Stable oxypyridinium triflate (OPT) salts for the synthesis of halobenzyl ethers

Article abstract of DOI:10.1080/00397910701818362

A collection of new oxypyridinium triflate reagents (1a-d) for the synthesis of halobenzyl ethers from alcohols under "mix-and-heat" conditions is described. The reagents are stable organic salts that can be stored indefinitely and handled without special

Full text of DOI:10.1080/00397910701818362

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Stable Oxypyridinium Triflate (OPT) Salts for
the Synthesis of Halobenzyl Ethers
Philip A. Albiniak a , Shawn M. Amisial a , Gregory B. Dudley a , Joseph P.
Hernandez a , Sarah E. House a , Margaret E. Matthews a , Ernest O. Nwoye a
, Maureen K. Reilly a & Sami F. Tlais a
a Department of Chemistry and Biochemistry , Florida State University ,
Tallahassee, Florida, USA
Published online: 15 Feb 2008.
To cite this article: Philip A. Albiniak , Shawn M. Amisial , Gregory B. Dudley , Joseph P. Hernandez ,
Sarah E. House , Margaret E. Matthews , Ernest O. Nwoye , Maureen K. Reilly & Sami F. Tlais (2008) Stable
Oxypyridinium Triflate (OPT) Salts for the Synthesis of Halobenzyl Ethers, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:5, 656-665, DOI:
10.1080/00397910701818362
To link to this article: http://dx.doi.org/10.1080/00397910701818362
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Synthetic Communicationsw, 38: 656–665, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701818362
Stable Oxypyridinium Triflate (OPT) Salts
for the Synthesis of Halobenzyl Ethers
Philip A. Albiniak, Shawn M. Amisial, Gregory B. Dudley,
Joseph P. Hernandez, Sarah E. House, Margaret E. Matthews,
Ernest O. Nwoye, Maureen K. Reilly, and Sami F. Tlais
Department of Chemistry and Biochemistry, Florida State University,
Tallahassee, Florida, USA
Abstract: A collection of new oxypyridinium triflate reagents (1a–d) for the
synthesis of halobenzyl ethers from alcohols under “mix-and-heat” conditions is
described. The reagents are stable organic salts that can be stored indefinitely and
handled without special precautions, making them attractive for general use in
organic synthesis. Halobenzylation of representative alcohols occurs in good to
excellent yield.
Keywords: oxypyridinium salt, p-bromobenzyl, p-iodobenzyl, p-chlorobenzyl,
o-bromobenzyl, arylmethylation
Recent reports from this laboratory describe the synthesis and reactivity of
2-benzyloxy-1-methylpyridinium triflate (benzyl-OPT, 4),[1] a stable organic
salt that gives rise to benzyl ethers under relatively neutral conditions upon
heating in the presence of a broad spectrum of primary and secondary
alcohols [Eq. (1)]. Magnesium oxide (MgO) is typically included as the
terminal acid scavenger to quench the immediate by-product of the
Received in the USA September 14, 2007
This paper is dedicated to Professor Ken Goldsby (FSU) for his promotion and
support of undergraduate research.
Address correspondence to Gregory B. Dudley, Department of Chemistry and Bio-
chemistry, Florida State University, Tallahassee, FL 32306-4290. E-mail: gdudley@
chem.fsu.edu
656

