An efficient means for generating p-methoxybenzyl (PMB) ethers under mildly acidic conditions

Article abstract of DOI:10.1055/s-2008-1032132

The protection of a wide variety of alcohols as their p-methoxybenzyl ethers can be performed with PMBO-lepidine in the presence of methyl tosylate or, preferably, camphorsulfonic acid. No inorganic promoters are required, thereby facilitating workup and product isolation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032132

PAPER
433
An Efficient Means for Generating p-Methoxybenzyl (PMB) Ethers under
Mildly Acidic Conditions
Mildand
E
fficien
a
t
p
-
Methox
t
ybenzy
h
l
(PMB)
E
th
e
er Formatio
r
n
ine A. Stewart, Xiaowen Peng, Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 5 October 2007; revised 20 November 2007
O
O
Abstract: The protection of a wide variety of alcohols as their p-
Cl
warm
methoxybenzyl ethers can be performed with PMBO-lepidine in the
N
O
N
O
presence of methyl tosylate or, preferably, camphorsulfonic acid.
No inorganic promoters are required, thereby facilitating workup
and product isolation.
O
5
Key words: p-methoxybenzyl ethers, protecting groups, camphor-
sulfonic acid, lepidine derivatives, methyl tosylate
O
O
O
O
N
N
O
The reaction of 2-alkoxypyridines 1 with alkyl halides or
sulfonate esters, initially developed as a regioselective
route to N-alkyl-2-pyridones 21,2 (Equation 1) to probe
their photochemistry,1a,3,4 has more recently been utilized
in a total synthesis of ( )-cytisine (as 3 → 4)5 (Equation 2).
Originally expanded by Paquette to include N-oxides such
as 5 for the purpose of accessing activated esters of type
66 (Equation 3), Dudley and Nwoye have lately called at-
tention to the utility of lepidine derivative 7 to serve as an
acetimidate surrogate for generating p-methoxybenzyl
(PMB) ethers.7
6
Equation 3
Since 1982,8 PMB derivatives have earned the reputation
of being one of the most popular protecting groups in use.9
Their formation under mildly acidic conditions is com-
monly performed using p-methoxybenzyl trichloroacet-
imidate.10 However, this reagent is unstable to long-term
storage and the companion trichloroacetamide by-product
frequently complicates purification. By comparison, 7 is
easier to handle, shelf-stable, and available from inexpen-
sive materials. These features cause 7 to serve as a practi-
cal and appealing alternative. The method of activation
earlier reported7 involved treatment with methyl triflate to
generate the reactive lepidinium intermediate. The co-
addition of an acid scavenger such as magnesium oxide
induced ultimate production of the PMB ether and 8
(Equation 4).
X
R'CH2X
R
O
N
heat
R
O
N
R'
R = H, Me
1
Me
O
N
R'
ROH
2
O
N
MeOTf, MgO
PhCF3, 0 °C to r.t.
Equation 1
MeO
7
Ph
Me
OSO2Me
N
toluene
heat
MeO
N
R–OPMB
O
N
N
N
Me
Ph
O
8
3
4
Equation 4
Equation 2
In the early stages of a synthetic study, we were presented
with the task of protecting the b-hydroxy group in lactone
9 prior to Tebbe olefination. Recourse to the Yonemitsu
SYNTHESIS 2008, No. 3, pp 0433–0437
Advanced online publication: 11.01.2008
DOI: 10.1055/s-2008-1032132; Art ID: M07307SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

434
C. A. Stewart et al.
PAPER
protocol (Table 1, entry 1) delivered 10 in ~65% yield. (CSA) served to promote the 9 → 10 conversion excep-
However, despite repeated chromatographic efforts, the tionally well (entry 6). Noteworthily, scale-up proved not
product remained contaminated with a substantial amount to be of concern, and the acetonide moiety was unaffected
of trichloroacetamide, which was found to consume the by the mildly acidic conditions.
