Simple and rapid p-methoxybenzylation of hydroxy and amide groups at room temperature by NaOt-Bu and DMSO

Article abstract of DOI:10.1016/j.tetlet.2019.151277

The p-methoxybenzylation of hydroxy and amide groups by p-methoxybenzyl chloride utilizing NaOt-Bu in DMSO is described. p-Methoxybenzylation of sterically hindered menthol using NaOt-Bu in DMSO proceeded faster than the commonly used methods which use Na

Full text of DOI:10.1016/j.tetlet.2019.151277

Journal Pre-proofs
Simple and Rapid p-Methoxybenzylation of Hydroxy and Amide Groups at
Room Temperature by NaOt-Bu and DMSO
Shohei Hamada, Koichi Sugimoto, Masashi Iida, Takumi Furuta
PII:
S0040-4039(19)31057-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151277
TETL 151277
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 August 2019
2 October 2019
11 October 2019
Please cite this article as: Hamada, S., Sugimoto, K., Iida, M., Furuta, T., Simple and Rapid p-Methoxybenzylation
of Hydroxy and Amide Groups at Room Temperature by NaOt-Bu and DMSO, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.151277
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Graphical Abstract
Simple and Rapid p-Methoxybenzylation of
Hydroxy and Amide Groups at Room
Temperature by NaOt-Bu and DMSO
Leave this area blank for abstract info.
Shohei Hamada*, Koichi Sugimoto, Masashi Iida, and Takumi Furuta
PMBCl (1.1 equiv.)
NaOt-Bu (1.2 equiv.)
PMBCl (1.1 equiv.)
NaOt-Bu (1.2 equiv.)
O
O
R3
R1 OH
R1 OPMB
R3
R2
N
R2
N
DMSO
DMSO
room temp.
H
PMB
room temp.
without activating source
without activating source

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Simple and Rapid p-Methoxybenzylation of Hydroxy and Amide Groups at Room
Temperature by NaOt-Bu and DMSO
Shohei Hamada, Koichi Sugimoto, Masashi Iida, and Takumi Furuta
Department of Pharmaceutical Chemistry, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8414, Japan
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +81-75-595-4666; e-mail: hamada@mb.kyoto-phu.ac.jp
Article history:
Received
The p-methoxybenzylation of hydroxy and amide groups by p-methoxybenzyl chloride utilizing
NaOt-Bu in DMSO is described. p-Methoxybenzylation of sterically hindered menthol using
Received in revised form
Accepted
Available online
NaOt-Bu in DMSO proceeded faster than the commonly used methods which use NaH in THF
or DMF for p-methoxybenzylation of hydroxy and amide groups. The described method was
applicable for sterically hindered substrates at room temperature without adding any activating
reagents such as tetrabutylammonium iodide.
Keywords:
Sodium tert-butoxide
DMSO
2009 Elsevier Ltd. All rights reserved.
p-Methoxybenzylation
Protecting group
1. Introduction
describe simple and rapid p-methoxybenzylation of hydroxy and
amide groups by PMBCl at room temperature using NaOt-Bu in
Benzyl and benzyl-derived protecting groups are widely used
to protect alcohols and amine derivatives.1 The p-methoxybenzyl
(PMB) group, in particular, is widely employed as it is generally
stable under a variety of reaction conditions and can be
selectively deprotected by oxidizing reagents such as 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) or ceric ammonium
nitrate (CAN).1,2 Due to the usefulness of the PMB group as a
protecting group, its protection methods have been well
developed. Nucleophilic substitutions of alcohols or amine
derivatives with p-methoxybenzyl chloride (PMBCl)3 have been
most commonly used. Acid-catalyzed coupling reactions with
PMB 2,2,2-trichloroacetimidate4 have also often been employed
for p-methoxybenzylation of alcohols. Moreover, a number of
alternative methods using imidate-type reagents,5 anisyl
alcohols,6 and other methods7 have been developed for the
protection of alcohols.
DMSO. 10
2. Results
In order to develop the highly reactive p-methoxybenzylation
method at room temperature, we investigated the suitable
reaction conditions for sterically hindered menthol 1a (Table 1).
Treatment of 1a and PMBCl with NaH in THF and DMF,
respectively, produced 2a in 1% and 53% yields, respectively
(entries 1 and 2). The addition of 10 mol% of TBAI did not
enhance the chemical yield (entry 3). To enhance the reactivity of
this nucleophilic substitution and increase the chemical yield, we
employed DMSO, which is a solvent with greater polarity than
DMF (entry 4). As expected, this reaction condition enhanced the
yield slightly (68%) compared to NaH/DMF. After examining
NaOt-Bu and KOt-Bu as bases (entries 5 and 6), NaOt-Bu was
found to be the most suitable for this reaction. Treatment of 1a
with 1.3 equivalents of PMBCl and 1.5 equivalents of NaOt-Bu
in DMSO at room temperature afforded PMB ether 2a in a 95%
yield (entry 5). Replacing DMSO with DMF decreased the yield
of 2a (entry 7). In addition to these positive results, NaOt-Bu is a
base which is suitable for large scale processes due to its safety
and cost-effectiveness.8a For these reasons, we feel that the NaOt-
Despite the large number of methods which have been
developed for p-methoxybenzylation, nucleophilic reactions
between alcohols or amine derivatives and PMBCl have been
most commonly used due to their simplicity, reliability, and cost-
effectiveness. 3 The strong base NaH in either THF or DMF has
been the most commonly used condition for this reaction.
However, these methods often require high temperatures and an
activator such as tetrabutylammonium iodide (TBAI).1
Furthermore, NaH is an undesired base for large scale processes,
as it is insoluble in most solvents and generates highly explosive
hydrogen gas.8 Recently, tertiary amine-mediated simple and
mild p-methoxybenzylation has been reported.9 Although this
method is applicable under weak basic conditions, it also requires
high temperatures and sodium iodide as an additive to achieve p-
methoxybenzylation of sterically hindered alcohols. Herein, we
Bu/DMSO system is
a
superior method for p-
methoxybenzylation of sterically hindered hydroxy groups.
Table 1. p-Methoxybenzylation of 1a with PMBCl
PMBCl (1.3 equiv.)
Base (1.5 equiv.)
OH
OPMB
Solvent
rt, 8 h
2a
1a

