Synthesis of para-methoxybenzyl (PMB) ethers under neutral conditions

Article abstract of DOI:10.1039/b617926f

2-(4-Methoxybenzyloxy)-4-methylquinoline reacts with methyl triflate in the presence of alcohols to generate a neutral organic salt that transfers the para-methoxybenzyl (PMB) protecting group onto alcohols in high yield and under mild conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b617926f

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Synthesis of para-methoxybenzyl (PMB) ethers under neutral
conditions
Ernest O. Nwoye and Gregory B. Dudley*
Received (in Bloomington, IN, USA) 8th December 2006, Accepted 13th February 2007
First published as an Advance Article on the web 26th February 2007
DOI: 10.1039/b617926f
2-(4-Methoxybenzyloxy)-4-methylquinoline reacts with methyl
triflate in the presence of alcohols to generate a neutral organic
salt that transfers the para-methoxybenzyl (PMB) protecting
group onto alcohols in high yield and under mild conditions.
ð2Þ
para-Methoxybenzyl (PMB) ethers are workhorse protecting
1
groups in organic synthesis. Like benzyl (Bn) ethers, PMB ethers
Preliminary experiments showed that lepidine derivative 8 is
withstand a wide range of reaction conditions, can be cleaved
2
under mild conditions, and are not subject to the unwanted
soluble in aromatic solvents: addition of methyl triflate (MeOTf)
9
to lepidine ether 1 in trifluorotoluene did not produce a visible
migration between neighboring functional groups that is observed
with ester, acetal, and silyl ether protecting groups. However, the
formation of PMB ethers can be problematic. Common methods
precipitate despite rapid consumption of 1 with concomitant
10
formation of polar material. Lepidine ether 1 is significantly
more stable than other PMB transfer reagents such as PMB
3
3
4
for the synthesis of PMB ethers—Williamson and trichloroace-
4
timidate coupling reactions—require basic or acidic media that
5
may not be compatible with complex systems. Furthermore,
chloride and PMB trichloroacetimidate. Furthermore, addition of
methyl triflate to mixtures containing alcohols 2 and lepidine 1
affords PMB ethers 3 (Table 1).{
neither PMB trichloroacetimidate (unstable to storage) nor PMB
chloride (lachrymator) is especially convenient for routine usage.
As shown in Table 1, the formation of PMB ethers using 1 and
methyl triflate occurs efficiently on a range of alcohols (depicted in
Fig. 2). The presence of magnesium oxide (MgO) provides for
higher yields and easier purification of 3. N-Methyl-lepidone (10) is
the expected by-product of this reaction; bis-PMB ether 11,
presumably derived from adventitious moisture and/or reaction
with magnesium oxide, is also observed in varying amounts.
We recently introduced 2-benzyloxy-1-methylpyridinium triflate
6
4), a stable organic salt that provides benzyl ethers upon
(
7
warming in the presence of alcohols (Eq. 1). An analogous
synthesis of the more versatile PMB ethers would be widely
8
applicable in synthetic chemistry. PMB salt 7 (Fig. 1) is reactive at
room temperature in methylene chloride, but it is not soluble in the
aromatic solvents (trifluorotoluene or toluene) that we found to be
optimal for reaction efficiency. We therefore targeted a more
hydrophobic reagent (i.e., lepidine salt 8) and prepared 2-(4-
methoxybenzyloxy)-4-methylquinoline (1, Eq. 2).{
Table 1 Arylmethylation of representative alcohols (2 A 3, see
Fig. 2)
a
ð1Þ
b
Entry
Alcohol 2
Ether 3
% yield
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3e
3f
3g
3h
3i
94
98
63
c
90
89
d
69
60
c
84
99
c
1
1
a
0
80
98
e
1
2i
3i
Fig. 1 PMB transfer salts.
Unless otherwise indicated, methyl triflate was added to a mixture
of alcohol 2, lepidine 1, MgO, and trifluorotoluene under argon.