Tebbe reagent in the ensuing step. To overcome this prob-
lem, we turned to the use of 7. Surprisingly, adaptation of
the procedure reported for 7 (entry 2) gave 10 inefficiently
Exploration of the global utility of the CSA-catalyzed pro-
cedure was carried out with a broad selection of alcohols,
many of which were selected specifically to assess stabil-
(35%). Substitution of MgO with K2CO3 (entry 3) result-
ity under the reaction conditions (Table 2). The first area
ed in decomposition of the starting lactone. In these labo-
of concern was the possible untoward effect on substrates
having acid-sensitive functionality. Alcohols 12, 15, and
19 are allylic in nature and, in principle, subject to com-
peting cation formation and subsequent loss of water or
rearrangement. Acetylenic carbinol 14 could behave sim-
ilarly, but in no case was anything but PMB ether forma-
tion noted. When the hemiacetal 13 and diacetonide 18
were likewise screened, excellent results were again re-
ratories, this development prompted the consideration of
methyl tosylate as the alkylating agent so as to deter the
degradation of 9. Under these circumstances good yields
(80%) could be achieved at modest scale (entry 4). Since
the utilization of methyl tosylate precludes the need for
MgO, the all-organic reaction mixture requires only sol-
vent removal prior to purification by column chromatog-
raphy. Interestingly, MgO in combination with methyl
corded.
tosylate shuts down the functionalization reaction (entry
The second point of consideration was whether this proto-
col would perform well when hindered and/or tertiary al-
5). On a positive note, N-methyl-2-lepidone (8) is a rather
insoluble polar substance, which remains at the TLC base-
cohols are involved. As recorded in Table 2, the
line, thereby allowing for clean and facile purification.
structurally complex molecules 11, 13, 16, 18, and 19 per-
formed well, although more prolonged reaction times
were sometimes required as expected. Comparably posi-
tive observations were made when tertiary hydroxyl
groups in less intricate reactants such as 14 and 17 were
involved.
Table 1 Screening of PMB Protection Alternatives
O
O
O
O
O
OH
OPMB
Thus, in situ activation of 7 can be accomplished either
with methyl tosylate under neutral conditions, or prefera-
bly in the presence of a catalytic quantity of CSA
(Equation 5). Direct subjection of the crude reaction mix-
ture to column chromatography delivers the product easi-
ly. This procedure is broadly applicable and avoids
complications in purification previously encountered dur-
ing the incorporation of this protecting group.
O
O
O
9
10
Entry
1
Conditions
PMB-acetimidate
Yield (%)
~65a
CSA or TfOH, Et2O
–10 to 10 °C
2
3
4
5
6
7, MeOTf, MgO
PhMe, 0 °C to r.t.
35
Me
7, MeOTf, K2CO3
PhMe, 0 °C to r.t.
dec.b
ROH
PMB
7
O
N
H
CSA, CH2Cl2
7, MeOTs
PhMe, 35 °C
80
R
O
H
7, MeOTs, MgO
PhMe, 35 °C
no reaction
85
Me
7, CSA (10 mol%)
CH2Cl2, r.t.
– H+
R–OPMB
a Contaminated with the amide by-product.
O
N
b Ref. 7 suggests K2CO3 as an alternative to MgO.
H
20
These results led us to consider that the targeted process Equation 5
may be catalyzed by trace amounts of acid generated in
the reaction. Consequently, attempts to drive the PMB
Melting points were determined on a Unimelt Thomas Hoover cap-
illary melting point apparatus. NMR spectra were recorded on a
Bruker DRX-500 (500 MHz) spectrometer fitted with a 5 mm
broadband probe. Chemical shifts (d) are reported in ppm relative to
CDCl3 (7.26 ppm) as internal standard.
transfer by acid catalysis were undertaken. The dealkyla-
tion of 2-alkoxypyridines in the presence of a proton
source is a well-known transformation.11 For our pur-
poses, the co-addition of 10 mol% camphorsulfonic acid
Synthesis 2008, No. 3, 433–437 © Thieme Stuttgart · New York

PAPER
Mild and Efficient p-Methoxybenzyl (PMB) Ether Formation
435
Table 2 PMB-Protection Using CSA/PMBO-Lepidine (7)
Substrate
Product
Time (h)
Yield (%)a
OPMB
OH
O
O
H
H
H
O
O
11
48
95b
H
O
O
O
O
12
24
96
73
91
HO
PMBO
TBDPSO
TBDPSO
H
O
H
O
13
OMe
OH
OMe
OPMB
OPMB
OH
14
48
24
91
94
15
Ph
OH
Ph
OPMB
16
17
72
67
82
94
H
H
H
H
H
H
HO
PMBO
OH
O
OPMB
O
O
O
O
OH
O
OPMB
18
19
48
48
quantc
O
O
O
O
PMBO
HO
79
H
H
a Yield after purification.
