1-Naphthylmethyl and 1-naphthylmethoxymethyl protecting groups: New members of the benzyl- and benzyloxymethyl-type family

Article abstract of DOI:10.1016/j.tetlet.2017.04.046

1-Naphthylmethyl (NAP^I) and 1-naphthylmethoxymethyl (NAPOM^I) protecting groups were developed as new members of the benzyl- and benzyloxymethyl-type family. NAP^I and NAPOM^I can be introduced under conventional conditions, such as NAP^IBr/NaH/room temperature (rt), or NAPOM^ICl/i-Pr₂EtN/rt. They can also be removed under conventional conditions, e.g., by dichlorodicyanobenzoquinone (DDQ)- or ceric ammonium nitrate (CAN)-mediated oxidation, or by hydrogenolysis. The specific advantages of these new protecting groups are: i) a less costly synthesis of NAPOM^ICl compared to NAPOM^IICl, ii) the possibility to remove NAPOM^II selectively in the presence of NAPOM^I by DDQ-mediated oxidation, and iii) the compatibility with strong acids even in the presence of hard nucleophiles.

Full text of DOI:10.1016/j.tetlet.2017.04.046

Accepted Manuscript
1-Naphthylmethyl and 1-Naphthylmethoxymethyl Protecting Groups: New
Members of the Benzyl- and Benzyloxymethyl-Type Family
Takuya Sato, Yohei Joh, Tohru Oishi, Kohei Torikai
PII:
S0040-4039(17)30486-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.046
TETL 48838
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 February 2017
12 April 2017
14 April 2017
Please cite this article as: Sato, T., Joh, Y., Oishi, T., Torikai, K., 1-Naphthylmethyl and 1-Naphthylmethoxymethyl
Protecting Groups: New Members of the Benzyl- and Benzyloxymethyl-Type Family, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.046
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1-Naphthylmethyl and 1-Naphthylmethoxymethyl Protecting Groups: New
Members of the Benzyl- and Benzyloxymethyl-Type Family
Takuya Sato†, Yohei Joh†, Tohru Oishi, and Kohei Torikai*
Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka
819-0395, Japan
*E-mail: torikai@chem.kyushu-univ.jp
† These authors contributed equally to this work.
(NAPI)
and
1-
spite the potential utility of their characteristic features and the
Abstract:
1-Naphthylmethyl
naphthylmethoxymethyl (NAPOMI) protecting groups were
developed as new members of the benzyl- and
benzyloxymethyl-type family. NAPI and NAPOMI can be in-
troduced under conventional conditions, such as
NAPIBr/NaH/room temperature (rt), or NAPOMICl/i-
Pr2EtN/rt. They can also be removed under conventional con-
ditions, e.g. by oxidation using dichlorodicyanobenzoquinone
(DDQ)- or ceric ammonium nitrate (CAN)-mediated, or by
hydrogenolysis. The specific advantages of these new protect-
ing groups are: i) a less costly synthesis of NAPOMICl com-
pared to NAPOMIICl, ii) the possibility to remove NAPOMII
selectively in the presence of NAPOMI by DDQ-mediated
oxidation, and iii) the compatibility with strong acids even in
the presence of hard nucleophiles.
lower costs relative to conventional protecting groups. Herein,
we report NAPI and NAPOMI as new members of the naph-