Reagents for the synthesis of halobenzyl ethers
657
reaction, hydroxypyridinium salt 5. Benzyl-OPT (4) is easy to prepare and
use,[2] it is now commercially available,[3] and it has proven effective at deli-
vering the benzyl protecting group[4] onto alcohol substrates even in difficult
cases for which benzyl bromide and benzyl trichloroacetimidate were reported
to be unsuitable [e.g., Eq. (2)].[5]
In addition to the benzyl (Bn) protecting group, many other arylmethyl
ethers have been developed for the myriad protecting group needs that arise
during complex organic synthetic endeavors.[4] In light of promising results
in the formation of benzyl ethers, research efforts continued with an exam-
ination of related oxypyridinium triflate (OPT) salts for accessing the full
complement of designer arylmethyl ethers. First to be investigated was the
synthesis of para-methoxybenzyl (PMB) ethers, but the protocol that was
optimal for making benzyl ethers did not translate into successful
synthesis of PMB ethers. Significant modifications to the original strategy
were required: in lieu of a pre-formed pyridinium triflate salt (cf. 4),
in situ methylation of PMBO-lepidine 6 was employed in the presence of
alcohols [Eq. (3)].[6]
In contrast, halobenzyl ethers[7] — para-bromobenzyl (PBB), para-
chlorobenzyl (PCB), para-iodobenzyl (PIB), and ortho-bromobenzyl (OBB) —
are readily prepared using the stable OPT salts depicted in Fig. 1. This
report describes the synthesis of an extended family of reagents suitable for
preparing halobenzyl ethers from alcohols.
Halobenzyl ethers fill an important niche among arylmethyl protecting
groups; the halide substitutent provides a convenient handle for derivatization
en route to their cleavage under mild conditions, as has been described in
detail previously.[7] For example, palladium-catalyzed amination technol-
ogy[8] discriminates between the various halobenzyl ethers [Eq. (4)] and

658
P. A. Albiniak et al.
Figure 1. Oxypyridinium triflates for the synthesis of halobenzyl ethers.
promotes their selective removal in the presence of many other common pro-
tecting groups.[7c,7f]
Methods employed for the synthesis of benzyl salt 4[1,2] proved to be
readily adaptable to the synthesis of oxypyridinium salts 1. Arylmethyl
alcohols (7) couple with 2-chloropyridine under basic conditions to provide
pyridyl ethers 8 in excellent yield (95–99%, Table 1). Toluene solutions of
8 were then treated with methyl triflate to produce OPT salts 1, which preci-
pitated from the reaction mixture and were recovered in 93–96% yield by fil-
tration and/or evaporation of the residual methyl triflate and solvent. Salts 1
were routinely stored in vials under ambient conditions without any
evidence of decomposition.
Table 1. Preparation of 1a–d, the halobenzyl-oxypyridinium salts
Entry
Ar
Pyridyl ether
Yield of 8
Triflate salt
Yield of 1
1
2
3
4
p-Br-Ph
p-Cl-Ph
p-I-Ph
8a
8b
8c
8d
97%
96%
99%
95%
1a
1b
1c
1d
96%
95%
96%
93%
o-Br-Ph

Reagents for the synthesis of halobenzyl ethers
659
Figure 2. Alcohol substrates referenced in Table 2.
To probe the reactivity of these new reagents, halobenzylation of repre-
sentative alcohols (Fig. 2) was examined under conditions similar to those pre-
viously reported for the synthesis of benzyl ethers.[1,2] As described in earlier
reports, benzyl ethers form using salt 4 when reaction mixtures are heated at
808C for 24 h. Perhaps because of the mild deactivating effect of the electro-
negative halides, in the present study optimal reactivity was observed at
1008C. Reaction with primary and secondary alcohols and adamantanol
reliably provided halobenzyl ethers 3 in good to excellent yield (Table 2).
Note that benzylation of Roche ester 2b (cf. entry 2) fails under Williamson
ether conditions[9] and that halobenzylations of anisole-derived alcohol 2a
(entries 1 and 6) proceeded smoothly despite the potential for Friedel–
Crafts-type benzylation of the electron-rich arene.[10,11]
In summary, this report describes a group of reagents that are suitable for
the synthesis of halobenzyl ethers. Given the special utility of diverse aryl-
methyl ethers, tools capable of introducing them into highly functionalized
Table 2. Synthesis of halobenzyl from alcohols
Entry
R-OH
OPT salt
Product (3)
CH2Ar
Yield
1
2
3
4
5
6
7
2a
2b
2c
2e
2a
2d
2a
1a
1a
1a
1a
1b
1c
1d
3aa
3ba
3ca
3ea
2cb
3ac
3dd
PBB
PBB
PBB
PBB
PCB
PIB
89%
79%
92%
86%
93%
92%
95%
OBB

