Facile Direct Coupling Reactions of MOM-protected Benzylic Alcohols Using Aluminum Chloride

Article abstract of DOI:10.1002/bkcs.12358

MOM group is one of the most commonly used protecting groups for alcohols. This study describes novel direct functionalization of the MOM-protected benzylic alcohols. Preparation of allylic compounds from benzyl MOM ethers was successfully achieved by utilization of allyltrimethylsilane and AlCl₃. In addition, direct azidation of benzyl MOM ethers using TMSN₃ was successful carried out under AlCl₃-mediated reaction conditions. These results demonstrate that this novel synthetic procedure is a promising approach to direct functionalization of MOM-protected alcohols including allylation and azidation.

Full text of DOI:10.1002/bkcs.12358

Communication
DOI: 10.1002/bkcs.12358
BULLETIN OF THE
T. T. Bui and H.-K. Kim
KOREAN CHEMICAL SOCIETY
Facile Direct Coupling Reactions of MOM-protected Benzylic Alcohols
Using Aluminum Chloride
†,‡,
Tien Tan Bui† and Hee-Kwon Kim
*
†Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center,
Jeonbuk National University Medical School and Hospital, Jeonju 54907, Republic of Korea
‡Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of
Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea. *E-mail: hkkim717@jbnu.ac.kr
Received May 28, 2021, Accepted July 5, 2021
MOM group is one of the most commonly used protecting groups for alcohols. This study describes novel
direct functionalization of the MOM-protected benzylic alcohols. Preparation of allylic compounds from
benzyl MOM ethers was successfully achieved by utilization of allyltrimethylsilane and AlCl3. In addi-
tion, direct azidation of benzyl MOM ethers using TMSN3 was successful carried out under AlCl3-
mediated reaction conditions. These results demonstrate that this novel synthetic procedure is a promising
approach to direct functionalization of MOM-protected alcohols including allylation and azidation.
Keywords: Allylation, Azidation, MOM-protected alcohols, Aluminum chloride, Lewis acid catalysts
Hydroxyl group is one of the most widely employed groups
in organic chemistry, and considerable utilization of hydroxyl
groups has been observed in various fields.1 Because many
organic syntheses of molecules bearing hydroxyl groups easily
generate undesirable byproducts alongside major products,
several types of protecting groups are commonly employed in
many organic synthetic procedures. Specifically, the
methoxymethyl ether has been broadly employed in multistep
organic procedures due to its chemical stability.2 The
methoxymethyl protective group is therefore preferable to the
tetrahydropyranyl group because it is simpler to differentiate
mono-protection from multiprotection and evaluate contami-
nation using nuclear magnetic resonance spectroscopy.2 Fur-
thermore, the MOM-protecting group is easily cleaved by
several conditions to yield a free hydroxyl moiety.3
Transformations of MOM-protected hydroxyl groups to use-
ful functional groups such as allyl and azido groups have
played a significant role in many organic syntheses. However,
two-step reactions are usually required to perform these trans-
formations: production of the free hydroxyl group is carried out
by cleavage of the protecting group, and then the target chemi-
cal structures are generated via reaction of the free hydroxyl
group. Thus, effective and straightforward transformation of a
MOM-protected hydroxyl group into another chemical moiety
could impart several advantages such as utilization of small
amounts of reagents and shorter reaction procedures. As devel-
opment of novel methodologies for efficient and selective for-
mation of carbon–carbon bonds is important in organic
synthesis, many synthetic procedures have been reported.4 For
example, the Sakurai–Hosomi reaction is a commonly used
reaction for formation of a carbon–carbon bond using
allylation5 been used to provide allylated products through acti-
vation. Other synthetic methods for C C bond formation via
reactions with free alcohols have been reported; in such reac-
tions, C C bond generation was achieved using reagents such
as calcium,6 indium,7 bismuth,8 and montmorillonite.9
The direct transformation of MOM-protecting hydroxy
substrates to C C coupling products is of interest due to its
feasibility to perform in one-step reaction. Herein, we
report novel, metal-catalyzed, direct transformation of
MOM-protected hydroxyl groups derived from secondary
and tertiary benzyl alcohols to generate allylic compounds
and then describe further application of these catalytic con-
ditions to yield azido compounds (Scheme 1).
