convenient than using the
dedicated MW reactor.
Notes and references
1 P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Organic
Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007.
250 | Org. Biomol. Chem., 2012, 10, 248–250
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