New convergent one pot synthesis of amino benzyl ethers bearing a nitrogen-containing bicycle

Article abstract of DOI:10.1080/00397911.2019.1568498

We report herein a new convergent one pot method for the synthesis of amino benzyl ethers containing a bicyclic amine, derived from different substituted benzyl alcohols and bicyclic amino alcohols such as tropine, pseudotropine, and 3-quinuclidinol, using chlorotrimethylsilane and sodium iodide. In order to avoid the competitive reaction with the nitrogen atom, a solution of the separately prepared alkoxide of tropine, pseudotropine, and 3-quinuclidinol was added to the preformed substituted benzyl iodides and allowed to reflux at 90 °C for 15 h under nitrogen atmosphere. This method provides an efficient alternative of the preparation of amino benzyl ethers in organic synthesis with good yields in comparison with existed methods.

Full text of DOI:10.1080/00397911.2019.1568498

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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New convergent one pot synthesis of amino
benzyl ethers bearing a nitrogen-containing
bicycle
Jhon J. López & Edwin G. Pérez
To cite this article: Jhon J. López & Edwin G. Pérez (2019): New convergent one pot synthesis
of amino benzyl ethers bearing a nitrogen-containing bicycle, Synthetic Communications, DOI:
10.1080/00397911.2019.1568498
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https://doi.org/10.1080/00397911.2019.1568498
New convergent one pot synthesis of amino benzyl ethers
bearing a nitrogen-containing bicycle
a
b
ꢀ
ꢀ
and Edwin G. Perez
Jhon J. Lopez
a
ꢀ
Department of Organic Chemistry, Faculty of Chemical Sciences, Universidad de Concepcion,
b
ꢀ
Concepcion, Chile; Department of Organic Chemistry, Faculty of Chemistry and Pharmacy, Pontificia
Universidad Catolica de Chile, Santiago, Chile
ꢀ
ABSTRACT
ARTICLE HISTORY
Received 25 October 2018
We report herein a new convergent one pot method for the synthe-
sis of amino benzyl ethers containing a bicyclic amine, derived from
different substituted benzyl alcohols and bicyclic amino alcohols
such as tropine, pseudotropine, and 3-quinuclidinol, using chlorotri-
methylsilane and sodium iodide. In order to avoid the competitive
reaction with the nitrogen atom, a solution of the separately pre-
pared alkoxide of tropine, pseudotropine, and 3-quinuclidinol was
added to the preformed substituted benzyl iodides and allowed to
reflux at 90 ꢀC for 15 h under nitrogen atmosphere. This method pro-
vides an efficient alternative of the preparation of amino benzyl
ethers in organic synthesis with good yields in comparison with
existed methods.
KEYWORDS
Amino benzyl ethers; benzyl
alcohols; bicyclic amino
alcohols; nicotinic
acetylcholine receptor;
Williamson reaction
GRAPHICAL ABSTRACT
Introduction
The benzylation of hydroxyl groups is a fundamental and very versatile reaction in
organic synthesis, used primarily as a way to protect these groups[1] as well as to obtain
]
bioactive compounds.[2a–c
One of the most widely used synthetic methods for
ꢀ
CONTACT Jhon J. Lopez
jhonlopez@udec.cl
Department of Organic Chemistry, Faculty of Chemical Sciences,
ꢀ
ꢀ
ꢀ
Universidad de Concepcion, Concepcion, Chile; Edwin G. Perez
eperezh@uc.cl
Department of Organic Chemistry,
ꢀ
Faculty of Chemistry and Pharmacy, Pontificia Universidad Catolica de Chile, Santiago, Chile.
JL and EP performed the research and analyzed the data. All the authors designed the research, wrote and critically
revised the manuscript.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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J. LOPEZ AND E. PEREZ
2
Figure 1. Chemical structures of bioactive bicyclic amino benzyl ethers.[13,14]
preparing alkyl benzyl ethers is the classic Williamson reaction, consisting of coupling
between alkoxides and alkyl halides under basic conditions, developed over 160 years
ago by the English chemist Alexander Williamson.[3a–b ] Since that time, alkyl benzyl
ethers have also been prepared using many different methodologies including the use of
a tertiary amine as a base,[4] from benzyl bromide and alcohols using FeSO4 as a medi-
ator in the absence of solvent,[5] by reaction of silyl ethers and aromatic aldehydes in
[6]
the presence of triethylsilane with catalytic amounts of FeCl3, from benzyl chloride
and various alcohols using Cu(acac)2 as catalyst,[7] from benzyl trichloroacetimidate or
silylation with triethylsilyl chloride[8] in an acidic medium or from 2-benzyloxy-1-meth-
ylpyridinium triflate in a neutral medium,[9] from the microwave reaction of benzyl
alcohol and various alcohols using Ph3PAuNTf2 as catalyst,[10] among others.
The Williamson reaction has also been used to prepare amino benzyl ethers from
benzyl halides and bicyclic amino alcohols such as 3-quinuclidinol and tropine.[11,12]
Compounds of this type have been shown to possess interesting biological activity. For
instance, 3-benzyloxy-8-methyl-8-azabicyclo-[3.2.1]-octane (1) inhibits the human neur-
onal dopamine transporter which is involved in cocaine addiction,[13] and 3-benzyloxy-
8-azabicyclo-[2.2.2]-octane (2) showed agonist activity at the nicotinic acetylcholine
receptor (nAChR) a7 subtype.[14] (Fig. 1).
Additionally, the bicyclic systems of tropine and quinuclidine are chemical moieties
present in many bioactive compounds isolated from plants.[15,16] This is a reason for
the extensive use of this type of cores as building blocks for the synthesis of molecules
with biological activity.[17–19]
In our current search for new ligands acting on nAChRs, we were interested in the
synthesis of new amino benzyl ethers with a nitrogen-containing bicycle. We decided to
synthesize 4-methoxybenzyl iodide in situ, from 4-methoxybenzyl alcohol (4a), using
chlorotrimethylsilane and sodium iodide.[20] In order to avoid the competitive reaction
with the nitrogen atom, a solution of the separately prepared alkoxide of tropine was
added to the preformed 4-methoxybenzyl iodide. Using this approach, compound 5a
(Figure 1) was obtained in 20% yield after column chromatography and recrystalliza-
tion. See Table 1.
It is worth mentioning that literature reports for the synthesis of nitrogen-containing
bicyclic amino benzyl ethers bearing quinuclidine and tropine rings (no reports were
found for pseudotropine) employ multi-step reactions. For instance, in the Schmitt
et al. synthesis of 1 the authors used a 4-step process including N-protection, alkoxide