b Using MeOTs, 48 h, yield was 65%.
c Using MeOTs, 48 h, yield was 93%.
PMBO-Lepidine Activation with Methyl Tosylate; General
Procedure
A mixture of the alcohol (4.62 mmol) and 7 (3.85 g, 13.9 mmol) in
toluene (5.6 mL) under N2 was treated with methyl tosylate (2.10
mL, 13.9 mmol) to afford a bright yellow mixture, which was heat-
ed at 35 °C for 48 h with stirring. The resulting off-white slurry was
concentrated in vacuo and purified by column chromatography
(Table 2).
Synthesis 2008, No. 3, 433–437 © Thieme Stuttgart · New York

436
C. A. Stewart et al.
PAPER
PMBO-Lepidine Activation with Camphorsulfonic Acid
(CSA); General Procedure
PMB Ether 14
Pale yellowish liquid.
A mixture of the alcohol (19.9 mmol) and 7 (11.0 g, 39.8 mmol) was
blanketed with argon, taken up in CH2Cl2 (40 mL), and treated with
CSA (462 mg, 1.99 mmol) to afford a clear, bright yellow solution.
The mixture was stirred for 24–96 h until conversion was complete
(TLC analysis), concentrated in vacuo, and purified chromato-
graphically. Alternatively, the mixture was filtered through a short
pad of silica gel (elution with 3:2 hexanes–EtOAc). The filtrate was
concentrated and processed chromatographically as described
above (Table 2).
IR (neat): 1614, 1586, 1514, 1450, 1248 cm–1.
1H NMR (500 MHz): d = 7.31 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7
Hz, 2 H), 4.59 (s, 2 H), 3.80 (s, 3 H), 2.52 (s, 1 H), 1.99–1.95 (m, 2
H), 1.75–1.68 (m, 4 H), 1.61–1.51 (m, 3 H), 1.38–1.29 (m, 1 H).
13C NMR (125 MHz): d = 159.1, 131.4, 129.4 (2 C), 113.9 (2 C),
85.7, 73.9, 65.3, 55.4, 37.4 (2 C), 25.5, 22.8.
PMB Ether 15
Colorless oil.
IR (neat): 3025, 2836, 1613, 1514, 1450, 1248 cm–1.
1H NMR (500 MHz): d = 7.42–7.40 (m, 2 H), 7.36–7.31 (m, 4 H),
7.28–7.24 (m, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.65 (d, J = 15.9 Hz,
1 H), 6.35 (dt, J = 6.0, 15.9 Hz, 1 H), 4.53 (s, 2 H), 4.20 (dd, J = 1.4,
6.0 Hz, 2 H), 3.83 (s, 3 H).
PMB Ether 10
White crystalline solid; mp 78–79 °C.
IR (neat): 1747, 1613, 1514, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 4.80 (d, J = 11.2 Hz, 1 H), 4.60 (d, J = 11.2 Hz, 1
H), 4.04–4.00 (m, 1 H), 3.97–3.91 (m, 2 H), 3.84–3.80 (m, 1 H),
3.81 (s, 3 H), 3.49–3.46 (m, 1 H), 2.64 (pent, J = 7.4 Hz, 1 H), 1.56
(s, 3 H), 1.48 (s, 3 H), 1.37 (d, J = 7.3 Hz, 3 H).
13C NMR (125 MHz): d = 159.3, 136.8, 132.5, 130.4, 129.5 (2 C),
128.6 (2 C), 127.7, 126.5 (2 C), 126.3, 113.9 (2 C), 71.9, 70.5, 55.3.