thalene-based protecting group family to increase the pool of
available protecting groups for the synthesis of complex mole-
cules, and we demonstrate their unique and highly useful se-
lective removal.
Initially, we examined the protection/deprotection of various
alcohols with NAPI (Table 1). For that purpose, alcohols were
treated with NAPIBr in the presence of NaH in DMF at rt (en-
tries 1-3). For primary (1a) and secondary alcohols (2a), the
reactions proceeded smoothly to afford the corresponding
NAPI ethers 1b (93%) and 2b (88%) in good yields. As is
often the case with tertiary alcohols such as 1c, the introduc-
tion of NAPI stopped prematurely at rt, to furnish the protected
ether 3b in 58% yield. In a second step, we attempted to re-
move the NAPI group from 1b-3b via oxidative (DDQ,
CH2Cl2/H2O = 4/1, rt) or reductive (1 atm H2, Pd/C, MeOH, rt)
conditions. As a result, the free alcohols 1a-3a were obtained
in high yields (97-100%). These results demonstrate the poten-
tial of the NAPI group as a novel member of the Bn-type fami-
ly protecting groups that can be removed oxidatively.
As the judicious selection of protecting groups is one of the
most important factors for the successful synthesis of complex
molecules with several functional groups, numerous protecting
groups have been developed to date.1 For the protection of
hydroxy groups, benzyl-type protecting groups such as benzyl
(Bn), p-methoxybenzyl (PMB), and 2-naphthylmethyl (NAP)
groups are especially popular, as they are relatively stable
under acidic and basic conditions, and as they can be removed
under neutral conditions via Pd-catalyzed hydrogenolysis. In
addition, PMB and NAP can also be removed by treatment
with oxidants such as dichlorodicyanobenzoquinone (DDQ) or
ceric ammonium nitrate (CAN). The introduction of benzyl-
type protecting groups is usually achieved under strongly acid-
ic (e.g., BnOC(NH)CCl3 or TfOH)2 or basic (e.g.,
NaH/BnBr/DMF or i-Pr2EtN/BnBr/neat/150 °C)3 conditions.4
Accordingly, benzyloxymethyl-type groups, such as
benzyloxymethyl (BOM), and p-methoxybenzyloxymethyl
(PMBOM) groups are highly useful for the protection of acid-
and/or base-sensitive compounds, as these protecting groups
can be installed under weakly basic conditions (e.g. BOMCl/i-
Pr2EtN/rt). During our studies on protecting groups for the
synthesis of natural products, we have recently developed the
2-naphthylmethoxymethyl (NAPOM)5,6 group, which can be
selectively removed in the presence of other Bn- or BOM-type
protecting groups such as PMB, NAP, or BOM. Curiously, 1-
naphthylmethyl (NAPI)7 and 1-naphthylmethoxymethyl
(NAPOMI) groups, which are regioisomers of NAPII and
NAPOMII,8 have not yet found widespread applications, de-
Table 1. Protection and Deprotection of alcoholic hydroxy
groups with NAPI.
a
b
Isolated yields after column chromatography on silica gel.
NAPIBr (1.1 equiv), NaH (1.5 equiv), DMF ([substrate] = 1.0
M), rt, 6-26 h; reactions were monitored by TLC and
c
quenched upon completion or stopping. DDQ (3 equiv),