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Table 1. Bicyclic aminoalcohol benzyl ethers produced under the conditions shown in Scheme 2.
Entry
Benzyl alcohols (R1)
Amino alcohols (R2)
Reaction Time (h)
Yield(a,b) (%)
Amino benzyl ethers
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
OCH3
OCH2CH3
O(CH2)2CH3
O(CH2)3CH3
O(CH2)4CH3
O(CH2)5CH3
O(CH2)6CH3
O(CH2)7CH3
Br
Tropine
Tropine
Tropine
Tropine
Tropine
Tropine
Tropine
Tropine
Tropine
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
44a [20]b
66a [33]b
73a [55]b
61a [39]b
40a [33]b
58a [47]b
61a [49]b
77a [58]b
83a [64]b
51a [25]b
48a [32]b
62a
5a
5b
5c
5d
5e
5f
5g
5h
5i
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4j
4g
4j
H
Tropine
1
6
2
O(CH2)6CH3
H
Pseudotropine
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
3-Quinuclidinol
Tropine
4a
4b
4c
4d
4e
4f
4g
4h
4k
4l
4m
4a
4a
4j
OCH3
85a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
8
9
10
11
OCH2CH3
O(CH2)2CH3
O(CH2)3CH3
O(CH2)4CH3
O(CH2)5CH3
O(CH2)6CH3
O(CH2)7CH3
OCH2Ph
85a
87a
42a
89a
57a
21a
26a
87a
OCH2-4-Cl-Ph
N(CH3)2
65a
0
0
0
0
OCH3
OCH3
H
2-Piperidineethanol
2-Morpholinoethanol
Nortropine
aYield obtained by column chromatography. byield obtained by recrystallization.
Scheme 1. Synthesis of 3-benzyloxy-8-methyl-8-azabicyclo-[3.2.1]-octane (1) and 3-benzyloxy-8-azabi-
cyclo-[2.2.2]-octane (2).[13,14]
generation, coupling with benzyl bromide, N-deprotection and finally N-methylation.[13]
In a similar fashion, 3-benzyloxy-8-azabicyclo 2 was synthesized by Tatsumi et al. using
BH3-protected 3-quinuclidinol with additional coupling and deprotection steps.[14]
Scheme 1.
Because of the multiple steps involved in the synthesis of these compounds, the very
long reaction times as well as the low overall yields (13 and 32% for 1 and 2, respect-
ively), we decided to investigate a new route to this kind of products. Thus, in this