660
P. A. Albiniak et al.
systems are valuable.[12] This nearly neutral mix-and-heat protocol for the
synthesis of halobenzyl ethers will help address specific challenges in
synthetic organic chemistry and promote further research into the synthetic
utility of bench-stable oxypyridinium triflate salts.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Varian 300-MHz spec-
trometer using CDCl3 or acetone-d6 as the deuterated solvent. The chemical
shifts (d) are reported in parts per million (ppm) relative to internal TMS
1
1
(0 ppm for H NMR) or the residual CHCl3 peak (7.26 ppm for H NMR,
77.0 ppm for 13C NMR). The coupling constants (J) are reported in hertz
(Hz). Mass spectra were recorded using chemical ionization (CI) or electron ion-
ization (EI) techniques. Toluene was purified by passing through a column of
activated alumina. Anhydrous a,a,a-trifluorotoluene was purchased in a Sure-
Sealw bottle and used as received. MgO was dried by heating at 1008C under
a vacuum overnight. Neutral organic compounds were purified by flash-
column chromatography using silica-gel F-254 (230–499 mesh). Yields refer
to isolated material judged to be at least 95% pure by 1H NMR spectroscopy.
Halobenzyloxypyridines 8 (General Procedure)
A mixture of halobenzyl alcohol 7 (1.0 equiv), 2-chloropyridine (1.2 equiv),
KOH (3.0 equiv), and 18-crown-6 (0.05 equiv) in toluene (2.0 mL/mmol of
7) was heated at reflux for 1 h with azeotropic removal of water. The reaction
mixture was then cooled to room temperature and partitioned between ethyl
acetate and water. The organics were washed (brine), dried (MgSO4), filtered,
concentrated in vacuo, and purified over silica gel to provide 8.
Halobenzyloxypyridinium Triflates 1 (General Procedure)
Methyl triflate (1.1 equiv) was added to an ice-cold solution of pyridine 8 (1.0
equiv) in toluene (1.0 mL/mmol of 8) under argon. The ice bath was removed,
and a precipitate formed. The slurry was diluted with hexanes and filtered to
collect the precipitate, which was dried under vacuum overnight to yield
triflate salts 1 as white crystalline solids.
Halobenzyl Ethers 3 (General Procedure)
A mixture of alcohol 2 (1.0 equiv), OPT salt 1 (2.0 equiv), and MgO (2.0
equiv) in trifluorotoluene (2.0 mL/mmol of 2) was heated in an oil bath at