d
CH2Cl2/H2O = 4/1, rt, 1.5-6.5 h. H2 (1 atm), Pd/C (5 mol%),
rt, 1.0-1.7 h.
easily migrates under slightly acidic or basic conditions (entry
5). Although acyl migration actually occurred when i-Pr2EtN
was used as a base, the use of 2,6-lutidine prevented this un-
wanted side reaction: treatment of 4a with NAPOMICl, 2,6-
lutidine, and a catalytic amount of tetrabutyl ammonium io-
dide (TBAI) in CH2Cl2 at rt furnished the desired NAPOMI
ether (4c) in 82% yield. Ester (entry 5), olefin (entry 6), silyl
ether and acetal (entry 7) moieties remained unaffected under
the applied conditions to install NAPOMI to afford 5c (72%)
and 6c (74%) from 5a and 6a,11 respectively.
Table 2. Protection of alcoholic hydroxy groups with
NAPOMI.
Then, we turned our attention to the removal of the NAPOMI
group (Table 3). Under oxidative conditions using DDQ,
NAPOMI ethers 1c-3c proved to be unexpectedly resistant,
which stands in contrast to the behavior of NAPOMII.
Table 3. Removal of the NAPOMI group from protected
hydroxy groups.
a
b
NAPOMICl (2-6 equiv), i-Pr2EtN (4-12 equiv). [Substrate]
= 0.1-0.5 M. c Isolated yields after column chromatography on
silica gel. NAPOMICl (6 equiv), 2,6-lutidine (12 equiv),
and TBAI (0.5 equiv).
d
With this encouraging result on NAPI in hand, we turned our
attention to the NAPOMI group. The synthesis of NAPOMICl
was successfully achieved following a procedure similar to
that of NAPOMIICl, i.e., a mixture of 1-naphthylmethyl alco-
hol and paraformaldehyde was treated with gaseous HCl in
pentane at -20 °C,9 which furnished NAPOMICl in 85%
yield.10 It is noteworthy that 1-naphthylmethyl alcohol is sub-
stantially cheaper than 2-naphthylmethyl alcohol, which is
required for the preparation of NAPOMIICl.
a [Substrate] = 0.1 M. b Reactions were monitored by TLC and
quenched upon completion or the formation of undesired
c
products. Isolated yields after column chromatography on
d
silica gel. Byproducts were observed (for details, see: Sup-
e
plementary Material). Obtained as an inseparable mixture
Subsequently, the protection of alcoholic hydroxy groups with
NAPOMI was examined (Table 2). A conventional treatment
of primary, secondary, or tertiary alcohols (1a-3a, entries 1-3)
with NAPOMICl and i-Pr2EtN in CH2Cl2 at rt, furnished
NAPOMI ethers 1c-3c in good yields (90-100%). Although the
required reaction time is different for primary and tertiary
alcohols, a selective installation of the NAPOMI group in pri-
mary alcohol 1a in the presence of tertiary alcohol 3a was not
possible under the applied reaction conditions. On the other
hand, the reaction time for tertiary alcohol 3a was shortened in
toluene (entry 4), which emerged as one of the best solvents
for these reactions5 without affecting the yield of 3c (94%).
We also attempted to use NAPOMI to protect the hydroxy
group of a 2-acetoxy-1-ol system (4a), whose acetyl group
containing 1-naphthalenemethanol; yields were determined
based on the 1H-NMR spectra of the mixture.
The successful removal of NAPOMI (entries 1, 4, and 7) re-
quired an increased amount of DDQ (3 equiv) in combination
with elevated temperatures (reflux), while NAPOMII can be
removed smoothly using only 1.5 equiv of DDQ at rt. Alt-
hough the yield of 3a (99%) was satisfactory, those of 1a
(64%) and 2a (86%) were not, due to the generation of by-
products, which probably formed on account of the harsh con-
ditions. Therefore, we also examined the milder oxidant CAN
(entries 2, 5, and 8). As expected, the yields improved in all
cases (83, 88, and 100%, respectively), although prolonged
reaction times were required. The reason why NAPOMI is