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J. LOPEZ AND E. PEREZ
4
Scheme 2. General reaction for the formation of bicyclic amine benzyl ethers.
paper, we present a new methodology which can be used in a simple and efficient way
to generate benzyl ethers of bicyclic amines.
Result and discussion
To achieve our goal, we first attempted a reported etherification of 4-methoxybenzyl
alcohol and tropine under Mitsunobu conditions.[21] Unfortunately, no product was
obtained. Then we decided to synthesize 4-methoxybenzyl iodide in situ, from 4-
methoxybenzyl alcohol (4a), using chlorotrimethylsilane and sodium iodide.[20] In order
to avoid the competitive reaction with the nitrogen atom, a solution of the separately
prepared alkoxide of tropine was added to the preformed 4-methoxybenzyl iodide.
Using this approach, compound 5a was obtained in 20% yield after column chromatog-
raphy and recrystallization. See Scheme 2 and Table 1.
With this result in hand and with the aim of studying the generality of this reaction,
we decided to synthesize a series of new compounds coupling different benzyl alcohols
(4a–4j) with three bicyclic aminoalcohols tropine, pseudotropine and 3-quinuclidinol.
See Scheme 2 and Table 1.
The coupling of p-substituted C2-C8 alkyloxy benzyl alcohols (4b–4h) with tropine
proceeded to give the ethers 5b–5h in yields ranging from 33% to 58% after purification
by column chromatography and recrystallization from CHCl3: MeOH. Unsubstituted
benzyl alcohol (4j) afforded the previously reported compound 1 in 25% yield, double
that reported in the four-step general synthesis shown in Scheme 1. Moreover, the reac-
tion of p-bromobenzyl alcohol (4i) with tropine produced the desired ether in 64%
yield. See Table 1, entry 9.
Besides, p-heptyloxybenzyl alcohol (4g) was combined with pseudotropine and ether
6 was obtained as the exclusive product under the same reaction conditions. Figure 2
shows that the proton (equatorial position) present in C-3 of the compound 5g only
can interact with the vecinal equatorial hydrogens atoms (C-2 and C-4) generating a
narrow band (chemical shifts 3.92 p.p.m), characteristic of tropine ethers.[22] However,
the proton (axial position) present in C-3 of the compound 6 generate strong interac-
tions (large band; chemical shifts 4.07–4.13 p.p.m) with vecinal axial hydrogen atoms
(C-2 and C-4 or C-1 and C5), characteristic of pseudotropine ethers.[22] The signs at
4.00 ppm correspond to the protons of the methylene group of the aliphatic chain in