Reagents for the synthesis of halobenzyl ethers
661
1008C for 24 h. The reaction mixture was filtered through Celitew, the filtrate
was concentrated in vacuo, and the resulting residue was purified over silica
gel to provide 3.
2-(4-Bromo-benzyloxy)-pyridine (8a)
Colorless oil (1.370 g, 97%); 1H NMR (300 MHz, CDCl3) d 8.16 (dd, J ¼ 5.1,
1.4, 1H), 7.59 (ddd, J ¼ 8.3, 7.2, 2.0 Hz, 1H), 7.49 (d, J ¼ 8.4 Hz, 2H), 7.34
(d, J ¼ 8.4 Hz, 2H), 6.89 (ddd, J ¼ 7.1, 5.1, 0.8 Hz, 1H), 6.80 (d, J ¼ 8.4 Hz,
1H), 5.33 (s, 2H); 13C NMR (75 MHz, CDCl3) d 163.3, 146.8, 138.7, 136.5,
131.5, 129.5, 121.7, 117.0, 111.2, 66.6.
2-(4-Chloro-benzyloxy)-pyridine (8b)
Colorless oil (683 mg, 96%); 1H NMR (300 MHz, CDCl3) d 8.17 (dd, J ¼ 5.1,
1.9 Hz, 1H), 7.63–7.57 (m, 1H), 7.41 (d, J ¼ 8.4 Hz, 2H), 7.34 (d, J ¼ 8.5 Hz,
2H), 6.92–6.88 (m, 1H), 6.81 (dd, J ¼ 8.3, 0.7 Hz, 1H), 5.35 (s, 2H); 13C
NMR (75 MHz, CDCl3) d 163.3, 146.8, 138.6, 135.9, 133.5, 129.2, 128.5,
117.0, 111.2, 66.5.
2-(4-Iodo-benzyloxy)-pyridine (8c)
Colorless oil (1.056 g, 99%); 1H NMR (300 MHz, CDCl3) d 8.16 (dd, J ¼ 5.1,
1.4 Hz, 1H), 7.69 (d, J ¼ 8.3 Hz, 2H), 7.59 (ddd, J ¼ 8.6, 7.2, 2.0 Hz, 1H),
7.21 (d, J ¼ 8.3 Hz, 2H), 6.89 (ddd, J ¼ 5.8, 5.1, 0.7 Hz, 1H), 6.80 (d, J ¼
8.4 Hz, 1H), 5.33 (s, 2H); 13C NMR (75 MHz, CDCl3) d 163.3, 146.8,
138.6, 137.5, 137.2, 129.7, 117.0, 111.2, 93.2, 66.7.
2-(2-Bromo-benzyloxy)-pyridine (8d)
1
Colorless oil (665 mg, 95%), H NMR (300 MHz, CDCl3) d 8.19 (d, J ¼
4.9 Hz, 1H), 7.63–7.53 (m, 3H), 7.32 (t, J ¼ 7.6 Hz, 1H), 7.17 (t, J ¼
7.6 Hz, 1H), 6.90 (t, J ¼ 6.1 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz, 1H), 5.48
(S, 2H); 13C NMR (75 MHz, CDCl3) d 163.3, 146.9, 138.6, 136.8, 132.6,
129.1, 127.3, 123.0, 117.0, 111.1, 67.0.
2-(4-Bromo-benzyloxy)-1-methylpyridinium Triflate (1a)
Colorless solid (1.856 g, 96%); mp: 119–1218C; 1H NMR (300 MHz, CDCl3)
d 8.41–8.32 (m, 2H), 7.62–7.58 (m, 3H), 7.48–7.41 (m, 3H), 5.54 (s, 2H),