13C NMR (100 MHz, CDCl3): d = 172.0, 159.2, 130.1, 129.7 (2 C),
113.9 (2 C), 99.8, 79.2, 73.7, 73.6, 68.7, 61.7, 55.3, 43.0, 29.0, 19.1,
15.8.
PMB Ether 16
White solid; mp 127–128 °C.
IR (film): 2935, 1612, 1514, 1466, 1247 cm–1.
1H NMR (500 MHz): d = 7.27 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6
Hz, 2 H), 5.35–5.33 (m, 1 H), 4.49 (s, 2 H), 3.80 (s, 3 H), 2.04–0.85
(series of m, 26 H), 1.01 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.88 (d,
J = 2.2 Hz, 3 H), 0.86 (d, J = 2.2 Hz, 3 H), 0.68 (s, 3 H).
13C NMR (125 MHz): d = 159.2, 141.2, 131.3, 129.2 (2 C), 121.6,
113.9 (2 C), 78.4, 69.7, 56.9, 56.3, 55.4, 50.4, 42.5, 39.9, 39.7, 39.3,
37.4, 37.0, 36.3, 35.9, 32.1, 32.0, 28.6, 28.4, 28.1, 24.4, 24.0, 22.9,
22.7, 21.2, 19.5, 18.8, 12.0.
PMB Ether 11
Clear colorless oil.
IR (neat): 1778, 1613, 1514, 1455, 1305 cm–1.
1H NMR (500 MHz): d = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7
Hz, 2 H), 5.52 (d, J = 6.5 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.44
(d, J = 11.7 Hz, 1 H), 3.92–3.90 (m, 1 H), 3.80 (s, 3 H), 3.49 (dt,
J = 4.2, 10.7 Hz, 1 H), 2.87 (dd, J = 5.2, 8.3 Hz, 1 H), 2.36–2.30 (m,
1 H), 2.22–2.15 (m, 1 H), 2.03–1.97 (m, 1 H), 1.93–1.87 (m, 1 H),
1.73–0.80 (series of m, 12 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.89 (d,
J = 7.1 Hz, 3 H), 0.81 (d, J = 6.9 Hz, 3 H).
13C NMR (125 MHz): d = 175.0, 159.2, 130.4, 129.1 (2 C), 113.9 (2
C), 104.2, 78.4, 71.8, 70.5, 55.4, 48.0, 45.5, 40.6, 40.5, 34.5, 31.5,
27.0, 25.5, 23.2, 22.4, 22.0, 21.1, 16.4, 15.9.
PMB Ether 17
Colorless oil.
IR (neat): 1613, 1513, 1462, 1247 cm–1.
1H NMR (500 MHz): d = 7.29 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7
Hz, 2 H), 4.34 (s, 2 H), 3.80 (s, 3 H), 1.84–1.78 (m, 2 H), 1.69–1.61
(m, 2 H), 1.58–1.52 (m, 1 H), 1.47–1.34 (m, 4 H), 1.32–1.22 (m, 1
H), 1.22 (s, 3 H).
PMB Ether 12
Colorless liquid.
13C NMR (125 MHz): d = 158.9, 132.3, 128.9 (2 C), 113.8 (2 C),
IR (neat): 1668, 1612, 1585, 1513 cm–1.
73.9, 62.5, 55.4, 36.7 (2 C), 26.0, 25.0, 22.4.
1H NMR (500 MHz): d = 7.29 (d, J = 8.6 Hz, 2 H), 7.07–7.05 (m, 1
H), 6.90 (d, J = 8.6 Hz, 2 H), 4.52 (s, 2 H), 4.19–4.17 (m, 2 H), 3.82
(s, 3 H), 2.47–2.44 (m, 2 H), 2.43–2.39 (m, 2 H), 2.04–1.99 (m, 2
H).
13C NMR (125 MHz): d = 198.8, 159.3, 146.5, 136.5, 130.5, 129.4
(2 C), 113.9 (2 C), 72.8, 66.7, 55.4, 38.4, 25.8, 22.9.
PMB Ether 18
Colorless oil.
IR (neat): 1613, 1514, 1372, 1249 cm–1.