more tolerant toward oxidation than NAPOMII remains un-
clear at this point.
BOM-type protecting group family increases the pool of avail-
able protecting groups, especially when oxidatively cleavable
protecting groups other than PMB, PMBOM, NAPII and
NAAPOMII are required for the synthesis of complex mole-
cules. This notion is supported by the successful cleavage of
NAPOMI ethers (1c) in the presence of PMB ethers (85% re-
covery of 1f; Scheme 1C), as well as BOM (1g)15 and MOM
(1h)16 ethers (82% and 97% recovery of 1g and 1h; Scheme
1D). Ester (quantitative recovery of 1i; Scheme 1E), olefin
(85% yield of 5a; Scheme 1F), silyl ether, and acetal (83%
yield of 6a; Scheme 1G) moieties remained unaffected during
the cleavage of NAPOMI.
Chart 1. A. Cationic intermediates during the oxidation of
NAPOMI and NAPOMII ethers. B. Structures of NAPOMII
ethers.
Before our investigations, and based on the conventional elec-
tronic theory in organic chemistry, we expected that NAPOMI
should be more reactive toward oxidants, given that cationic
intermediate 7 should be more stable than cation 8 on account
of the resonance effect (Chart 1A). However, the experimental
results did not match our expectations. Interestingly, the oxi-
dation potentials of 1c, 1d, 3c, and 3d (Chart 1B), measured
by cyclic voltammetry, could not be used to rationalize the
experimental results either, as the oxidation potentials of 1c,
1d, 3c, and 3d were almost identical (for details, see: Supple-
mentary Material).
Scheme 1. Selective Removal of NAPOMI Protecting Groups.
Therefore, we went on to test a hydrogenolytic removal of the
NAPOMI group (entries 3, 6, and 9; Table 3). Stirring MeOH
solutions of NAPOMI ethers 1c, 2c, or 3c in the presence of
Pd/C (5 mol%) under an atmosphere of H2 (1 atm) provided
the deprotected alcohols 1a, 2a, and 3a in 81-83% yields.
Again, these reactions were more sluggish than those of the
corresponding NAPOMII substrates. Taking the fast
hydrogenolytic removal of NAPI (Table 1) into consideration,
a possible explanation for the slow hydrogenolysis may be the
binding of acetal oxygen atoms of NAPOMI to Pd, resulting in
a specific conformation that potentially facilitates the dis-
charge of the naphthalene moiety from the surface of the Pd
catalyst.12
As the last part of our deprotection experiments, were treated
NAPOMI ethers with various acids, in order to determine the
stability of the NAPOMI group under acidic conditions.
Treatment of NAPOMI ether 1c with 8 equiv of p-TsOH in
THF or MeOH at rt did not show any effect (entry 10),13
whereas the prolonged (22 h) exposure of 1c to p-TsOH at
elevated temperatures (reflux) cleaved the NAPOMI group to
furnish alcohol 1a in quantitative yield (entry 11).13 Combina-
tions of a strong Lewis acid and a hard nucleophile (e.g.,
BF3·OEt2/Et3SiH), which are frequently used for reductive
etherifications14 or for the removal of t-butoxycarbonyl groups,
resulted in the quantitative recovery of 1c, even at elevated
temperatures up to -30 °C (entry 12).13
Our results so far have shown that NAPI and NAPOMI can be
effectively used as protecting groups. Therefore, we wanted to
investigate the possibility of a selective removal of NAPI and
NAPOMI in the presence of other protecting groups (Scheme
1).
The characteristic stability of NAPOMI group in acidic media,
allowed a treatment of a mixture of 1c and 1e with camphor
sulfonic acid (CSA) in MeOH at 0 °C, which selectively re-
moved the triisopropylsilyl (TIPS) group from 1e, but allowed
to recover NAPOMI ether 1c in 99% yield (Scheme 1A). More
importantly, the unexpectedly sluggish cleavage of NAPOMI
with DDQ can be used to induce a very unique selectivity, i.e.,
NAPOMII ether 1b was deprotected by DDQ in the presence
of NAPOMI ether 1c in 87% yield (B). This observation clear-
ly shows that the addition of NAPOMI as a new member of
a
A 1:1 (:1) (mol/mol) mixture of substrates was used. For
each entry, the protecting and functional groups that remained
unaffected are highlighted in red.
Herein, we have reported the development of NAPI and
NAPOMI protection groups, i.e., new members of the Bn- and
BOM-type family for the protection of hydroxy groups. The
specific advantages of the NAPOMI group are: i) the possibil-
ity to selectively remove NAPOMII in the presence of
NAPOMI, ii) the compatibility with strong Lewis and protic
acids, even in the presence of hard nucleophiles, and iii) the
possibility to synthesize these protecting groups from cheap
commercially available materials. These characteristic should
find the NAPI and NAPOMI groups widespread applications in
the research communities that are concerned with the synthesis
of complex molecules. Application studies involving these
NAPOM groups are currently in progress in our laboratory.
Key words
Protecting
group;
Oxidative
cleavage;
Benzyl;
Benzyloxymethyl; Naphthylmethyl; Naphthylmethoxymethyl;
NAP; NAPOM
Supplementary Material