Initially, investigation of proper direct allylation conditions of
MOM-protected alcohols was carried out. ((Methoxymethoxy)
methylene)dibenzene, and CH2Cl2 were chosen as substrate and
reaction solvent, respectively, and reactions were conducted at
room temperature. First, reactions of ((methoxymethoxy)methy-
lene)dibenzene with allyltrimethylsilane (TMS-allyl) in the pres-
ence of various catalysts were attempted to determine
conditions yielding C C bond formation (Table 1).
CuCl2, MnCl2, and BiCl3 were employed as catalysts;
however, they failed to produce the desired allylation product.
Utilization of SnCl2 for the reaction successfully generated
the target product, despite the poor yield. Other catalytic
reagents such as TiCl4, ZrCl4, and BF3.Et2O promoted the
reaction to produce the corresponding allyl product in yields
ranging from 40% to 55%. Then, examination of AlCl3 as a
catalyst for this reaction was performed, and the target allyl
compound was prepared in high yield (Table 1, entry 7).
Next, several solvents were examined for direct allylation
from ((methoxymethoxy)methylene)dibenzene (Table 1,
entries 9–13). With dimethylformamide (DMF) and tetrahy-
drofuran (THF), reactions were unsuccessful in providing
the target product; when 1,4-dioxane or toluene was
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Table 2. Screening of amount of reagent and catalyst for the
preparation of allyl compounda.
TMS-allyl
Entry (equiv.)
AlCl3
(equiv.)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
0.5
1
1.4
2
3.0
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.2
0.2
0.2
0.2
0.2
0.01
0.05
0.1
0.15
0.3
0.5
1.0
2
2
2
2
2
2
2
2
2
2
2
2
31
67
93
93
93
2
Scheme 1. Allylation of benzylic alcohols.
5
Table 1. Screening of reaction conditions for the preparation of
72
88
93
93
93
allyl compoundsa.
9
10
11
12
a Reaction conditions: compound 1a (1.0 mmol), allyltrimethylsilane
(1.4 mmol), AlCl3 (0.2 mmol), room temperature.
b Isolated yield after column purification.
Entry
Azide agent
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
TMS-allyl
CuCl2
MnCl2
BiCl3
SnCl2
TiCl4
ZrCl4
AlCl3
BF3.Et2O
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
No
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
NRc
NRc
NRc
9
52
55
93
40
NRc
NRc
12
AlCl3 were also investigated for this allylation, and employ-
ment of 0.2, 0.3, 0.5, and 1.0 equiv. of AlCl3 readily produced
the desired product in satisfactory yield (93%) (Supporting
Information SI).
With promising conditions for allylation, the substrate of
direct AlCl3-catalyzed allylation was examined using sev-
eral MOM-protected benzylic alcohols (benzyl MOM
ethers) (Table 3). First, mono-substituted benzhydrol
MOM ethers [((methoxymethoxy)methylene)dibenzene]
were employed for the synthesis of allyl products. Reactions
of ((methoxymethoxy)methylene)dibenzene bearing an
electron-donating group (methyl-) or an electron-withdrawing
group (bromo-) on the aromatic ring with allyltrimethylsilane
in the presence of AlCl3 generated the desired allyl products in
high yields (Table 3, entries 2–3). Allylations of di-substituted
MOM ethers were carried out under the same reaction condi-
tions, and the corresponding allyl products, such as 4,40-(but-
3-ene-1,1-diyl)bis(chlorobenzene) and 4,40-(but-3-ene-1,1-diyl)
bis(methoxybenzene), were successfully synthesized
(91% for 2d and 94% for 2e). Furthermore, reaction of
various alkyl-substituted benzyl MOM ethers, such as
9
10
11
12
13
14
THF
1,4-dioxane
Toluene
MeCN
35
74
NRc
CH2Cl2
a Reaction conditions: compound 1a (1.0 mmol), allyltrimethylsilane
(1.4 mmol), Catalyst (0.2 mmol), room temperature, 2 h.
b Isolated yield after column purification.
c No reaction.
employed as solvent, the synthetic yield of the desired
product improved slightly. The use of MeCN further
improved the synthetic yield, generating the corresponding
(1-(methoxymethoxy)butyl)benzene including
a
n-butyl
allyl compound in 71% yield.
group, (1-(methoxymethoxy)-2,2-dimethylpropyl)benzene
Furthermore, examination of efficacy of allyltrimethylsilane
and AlCl3 was performed. ((Methoxymethoxy)methylene)
including the tert-butyl group, and cyclohexyl
(methoxymethoxy)methyl)benzene including a cyclohexyl
group, with allyltrimethylsilane successfully produced the
desired allylic compounds in good yields from 87% to 94%
(Table 3, entries 6–9). Reaction of a benzyl MOM ether
bearing a heterocyclic structure and a benzyl MOM ether
derived from 1-indanol was also examined and provided
dibenzene was treated with
a series of amounts of
allyltrimethylsilane in the presence of 0.2 equiv. of AlCl3.