1H NMR (500 MHz): d = 7.27 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7
Hz, 2 H), 5.88 (d, J = 3.7 Hz, 1 H), 4.62–4.55 (m, 3 H), 4.36–4.32
(m, 1 H), 4.14 (dd, J = 7.7, 3.1 Hz, 1 H), 4.10 (dd, J = 8.6, 6.3 Hz,
1 H), 4.01–3.98 (m, 2 H), 3.81 (s, 3 H), 1.49 (s, 3 H), 1.43 (s, 3 H),
1.38 (s, 3 H), 1.31 (s, 3 H).
13C NMR (125 MHz): d = 159.5, 129.9, 129.5 (2 C), 114.0 (2 C),
111.9, 109.1, 105.4, 82.9, 81.50, 81.47, 72.7, 72.3, 67.5, 55.4, 27.0,
26.9, 26.4, 25.6.
PMB Ether 13
Colorless oil.
IR (neat): 1613, 1588, 1512, 1464 cm–1.
1H NMR (500 MHz): d = 7.68–7.64 (m, 4 H), 7.45–7.44 (m, 2 H),
7.41–7.38 (m, 4 H), 7.29 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2
H), 5.94 (dd, J = 17.4, 10.9 Hz, 1 H), 5.25 (dd, J = 17.4, 1.3 Hz, 1
H), 5.06 (dd, J = 10.9, 1.3 Hz, 1 H), 4.83 (d, J = 4.3 Hz, 1 H), 4.55
(d, J = 1.7 Hz, 2 H), 4.27–4.23 (m, 1 H), 3.82 (s, 3 H), 3.52 (d,
J = 10.5 Hz, 1 H), 3.46 (d, J = 10.5 Hz, 1 H), 3.45 (s, 3 H), 2.46 (dd,
J = 11.8, 8.1 Hz, 1 H), 2.04 (dd, J = 11.6, 10.6 Hz, 1 H), 1.04 (s, 9
H).
13C NMR (125 MHz): d = 159.3, 141.0, 135.7 (2 C), 135.6 (2 C),
133.4, 133.2, 130.2, 129.74, 129.68, 129.63 (2 C), 127.71 (2 C),
127.69 (2 C), 113.8 (2 C), 113.6, 102.2, 84.5, 78.4, 72.1, 69.3, 55.3,
54.9, 35.8, 26.9, 19.3.
PMB Ether 19
Pale yellow oil.
IR (neat): 2934, 1613, 1513, 1461, 1246 cm–1.
1H NMR (500 MHz): d = 7.26 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7
Hz, 2 H), 5.89–5.83 (m, 1 H), 5.21–5.20 (m, 1 H), 5.17 (dd, J = 4.9,
1.3 Hz, 1 H), 4.81 (d, J = 1.3 Hz, 1 H), 4.54 (d, J = 1.0 Hz, 1 H),
4.34–4.29 (m, 2 H), 3.80 (s, 3 H), 2.38 (ddd, J = 12.7, 4.2, 2.4 Hz,
1 H), 1.96 (dt, J = 12.9, 5.0 Hz, 1 H), 1.84–0.80 (series of m, 14 H).
Synthesis 2008, No. 3, 433–437 © Thieme Stuttgart · New York

PAPER
Mild and Efficient p-Methoxybenzyl (PMB) Ether Formation
437
13C NMR (125 MHz): d = 158.9, 149.0, 143.5, 132.2, 128.7 (2 C),
114.6, 113.8 (2 C), 106.5, 78.2, 64.1, 57.7, 55.7, 55.4, 42.4, 40.0,
39.6, 39.2, 38.5, 33.74, 33.70, 24.6, 22.3, 21.8, 19.6, 17.7, 14.6.
Photochemistry and Photobiology; Horspool, W., Ed.; CRC
Press: Boca Raton FL, 2003, 2nd ed., 103-1 to 103-18.
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Acknowledgment
(5) O’Neill, B. T.; Yohannes, D.; Bundesmann, M. W.; Arnold,
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The authors thank Sean Butler for a generous gift of alcohol 11.
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Synthesis 2008, No. 3, 433–437 © Thieme Stuttgart · New York