2
Tetrahedron Letters
Entry
Substrate
Product
Yield (%)a
99
Entry
Base
NaH
Solvent
THF
Yield (%)a
OH
OPMB
1
2
3b
1
1
2
1b
2b
NaH
DMF
53
47
68
95
93
79
NaH
DMF
99
93
OH
OPMB
4
NaH
DMSO
DMSO
DMSO
DMF
1c
2c
5
NaOt-Bu
KOt-Bu
NaOt-Bu
OH
OPMB
6
3
7
a Yields were determined by 1H-NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard.
1d
2d
b 10 mol% of TBAI was added as an additive.
4
98
40
5b
OH
1e
OPMB
2e
To investigate the scope of the p-methoxybenzylation, we
treated various alcohols with PMBCl and NaOt-Bu in DMSO at
room temperature (Table 2).
6c
7d
84
41
OH
OPMB
Treatment of the primary alcohol 1b with 1.1 equivalents of
PMBCl and 1.2 equivalents of NaOt-Bu in DMSO at room
temperature for 3 h gave PMB ether 2b in a nearly quantitative
yield (entry 1). The reaction of secondary alcohols 1c–d afforded
the corresponding PMB ethers (2c–d), respectively, in excellent
yields (99 and 93%; entries 2 and 3, respectively). Sterically
hindered alcohols such as 1e and 1f11 were also converted into 2e
and 2f, respectively, in good yields (98 and 84%; entries 4 and 6,
respectively). On the other hand, treatment of 1e and 1f with
PMBCl and NaH, respectively, in DMF diminished the yields (40
and 41%; entries 5 and 7, respectively). Secondary alcohols
containing a tetrahydropyran ring (1g) were also converted into
PMB ether at a 93% yield (entry 8). Galactopyranoside 1h was
treated with 4.8 equivalents of PMBCl and NaOt-Bu to produce
the tetrabenzylated product 2h in good yield (entry 9). This
reaction was also applicable to 2-naphthol (1i) whose conjugate
base is less nucleophilic than that of the alcohols (entry 10). On
the other hand, benzoic acid 1j converted into PMB ester 2j in a
lower yield than the alcohols and naphthol (entry 11). In addition
to p-methoxybenzylation, NaOt-Bu/DMSO system was effective
for benzylation as well as 2,3- and 2,4-dimethoxybenzylation
(See the supporting information).
1f
2f
O
OH
O
OPMB
8
93
88
1g
OH
O
2g
OPMB
O
OH
PMBO
PMBO
9e
HO
OPh
OPh
OH
OPMB
1h
2h
OH
OPMB
10c
11f
96
44
1i
2i
CO2H
CO2PMB
1j
2j
a Isolated yield.
b Reaction was run using 1.2 equiv. of NaH and DMF instead of NaOt-Bu and
DMSO.
c Reaction was run using 1.5 equiv. of NaOt-Bu and PMBCl.
d Reaction was run using 1.5 equiv. of NaH and DMF instead of NaOt-Bu and
DMSO.
e Reaction was run using 4.8 equiv. of NaOt-Bu and PMBCl.
f Reaction was run for 5 h.
As shown by the investigations detailed in Tables 1 and 2, the
NaOt-Bu/DMSO system gave high yields in the p-
methoxybenzylation of sterically hindered alcohols compared
with the NaH/THF and NaH/DMF systems. This difference in
outcomes seems to be due to a difference in reaction rates.
Therefore, we conducted a close comparison of the reactivities of
the NaH/DMF, NaH/DMSO, NaOt-Bu/DMF, and NaOt-
Bu/DMSO systems using alcohol 1a as a substrate (Scheme 1). It
was found that the NaOt-Bu/DMSO and NaOt-Bu/DMF system
afforded PMB ether in a 72% yield 25 min after the reaction
started while the NaH/DMSO and NaH/DMF systems afforded
12% and 6% yields, respectively, in the same amount of time.
These data suggest that NaOt-Bu showed higher reactivity than
NaH in the p-methoxybenzylation of sterically hindered alcohols.
The reason why NaOt-Bu is more reactive than NaH against 1a
should be due to the higher deprotonation activity of NaOt-Bu in
Table 2. Substrate scope of p-methoxybenzylation of hydroxy
groups
PMBCl (1.1 equiv.)
NaOt-Bu (1.2 equiv.)
R OH
R OPMB
DMSO
rt, 3 h
1
2