Introduction of 1.4, 2.0, and 3.0 equiv. of allyltrimethylsilane
generated the corresponding compound in high yield
(Table 2, entries 3–5). Reactions using different amounts of
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Table 3. Scope of allylation from various MOM-protected
Table 4. Scope of synthesis of azides from various MOM-
benzylic alcoholsa
protected benzylic alcoholsa.
Entry MOM-protected alcohol
Product
Yieldb (%)
Entry MOM-protected alcohol
Product
Yieldb (%)
a Reaction conditions: compound 3 (1.0 mmol), TMSN3 (1.4 mmol),
AlCl3 (0.2 mmol), room temperature, 10 min.
b Isolated yield after purification by flash column chromatography.
a Reaction conditions: compound 1 (1.0 mmol), allyltrimethylsilane
(1.4 mmol), AlCl3 (0.2 mmol), room temperature, 2 h.
readily produced the corresponding product in a satisfactory
yield of 88% (Table 3, entry 12). These results imply that this
novel procedure using allyltrimethylsilane and AlCl3 is an
effective method for direct preparation of allyl products from
various MOM-protected alcohols.
Azides are also valuable moieties in organic synthesis and
serve as precursors in the preparation of amines and heterocy-
cles.10 In particular, exploitation of azides in the Huisgen reac-
tion or in Click chemistry provides crucial methods for coupling
b Isolated yield after purification by flash column chromatography.
2-(1-phenylbut-3-en-1-yl)thiophene in 89% yield and 1-allyl-
2,3-dihydro-1H-indene in 90% yield, respectively (Table 3,
entries 10–11). Additionally, ((methoxymethoxy)methanetriyl)
tribenzene, a tertiary benzyl MOM ether that has greater steric
hindrance, was subjected to the same reaction conditions and
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Moreover, this protocol uses an economical catalyst and pro-
vides a practical reaction process. Our results provide a basis
to develop novel promising protocols for direct conversion of
MOM-protected alcohols to other invaluable structures.
ACKNOWLEDGMENTS. This work was supported by
the National Research Foundation of Korea(NRF) grant
funded by the Korea government (MSIT) (NRF-
2021R1A2C1011204).
Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
Scheme 2. Proposed reaction pathway for allylic compounds from
MOM-protected alcohols
REFERENCES
between biomarkers and macromolecules.11 However, in most
synthetic protocols for azido compounds, free alcohols are
employed as substrates.12 Therefore, the scope of the AlCl3-
catalyzed protocol was extended to direct azidation from MOM-
protected alcohols, as illustrated in Table 4. Monoꢀ/di-
substituted ((methoxymethoxy)methylene)dibenzenes con-
taining electron-withdrawing substituents (chloro-, and fluoro-)
or electron-donating substituents (methyl-, and methoxy-) read-
ily reacted with TMSN3 in the presence of AlCl3 to yield the
corresponding azido products in good yields (Table 4, entries 1–
6). Next, reactions of several methoxymethyl benzyl ethers
including alkyl groups such as methyl and cyclohexyl reacted
with TMSN3 to produce the target azido compounds in high
yields (Table 4, entries 7 and 8). Methoxymethyl benzyl ethers
derived from several kinds of alcohols such as 1-indanol,
4-phenyl-3-buten-2-ol, 1,1-diphenylethan-1-ol, and trip-
henylmethanol were similarly employed for direct azidation and
provided the corresponding azide compounds in the range of
88–92% (Table 4, entries 9–12).
1. (a)Z. Li, R. Yazaki, T. Ohshima, Org. Lett. 2016, 18, 3350. (b)
S. F. Nielsen, T. Boesen, M. Larsen, K. Schønning, H. Kromann,
Bioorg. Med. Chem. 2004, 12, 3047. (c)H. Jia, Q. Li, A. Bayaguud,
S. She, Y. Huang, K. Chen, Y. Wei, Sci. Rep. 2017, 7, 1.
2. (a)M. Moghadam, S. Tangestaninejad, V. Mirkhani, I.