1
Synthetic procedures, spectral data, and H and 13C NMR
coordination of acetal oxygen atoms may be connected in a similar way to
the sluggish oxidative removal of NAPOMI with DDQ, i.e., we suspect an
interaction between a pair of oxygen atoms and DDQ.
(13) Corresponding NAPOMII ethers afforded similar results (data not
shown).
charts of all new compounds. This material is available free of
charge via the Internet.
Acknowledgments
(14) For examples, see: (a) Nicolaou, K. C.; Hwang, C. K.; Nugiel, D. A.
J. Am. Chem. Soc. 1989, 111, 4136-4137.; (b) Torikai, K.; Watanabe, K.;
Minato, H.; Imaizumi, T.; Murata, M.; Oishi, T. Synlett 2008, 2368-2372.
(15) Oriyama, T.; Kimura, M.; Koga, G. Bull. Chem. Soc. Jpn. 1994, 67,
885-887.
(16) (a) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
3912-3920. (b) Kyasa, S.; Meier, R. N.; Pardini, R. A.; Truttmann, T. K.;
Kuwata, K. T.; Dussault, P. H. J. Org. Chem. 2015, 80, 12100-12114.
We are grateful to Profs. Ken Sakai and Kosei Yamauchi
(Kyushu University) for providing us with access to cyclic
voltammetry instrumentation, and to Prof. Masahiko Suenaga
(Kyushu University) for invaluable discussions. We also thank
Mr. Keiya Yamamoto (Kyushu University) for technical sup-
port with cyclic voltammetry measurements. Mr. Naoto Yanai
(our laboratory) is acknowledged for providing 6a. This work
was financially supported by a Grant-in-Aid for Young Scien-
tists (B) (No. 15K21210 to K.T.) from the JSPS, and a grant
from Wako Pure Chemical Industries (to K.T.), as well as by a
Wako Award in Synthetic Organic Chemistry (Japan). K.T.
would like to express his deepest gratitude to Ms. Miyoko
Ueno, Mr. and Ms. Takaaki and Rumiko Torikai, Mr. Kazuo
Fushiki, Ms. Yukiko Ueno, and Mr. and Ms. Motoaki and
Michie Yamaoka for their generous financial donations to his
project. The authors declare that a patent regarding the use of
NAPOMCl for the protection of alcohols and thiols is pending
(PCT Int. Appl. WO 2016056448 A1 20160414, 2016).
References and Notes
(1) Wuts, P. G. M. Greene’s Protective Groups in Organic Synthesis, 5th
ed.; John Wiley & Sons: New Jersey, 2014.
(2) Iversen, T.; Bundle, K. R. J. Chem. Soc., Chem. Commun. 1981, 1240-
1241.
(3) Gathirwa, J. W.; Maki, T. Tetrahedron 2012, 68, 370-375.
(4) Recently, several mild benzylation methods have been developed. For
examples, see: (a) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett
2005, 3142-3144.; (b) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006,
71, 3923-3927.; (c) Kotturi, S. R.; Tan, J. S.; Lear, M. J. Tetrahedron Lett.
2009, 50, 5267-5269. (d) Yamada, K.; Fujita, H.; Kunishima, M. Org. Lett.
2012, 14, 5026-5029.; (e) Yamada, K.; Fujita, H.; Kitamura, M.;
Kunishima, M. Synthesis 2013, 45, 2989-2997.; (f) Yamada, K.; Tsukada,
Y.; Karuo, Y.; Kitamura, M.; Kunishima, M. Chem.–Eur. J. 2014, 20,
12274-12278.
(5) Sato, T.; Oishi, T.; Torikai, K. Org. Lett. 2015, 17, 3110-3113. Should
a shorter abbreviation for NAPOM be required, the authors propose to use
NOM.
(6) Kyushu University, PCT Int. Appl. WO 2016056448 A1 20160414,
2016.
(7) NAPI has previously been used only as a protecting group for carboxy
groups, and removed via homogeneous Pd-catalyzed hydrogenolysis. For
details, see: Boutros, A.; Legros, J.-Y.; Fiaud, J.-C. Tetrahedron 2000, 56,
2239-2246. In this paper, the 1-naphthylmethyl group is intentionally
abbreviated to NAPI, although it should be 1-NAP when considering
precise nomenclature. NAPI has been used in order to minimize the re-
quired
space
in
synthetic
schemes.
Likewise,
the
1-
naphthylmethoxymethyl group was abbreviated to NAPOMI.
(8) In this paper, the 2-naphthylmethyl and 2-naphthylmethoxymethyl
groups are abbreviated as NAPII and NAPOMII respectively, to clearly
show the difference to NAPOMI. It is left to the reader’s discretion, which
abbreviation to use in the future.
(9) Cooling to -20 °C was critical to suppress side reactions forming 1-
chloromethyl naphthalene, which was reported in the following literatures
as a main contaminant. (a) Hill, A. J.; Keach, D. W. T. J. Am. Chem. Soc.
1926, 48, 257-262. (b) Bedford, C. D.; Harris, R. N.; Howd, R. A.; Miller,
A.; Nolen, H. W.; Kenley, R. A. J. Med. Chem. 1984, 27, 1431-1438.
(10) NAPOMICl was storable at -20 °C for a minimum of 2 months.
(11) Alcohol 6a is an intermediate in the synthesis of amphidinol 3; for
details, see: Tsuruda, T.; Ebine, M.; Umeda, A.; Oishi, T. J. Org. Chem.
2015, 80, 859-871.
(12) For a review on the importance of coordination, resulting in the fixa-
tion of molecules on the surface of catalysts in hydrogenolysis, see: Mitsui,
S. J. Synth. Org. Chem. Jpn. 1960, 18, 305-317. We envisaged that the