3
DMSO and DMF compared to those of NaH.12 Actually, it has
Entry
1
Substrate
Product
Yield (%)a
99
been reported that NaH was not effective for deprotonation of
sterically hindered tertiary alcohols.13
O
O
N
N
H
PMB
3a
4a
PMBCl (1.3 equiv.)
Base (1.5 equiv.)
PMB
H
N
N
OH
OPMB
2
3
98
78
Solvent
23 oC
O
O
3b
4b
2a
1a
O
O
NaOt-Bu, DMSO
PMB
NH
N
100
80
60
40
20
0
3c
4c
O
O
NH
N
PMB
PMB
4
5
96
93
NaOt-Bu, DMF
NaH, DMSO
3d
4d
O
O
NaH, DMF
NH
N
0
20
40
60
80
100
120
time (min)
3e
4e
O
O
Scheme 1. Comparison of the reactivity between NaOt-Bu and
NaH.
NH
N PMB
6
7
92
O
O
Next, we investigated p-methoxybenzylation of amide, imide,
sulfoneamide, and azole compounds using the NaOt-Bu/DMSO
system at room temperature (Table 3).
3f
4f
O
O
O
O
S
S
N
N
84
97
H
PMB
N-Methylbenzamide (3a) treated with PMBCl and NaOt-Bu in
DMSO afforded N-PMB-N-methylbenzenamide (4a) in a 99%
yield (entry 1). Acetanilide (3b) bearing a N-phenylamide moiety
also provided the desired compound (4b) in a 98% yield (entry 2).
Cyclic amides such as -valerolactam (3c) and -caprolactam
(3d) gave 4c and 4d in high yields of 78 and 96%, respectively
(entries 3 and 4). -Lactam (3e), possessing a tetra-substituted
carbon next to the N-H group, also afforded N-p-
methoxybenzylation product 4e selectively in a 93% yield in a
short time (entry 5). Imide (3f) and sulfonamide (3g) were also
efficiently converted into the desired products 4f and 4g,
respectively, in high yields of 92% and 84% (entries 6 and 7).
The heteroaromatic compound, imidazole (3h), provided the p-
methoxybenzylated product 4h in a 97% yield (entry 8). N-
benzylation of the amide 3a also proceeded smoothly (See the
supporting information).
3g
4g
PMB
H
N
N
8
N
3h
N
4h
a Isolated yield.
A gram-scale p-methoxybenzylation by the NaOt-Bu/DMSO
system was then examined (Scheme 2). Treatment of 1.0 g of 1a
with 1.1 equivalents of PMBCl and 1.2 equivalents of NaOt-Bu
resulted in the smooth formation of PMB ether 2a without
obvious loss of reaction efficiency.
PMBCl (1.1 equiv.)
NaOt-Bu (1.2 equiv.)
OH
OPMB
DMSO
3 h, rt
2a
92%
1a
1.0 g
Scheme 2. A gram scale synthesis of 2a
In conclusion, we developed a simple and highly active p-
methoxybenzylation method for hydroxy and amide groups using
PMBCl. NaOt-Bu/DMSO showed higher reactivity than the
commonly used NaH/THF or DMF, therefore, NaOt-Bu/DMSO
is an option for use with sterically hindered substrates at room
temperature without the need for activating reagents such as an
iodide source. This method would be suitable for large-scale
synthesis, as it does not require complex reaction conditions or
expensive reagents. We have great hopes that the NaOt-
Table 3. N-p-Methoxybenzylation using NaOt-Bu/DMSO system
PMBCl (1.1 equiv.)
PMB
NaOt-Bu (1.2 equiv.)
H
N
N
R
R'
R
R'
DMSO
rt, 3 h
3
4