662
P. A. Albiniak et al.
4.11 (s, 3H); 13C NMR (75 MHz, acetone-d6) d 161.8, 150.0, 145.9, 135.0,
133.7, 132.4, 124.6, 120.8, 114.0, 75.0, 43.5; HRMS (ESI þ ) 278.0175
(M-OTf)þ (calculated for C13H13NOBrþ 278.0181).
2-(4-Chloro-benzyloxy)-1-methylpyridinium Triflate (1b)
Yield 726 mg (95%); mp: 116–1188C; 1H NMR (300 MHz, CDCl3) d 8.40–
8.32 (m, 2H), 7.60 (d, J ¼ 8.9 Hz, 1H), 7.51–7.42 (m, 5H), 5.56 (s, 2H), 4.11
(s, 3H); 13C NMR (75 MHz, CDCl3) d 150.0, 145.9, 136.5, 134.6, 132.2,
130.8, 120.8, 114.0, 75.0, 43.6; HRMS (ESI þ ) 234.0670 (M-OTf)þ (calcu-
lated for C13H13NOClþ 234.0680).
2-(4-Iodo-benzyloxy)-1-methylpyridinium Triflate (1c)
White crystalline solid. (91 mg, 96%); mp: 109–1128C 1H NMR (300 MHz,
CDCl3) d 8.36 (d, J ¼ 6.3 Hz, 1H), 8.31 (t, J ¼ 8.3 Hz, 1H), 7.72 (d, J ¼
8.4 Hz, 2H), 7.57 (d, J ¼ 8.7 Hz, 1H), 7.40 (t, J ¼ 6.5 Hz, 1H), 7.22 (d, J ¼
8.3 Hz, 2H), 5.44 (s, 2H), 4.01 (s, 3H); 13C NMR (75 MHz, CDCl3) d
159.2, 147.8, 143.4, 137.8, 132.0, 130.0, 118.8, 116.3, 111.8, 95.1, 73.4,
41.7; HRMS (ESI þ ) 326.0030 (M-OTf)þ (calculated for C13H13NOIþ
326.0041).
2-(2-Bromo-benzyloxy)-1-methylpyridinium Triflate (1d)
White crystalline solid. (331.5 mg, 93%); mp: 98–1008C 1H NMR (300 MHz,
CDCl3) d 8.58 (d, J ¼ 5.8 Hz, 1H), 8.42 (t, J ¼ 7.8 Hz, 1H), 7.77 (d, J ¼
8.7 Hz, 1H), 7.64 (d, J ¼ 7.7 Hz, 2H), 7.47 (t, J ¼ 6.7 Hz, 1H), 7.40 (t, J
¼ 7.4 Hz, 1H), 7.31 (t, J ¼ 7.4 Hz, 1H), 5.63 (s, 2H), 4.09 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 159.3, 148.3, 144.1, 133.2, 131.9, 131.7, 128.2,
124.1, 119.3, 112.0, 74.0, 42.0; HRMS (ESI þ ) 278.0169 (M-OTf)þ (calcu-
lated for C13H13NOBrþ 278.0181).
1-(4-Bromo-benyzloxy)-4-(4-methoxyphenyl)-butane (3aa)
1
Colorless oil (91.3 mg, 89%); H NMR (300 MHz, CDCl3) d 7.47 (d, J ¼
8.3 Hz, 2H), 7.21 (d, J ¼ 8.1 Hz, 2H), 7.09 (d, J ¼ 8.3 Hz, 2H), 6.83 (d, J
¼ 8.4 Hz, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.47 (t, J ¼ 5.8 Hz, 2H), 2.58
(t, J ¼ 7.0 Hz, 2H) 1.70–1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) d
157.7, 137.7, 134.4, 131.4, 129.3, 129.2, 121.3, 113.7, 72.1, 70.1, 55.2,
34.8, 29.3, 28.2.