Mohammadpoor-Baltork, M. Khajehzadeh, F. Kosari, M.
Araghi, Polyhedron 2010, 29, 238. (b)F. Shirini, M. A.
Zolfigol, J. Albadi, Synth. Commun. 2010, 40, 910. (c)B.
Sreedhar, V. Swapna, C. Sridhar, Catal. Commun. 2005, 6,
293. (d)K. Niknam, M. A. Zolfigol, A. Khorramabadi-Zad, R.
Zare, M. Shayegh, Catal. Commun. 2006, 7, 494.
3. (a) G. V. M. Sharma, K. L. Reddy, P. S. Lakshmi, P. R.
Krishna, Tetrahedron Lett. 2004, 45, 9229. (b) R. E. Ireland,
M. D. Varney, J. Org. Chem. 1986, 51, 635.
4. (a) S. Burling, B. M. Paine, D. Nama, V. S. Brown, M. F. Mahon,
T. J. Prior, P. S. Pregosin, M. K. Whittlesey, J. M. Williams,
J. Am. Chem. Soc. 2007, 129, 1987. (b) A. V. Subrahmanyam, S.
Thayumanavan, G. W. Huber, ChemSusChem 2010, 3, 1158.
5. (a)S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763. (b)A.
Hosomi, K. Miura, Bull Chem. Soc. Jpn. 2004, 77, 835.
6. V. J. Meyer, M. Niggemann, Eur. J. Org. Chem. 2011,
2011, 3671.
7. (a) M. Yasuda, T. Saito, M. Ueba, A. Baba, Angew. Chem.
2004, 116, 1438. (b) M. Yasuda, T. Saito, M. Ueba, A. Baba,
Angew. Chem. Int. Ed. 2004, 43, 1414.
8. S. K. De, R. A. Gibbs, Tetrahedron Lett. 2005, 46, 8345.
9. K. Motokura, N. Nakagiri, T. Mizugaki, K. Ebitani, K.
Kaneda, J. Org. Chem. 2007, 72, 6006.
A plausible mechanism for the allylation reaction is
shown in Scheme 2. In initiation of the reaction, a complex
including allyltrimethylsilane and AlCl3 is generated. With
activation of the oxygen atom of the MOM-protected alco-
hol by AlCl3, the complex affords the secondary benzyl
intermediate 6. Subsequent attack by the allyl group pro-
duces the target allyl product 2 (Scheme 2).
In summary, a novel practical procedure for direct transfor-
mation of MOM-protected alcohols to allylic compounds is
described. Methylmethoxy (MOM) group is a vital protecting
group for hydroxy moiety because it is resistant to a variety of
harsh condition including strong bases, Grignard reagent, and
so on. It is useful for further transformation including C C
coupling reaction and azidation because it is viable to be
converted directly into desired moieties without deprotection
procedure. Allyltrimethylsilane and AlCl3 were used as the
key allylation reagents to yield allylated compounds. Further-
more, this novel protocol was successfully applied for direct
synthesis of azido compounds using TMSN3 and AlCl3.
10. (a) Y. Pei, B. O. S. Wickham, Tetrahedron Lett 1993, 34, 7509.
(b)A. Capperucci, A. Deglinnocenti, M. Funicello, G. Mauriello,
P. Scafato, P. Spagnolo, J. Org. Chem. 1995, 60, 2254. (c)P. T.
Nyffeler, C.-H. Liang, K. M. Koeller, C.-H. Wong, J. Am. Chem.
Soc 2002, 124, 10773. (d)P. S. Baran, A. L. Zografos, D.
O’Malley, J. Am. Chem. Soc. 2004, 126, 3726.
11. (a) A. H. El-Sagheer, T. Brown, Chem. Soc. Rev 2010, 39,
1388. (b) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev.
2007, 36, 1249.
12. (a)X.-P. Yin, L. Zhu, J. Zhou, Adv. Synth. Catal. 2018, 360,
1116. (b)A. Singh, H. Singh, J. M. Khurana, Tetrahedron
Lett. 2017, 58, 2498. (c)A. Kumar, R. K. Sharma, T. V.
Singh, P. Venugopalan, Tetrahedron 2013, 69, 10724.
Bull. Korean Chem. Soc. 2021
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