Isolated yield. Alcohol 2 was not fully consumed after 1 h.
b
c
Department of Chemistry and Biochemistry, Florida State University,
Tallahassee, FL, USA. E-mail: gdudley@chem.fsu.edu;
Fax: 850-644-8281; Tel: 850-644-2333
d
e
) employed in lieu of MgO. Toluene
Potassium carbonate (K
2
CO
3
3
employed in lieu of PhCF .
1
436 | Chem. Commun., 2007, 1436–1437
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In summary, we report a new p-methoxybenzyloxy derivative of
lepidine that, upon treatment with methyl triflate, transfers the
PMB group to an awaiting alcohol substrate. Methylation of the
lepidine core generates an activated reagent under effectively
neutral conditions, allowing acid- and base-sensitive alcohols (e.g.,
2j) to be protected as PMB ethers. We expect this protocol to be of
considerable utility.
We thank the FSU Department of Chemistry and Biochemistry
and the James and Ester King Biomedical Research Program
(Florida Department of Health) for generous financial support.
Notes and references
{
2-(4-Methoxybenzyloxy)-4-methylquinoline (1) A mixture of 4-methoxy-
benzyl alcohol (3.6 g, 26 mmol), 2-chlorolepidine (3.6 g, 21 mmol), KOH
4.8 g, 86 mmol, ground with a mortar and pestle), toluene (41 mL) and 18-
(
crown-6 (318 mg, 1.2 mmol) was heated at reflux for 1 h with azeotropic
removal of water (Dean–Stark trap). The reaction mixture was then cooled
to room temperature and partitioned between ethyl acetate (100 mL) and
water (50 mL). The organics were washed (brine), dried (MgSO
4
), filtered,
concentrated under vacuum, and purified on silica gel (elution with 5%
Fig. 2 Substrates and products from the arylmethylation reactions listed
in Table 1. For 2a–i, P 5 H. For 3a–i, P 5 PMB.
1
EtOAc–hexanes) to provide 5.3 g of 1 (93% yield) as a white solid:
NMR (300 MHz, CDCl ) d 7.87 (br d, J 5 8.4 Hz, 2H), 7.62 (td, J 5 7.6,
.3 Hz, 1H), 7.49–7.37 (m, 3H), 6.92 (d, J 5 6.7 Hz, 2H), 6.79 (s, 1H), 5.46
H
3
1
13
(
1
s, 2H), 3.82 (s, 3H), 2.62 (s, 3H); C NMR (75 MHz, CDCl
59.7, 147.0, 146.8, 130.3, 129.8, 129.5, 128.0, 125.8, 124.0, 123.9, 114.1,
113.5, 67.4, 55.5, 18.9. IR 1611, 1573, 1514, 1470, 1448, 1396, 1329, 1303,
3
) d 162.1,
Other aromatic solvents (e.g., toluene, entry 11) and hetero-
geneous acid scavengers (e.g., potassium carbonate, entry 6) may
be employed in lieu of trifluorotoluene and magnesium oxide.
Simple primary and secondary alcohols (entries 1–6) gave rise to
the corresponding PMB ethers (3a–e) generally in good to excellent
yield. Allylic alcohol 2c was not fully consumed for some reason
21
+
1246, 1174, 1130, 1039, 1020 cm . HRMS (ESI ) found 302.1163 (calcd
for C18 17NO Na: 302.1157).
Standard procedure for the arylmethylation of alcohols (2 A 3) An ice-cold
mixture of 2-PMBO-lepidine 1 (200 mg, 0.72 mmol), benzotrifluoride
(PhCF , 3.6 mL), MgO (29 mg, 0.72 mmol, vacuum-dried), and alcohol 2
0.36 mmol) was treated dropwise with methyl triflate (82 mL, 0.72 mmol).