Reagents for the synthesis of halobenzyl ethers
663
1-(4-Bromo-benyzloxy)-2-methyl-propionic Acid Methyl Ester (3ba)
1
Colorless oil (51.4 mg, 79%); H NMR (300 MHz, CDCl3) d 7.46 (d, J ¼
8.3 Hz, 1H), 7.18 (d, J ¼ 8.2 Hz, 1H), 4.46 (s, 2H), 3.69 (s, 3H), 3.64 (dd,
J ¼ 9.0, 7.4 Hz, 1H), 3.48 (dd, J ¼ 9.0, 5.8 Hz, 1H), 2.78 (d of apparent
quintets, J ¼ 5.8, 7.2 Hz, 1H), 1.18 (d, J ¼ 7.1 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 175.1, 137.2, 131.5, 129.2, 121.4, 72.3, 72.1, 51.7,
40.2, 14.0.
5a-Cholester-3ß-yl p-Bromobenzyl Ether (3ca)
White solid (125.3 mg, 92%); mp: 128–1328C; 1H NMR (300 MHz, CDCl3) d
7.37 (d, J ¼ 8.3 Hz, 2H), 7.15 (d, J ¼ 8.2 Hz, 2H), 5.27 (d, J ¼ 4.8 Hz, 1H),
4.43 (s, 2H), 3.18 (m, 1H), 2.36–2.16 (m, 2H), 1.97–0.83 (m, 26H), 0.94
(s, 3H), 0.84 (d, J ¼ 6.5 Hz, 3H), 0.792 (d, J ¼ 6.6 Hz, 6H), 0.60 9s, 3H);
13C NMR (75 MHz, CDCl3) d 140.8, 138.2, 131.4, 129.1, 121.7, 121.2,
78.8, 69.1, 56.8, 56.2, 50.2, 42.3, 39.8, 39.5, 39.2, 37.2, 36.9, 36.2, 35.8,
32.0, 31.9, 28.4, 28.2, 28.0, 24.3, 23.9, 22.8, 22.6, 21.1, 19.4, 18.7, 11.9.
1-(4-Bromo-benyzloxy)-adamantane (3ea)
1
White solid (53.1 mg, 86%); mp: 48–498C H NMR (300 MHz, CDCl3) d
7.35 (d, J ¼ 8.4 Hz, 2H), 7.14 (d, J ¼ 8.3 Hz, 2H), 4.37 (s, 2H), 2.09 (br s,
3H), 1.74 (br s, 6H), 1.56 (br s, 6H); 13C NMR (75 MHz, CDCl3) d 139.3,
131.3, 129.0, 120.8, 72.9, 61.6, 41.7, 36.5, 30.6.
5a-Cholester-3ß-yl p-Chlorobenzyl Ether (3cb)
1
White solid (95 mg, 93%); mp: 136–1398C H NMR (300 MHz, CDCl3) d
7.27–7.19 (m, 4H), 5.27 (d, J ¼ 5.1 Hz, 1H), 4.45 (s, 2H), 3.18 (tt, J ¼
11.1, 4.4, 1H), 2.33 (ddd, J ¼ 13.1, 4.6, 1.9, 1H), 2.24–2.15 (m, 1H),
(m, 26H), 0.94 (s, 3H), 0.84 (d, J ¼ 6.5 Hz, 3H), 0.79 (d, J ¼ 6.6 Hz, 6H),
0.60 (s, 3H); 13C NMR (75 MHz, CDCl3) d 140.8, 137.6, 133.1, 128.8,
128.4, 121.7, 78.8, 69.1, 56.8, 56.2, 50.2, 42.3, 39.8, 39.5, 39.1, 37.2, 36.9,
36.2, 35.8, 32.0, 31.9, 28.4, 28.2, 28.0, 24.3, 23.8, 22.8, 22.6, 21.1, 19.4,
18.7, 11.9.
1-(2-Bromo-benyzloxy)-1-phenylpropane (3dd)
Yield 72 mg (95%); 1H NMR (300 MHz, CDCl3) d 7.53–7.45 (m, 2H), 7.31–
7.09 (m, 7H), 4.54 (s, 2H), 3.55 (t, J ¼ 6.3 Hz, 2H), 2.73 (d, J ¼ 8.0 Hz, 2H),

664
P. A. Albiniak et al.
1.96 (m, 2H); 13C NMR (75 MHz, CDCl3) d 146.2, 142.3, 136.8, 133.4, 133.1,
132.8, 132.7, 131.7 130.1, 127.0, 76.5, 74.4, 36.7, 35.7.
ACKNOWLEDGMENT
This research was supported by the FSU Department of Chemistry and Bio-
chemistry. S. M. A. and S. E. H. received Brautlecht Fellowships for
summer undergraduate research. J. P. M. and M. E. M. contributed to the
project in partial fulfillment of requirements for CHM 1051L, the laboratory
component of Honors General Chemistry II. M. K. R. was a visiting under-
graduate research associate from Smith College, Northampton, MA. We
thank Professor Kevin Shea (Smith College) for helpful guidance and discus-
sion. We thank Tom Gedris for assistance with the NMR facilities, Umesh
Goli for the mass spectrometric analyses, and the Krafft Lab for use of their
FT-IR instrument.
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