4
Tetrahedron Letters
7.
(a) Kamaike, K.; Tsuchiya, H.; Imai, K.; Takaku, H. Tetrahedron
1986, 42, 4701–4711; (b) Hanessian, S.; Huynh, H. K.
Tetrahedron Lett. 1999, 40, 671–674; (c) Kotturi, S. R.; Tan, J. S.;
Lear, M. J. Tetrahedron Lett. 2009, 50, 5267–5269; (d)
Kasprzycka, A.; Ptaszek-Budniok, A.; Szeja, W. Synth. Commun.
2014, 44, 2276–2284.
Bu/DMSO system for p-methoxybenzylation of alcohols and
amides will be applicable and useful in fine organic synthesis.
Acknowledgements
8.
9.
(a) Yu, R. H.; Schultze, L. M.; Rohloff, J. C.; Dudzinski, P. W.;
Kelly, D. E. Org. Process. Res. Dev. 1999, 3, 53–55; (b) Dunn, J.
M. M.; Duran-Capece, A.; Meehan, B.; Ulis, J.; Iwama, T.; Gloor,
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1446.
This research was supported by MEXT KAKENHI, Grant No.
19K16327 (S.H.).
References and notes
Gathirwa, J. W.; Maki, T.; Tetrahedron 2012, 68, 370–375.
10. To the best of our knowledge, there has been no report of p-
methoxybenzylation by PMBCl and NaOt-Bu in DMSO. Mullens
and his coworkers reported p-methoxybenzylation of a 2-
aminopyrimidine derivative by using PMBCl and NaOt-Bu in
DMF. See: Mullens, P.; Cleator, E.; McLaughlin, M.; Bishop, B.;
Edwards, J.; Goodyear, A.; Andreani, T.; Jin, Y.; Kong, J.; Li, H.;
Williams, M.; Zacuto, M.; Org. Process. Res. Dev. 2016, 20,
1075–1087.
11. p-Methoxybenzylation of tertiary alocohol 1f required 1.5 equiv.
of NaOt-Bu because p-methoxybenzylation of NaOt-Bu also
proceeded.
12. We investigated deprotonation of 1a (1.0 equiv.) by NaH (0.5
equiv.) in DMF. The mixture of 1a and NaH in DMF was stirred
at room temperature for 30 min. After the reaction mixture was
quenched with aqueous NH4Cl, gas was generated immediately.
This result indicates that H2 gas was generated after quenching the
reaction and, therefore, deprotonation of 1a by NaH did not
proceed smoothly.
1.
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Supplementary Material
Supplementary material related to this article can be found
online.
6.
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Click here to remove instruction text...
relationships that could have appeared to influence
the work reported in this paper.
PMBCl (1.1 equiv.)
O
PMBCl (1.1 equiv.)
NaOt-Bu (1.2 equiv.)
O
NaO☐t-BuTh(1e.2aeuqtuhivo.)rs deRcl2are the following financial
R3
R1 OH
R1 OPMB
R3
N
R2
N
DMSO
DMSO
room temp.
without iodide source
interests/personal relationships which may be
H
PMB
room temp.
considered as potential competing interests:
without iodide source
• p-Methoxybenzylation of hydroxy and amide groups
using NaOt-Bu in DMSO is described.
• Simple, rapid, and cost-effective method.
• p-Methoxybenzylation of sterically hindered substrates
proceeded at room temperature.
Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal

5