5

Table 1. Protection and Deprotection of alcoholic hydroxy groups with NAPI.
Entry
Substrate and Product
Yield / %a
Removal
Introductionb
[O]c
[R]d
1
2
93
98
97
1a:
1b:
2a:
88
58
quant
quant
99
97
2b:
3
3a:
3b:
a Isolated yields after column chromatography on silica gel. b NAPIBr (1.1 equiv), NaH (1.5 equiv), DMF ([substrate] = 1.0 M), rt,
6-26 h; reactions were monitored by TLC and quenched upon completion or stopping. c DDQ (3 equiv), CH2Cl2/H2O = 4/1, rt, 1.5-
6.5 h. d H2 (1 atm), Pd/C (5 mol%), rt, 1.0-1.7 h.
6

Table 2. Protection of alcoholic hydroxy groups with NAPOMI.
En- Substrate (1a-6a) and Product (1c-6c)
try
Reagentsa Solventb Time /
Yield / %c
h
1
NAPOMICl CH Cl
7.4
quant
1a
2
2
i-Pr EtN
1c:
2
2
NAPOMICl CH Cl
16
19
90
96
2a
2
2
i-Pr EtN
2c:
2
3
NAPOMICl CH Cl
3a
2
2
i-Pr EtN
3c:
2
4
NAPOMICl toluene
6
94
82
3a
i-Pr EtN
3c
2
5
CH Cl
24.5
NAPO-
MICld
4a:
2
2
2,6-lutidine
TBAI
4c:
6
NAPOMICl CH Cl
19
72
5a:
2
2
i-Pr EtN
2
5c:
7

7
NAPOMICl CH Cl
49.5
74
6a:
6c:
2
2
i-Pr EtN
2
a NAPOMICl (2-6 equiv), i-Pr2EtN (4-12 equiv). b [Substrate] = 0.1-0.5 M. c Isolated yields after column chromatography on sili-
ca gel. d NAPOMICl (6 equiv), 2,6-lutidine (12 equiv), and TBAI (0.5 equiv).
Table 3. Removal of the NAPOMI group from protected hydroxy groups.
RONAPOMI
ROH
conditions
En-
try
Substrate (1c-3c) and
Reagent and Solventa Tempera-
ture
Time
/ hb
Yield /
c
%
c
Product (1a-3a)
a
1
DDQ (3 equiv)
reflux
19.5
0
1c:
64d
CH Cl /H O (4/1)
2
2
2
1a
1c
1a
1c
1a
2c:
2
3
4
CAN (8 equiv)
rt
rt
149
8
0
83
0
Acetone/H O (9/1)
2
H , Pd/C (5 mol%)
2
81d
0
MeOH
DDQ (3 equiv)
CH Cl /H O (4/1)
reflux
15
86d
2
2
2
2a
8

5
6
7
CAN (6 equiv)
rt
rt
121
6.5
27
0
88e
0
2c
2a
2c
2a
3c:
Acetone/H O (9/1)
2
H , Pd/C (5 mol%)
2
83d
0
MeOH
DDQ (3 equiv)
CH Cl /H O (4/1)
reflux
99
2
2
2
3a
3c
3a
3c
3a
1c:
8
9
CAN (4 equiv)
rt
rt
rt
26.5
8.5
5
0
quante
0
Acetone/H O (9/1)
2
H , Pd/C (5 mol%)
2
81d
MeOH
10
97
p-TsOH (8 equiv)
THF, MeOH
trace
1a
1c
1a
1c
1a
11
12
reflux
22
3
0
p-TsOH (8 equiv)
THF, MeOH
quante
quant
trace
BF ꢀOEt (1 equiv)
-78 to -30 °C
3
2
Et SiH (5 equiv)
3
CH Cl
2
2
a [Substrate] = 0.1 M. b Reactions were monitored by TLC and quenched upon completion or the formation of undesired products. c
Isolated yields after column chromatography on silica gel. d Byproducts were observed (for details, see: Supplementary Material). e
Obtained as an inseparable mixture containing 1-naphthalenemethanol; yields were determined based on the 1H-NMR spectra of the
mixture.
9

ꢁ
The 2-Naphthylmethoxymethyl group can be removed in the presence of 1-naphthylmethoxymethyl group with
DDQ.
ꢁ
ꢁ
1-Naphthylmethoxymethyl chloride is more readily prepared than 2-naphthylmethoxymethyl chloride.
Naphthylmethoxymethyl groups are compatible with strong acids even in the presence of hard nucleophiles.
10