H
2
{
3
(
(entry 3), whereas benzylic alcohols 2e and 2h proved to be good
The ice bath was removed, and the reaction mixture was stirred at room
temperature for 30–60 min until TLC analysis showed consumption of
alcohol 2. The mixture was then diluted with ethyl acetate, decanted away
from the MgO residue, washed (H O), dried (MgSO ), filtered,
2 4
concentrated at reduced pressure, and purified on silica gel to yield PMB
ether 3 (see Table 1).
substrates (entries 5 and 9). Tertiary alcohols (e.g., 2f, entry 7) were
less reactive. PMB-protection of cholesterol (2i A 3i, entry 10)
proceeded reasonably under the standard conditions (80%) despite
limited solubility of 2i in trifluorotoluene. The same reaction in
toluene afforded 3i in nearly quantitative yield (entry 11). The
Roche ester (2g) gave rise to PMB ether 3g in 84% yield (entry 8).
1
(a) T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley and Sons, New York, 3rd edn, 1999; (b)
P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 3rd edn, 2003.
Y. Oikawa, T. Yoshioka and O. Yonemitsu, Tetrahedron Lett., 1982,
2
3
ð3Þ
23, 885.
P. G. M. Wuts, p-Methoxybenzyl Chloride, in Encyclopedia of Reagents
for Organic Synthesis, ed. L. A. Paquette, John Wiley and Sons, New
York, 1995, Vol. 5, p. 3326.
The etherification of alcohol 2j (Eq. 3) illustrates the tolerance of
the reaction conditions to sensitive functionality. Alcohol 2j is
4
5
(a) P. G. M. Wuts, 4-Methoxybenzyl 2,2,2-Trichloroacetimidate, in
Encyclopedia of Reagents for Organic Synthesis, ed. L. A. Paquette, John
Wiley and Sons, New York, 1995, Vol. 5, p. 3329; (b) Attractive method
for the synthesis of PMB ethers using catalytic lanthanum triflate:
A. N. Rai and A. Basu, Tetrahedron Lett., 2003, 44, 2267.
The Chemical Synthesis of Natural Products, ed. K. Hale, CRC Press,
Boca Raton, Florida, 2000.
1
1
subject to Peterson elimination under acidic or basic conditions,
but transfer of the PMB-group provides ether 3j with no evidence
of the potential elimination by-product, 4-phenyl-1-butene.
In keeping with our earlier work on the synthesis of benzyl
6
6 (a) K. W. C. Poon and G. B. Dudley, J. Org. Chem., 2006, 71, 3923; (b)
K. W. C. Poon, S. E. House and G. B. Dudley, Synlett, 2005, 3142; (c)
G. B. Dudley, US Pat. Appl. No. 11/399,300, 2006.
ethers, we propose that the current synthesis of PMB ethers
proceeds by an S 1-type mechanism analogous to that observed
N
from trichloroacetimidates. Critical to the success of our approach
7 Benzyloxy salt 4 is commercially available from Sigma-Aldrich
Chemical Co. (catalog # 679674-1g, 679674-5g).
12
is that the neutral alcohol (2) does not react with methyl triflate,
8
Typical reagents for the formation of PMB ethers are more reactive and
less stable than reagents for the synthesis of benzyl ethers; see
P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 3rd edn, 2003,
p. 257.
whereas alcohol 2 does react with the p-methoxybenzyl cation as it
is released from active reagent 8.
Lepidine ether 1 provides several key advantages over PMB
trichloroacetimidate: (1) ether 1 is more stable; (2) active reagent 8
is generated under non-acidic conditions; and (3) the by-product,
lepidone 10, remains in solution until it is purged either during
aqueous workup or on silica gel chromatography. In contrast, the
acetamide by-product of trichloroacetimidate coupling reactions
can cause problems during purification.
9
Trifluorotoluene, also known as benzotrifluoride or BTF, is often used
industrially as an alternative to dichloromethane.
0 An analogous modification of Mukaiyama’s reagent improved its
1
solubility in non-polar solvents; see: S. H. Oh, G. S. Cortez and
D. Romo, J. Org. Chem., 2005, 70, 2835.
1 D. J. Ager, Org. React., 1990, 38, 1.
1
12 Methyl tosylate, dimethyl sulfate and methyl iodide were not effective
substitutes for methyl triflate.
This journal is ß The Royal Society of Chemistry 2007
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