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1
Figure 2. Comparison of the H-NMR spectra of 5g and 6 showing the different multiplicity of the
signal of the proton attached Tropine (A) and pseudotropine (B) C-3.
position p with respect to the aromatic ring. This result suggests that these conditions
do not lead to the inversion of configuration.
With the aim of extending this methodology to other bicyclic aminoalcohols, we
chose 3-quinuclidinol to synthesize ethers such as 2. Thus, 2 was obtained in 62% yield
combining the above mentioned quinuclidinol with benzyl alcohol (4j) under the same
conditions shown in Scheme 2. Again, this yield is twice as high as that reported in the
three-step synthesis shown in Scheme 1.
Furthermore, the same p-substituted C1-C8 alkyloxy benzyl alcohols (4a–4h) were
coupled with 3-quinuclidinol furnishing ethers 7a–7h in yields ranging from 21% to
87% after purification by column chromatography. See Table 1, entries 12–21.
In addition, 3-quinuclidinol was coupled with p-benzyloxybenzyl alcohol (4k) and
p-(4-chlorobenzyloxy) benzyl alcohol (4l) furnishing the corresponding ethers in 87 and
65% yield, respectively.
Unfortunately, the reaction between p-N,N-dimethylbenzyl alcohol and tropine did
not produce the expected ether, there was also no reaction between a secondary amine
(Nortropine) and benzyl alcohol and the attempted couplings of the monocyclic 2-
piperidineethanol and 2-morpholinoethanol with p-methoxybenzyl alcohol were also
unsuccessful. See Table 1, entries 23–26.
Experimental section
Materials and methods
All solvents and all deuterated solvents were purchased from Merck, reagents from
Aldrich, Merck and AK Scientific. Column chromatography was performed with silica
gel (Merck, type 60, 0.063–0.2 mm). NMR spectra were recorded on a Bruker Avance
400 MHz spectrometer (Bruker, MA, USA). All chemical shifts in NMR experiments
were reported as ppm downfield from TMS. Melting points were determined on a
Reichert Galen III hot plate microscope apparatus and are uncorrected.

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J. LOPEZ AND E. PEREZ
6
Procedures
Preparation of substituted benzaldehydes[23,24]
The Williamson method was initially used to couple 4-hydroxylbenzaldehyde and alkyl
halides to produce the corresponding alkyloxy benzaldehydes. In round-bottomed flask
100 mL fitted with a magnetic stir bar is charged with K2CO3 (6 g, 43.4 mmol), ethanol
(30 mL), 4-hydroxylbenzaldehyde (6 g, 49.1 mmol), and alkyl halides (4.0 mL,
49.1 mmol). The mixture was refluxed for 18 h under nitrogen with stirring. The result-
ing suspension was vacuum filtered, and the solvent removed under reduced pressure
on a rotary evaporator. Finally, the compound was purified by column chromatography
(silica gel from 0.063 to 0.2 mm, CH2Cl2) to affording the substituted benzaldehydes.
Preparation of benzyl alcohols[18]
In a round bottom flask of 250 mL, substituted benzaldehydes (2.8 g, 20.57 mmol) and
100 mL of methanol are added. Subsequently, the reaction mixture was allowed to stir
and then NaBH4 was slowly added (excess). The mixture was allowed to stir for 2 h.
Subsequently, 50 ml of acetone were added to neutralize excess NaBH4. Then the reac-
tion mixture was concentrated under reduced pressure on a rotary evaporator. After
50 mL was added water to the reaction mixture, which was extracted with chloroform
(3 ꢁ 20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure.
The product was purified by chromatography column (from 0.063 to 0.2 mm silica
gel, CH2Cl2) affording the benzyl alcohols. Compounds 4a–4m were prepared from the
respective substituted benzaldehydes commercial, 4-bromo benzaldehyde, benzaldehyde,
4-dimethylamino benzaldehyde, and 4-metoxy benzaldehyde.
Preparation of benzyl ethers amino tropane ring
To a solution of different benzyl alcohols (7.82 mmol) in acetonitrile (27 mL), chlorotri-
methylsilane (8.73 mmol) was added and then sodium iodide (8.05 mmol) was slowly
added. This mixture was allowed to reflux with constant stirring at 90 ꢀC for 2 h, under
nitrogen. In another testing column, tropine was added (11.73 mmol) and dissolved in
DMF (25 mL), then NaH (11.73 mmol) was added slowly and allowed to stir for 2 h.
After this time, the mixture containing tropine (tropine alkoxide), was slowly added to
the reaction mixture, benzyl alcohol previously cooled and is allowed to reflux at 90 ꢀC
for 15 h under nitrogen atmosphere. Then the reaction mixture was concentrated under
reduced pressure and the product purified by column chromatography using as solvent
methanol-triethylamine-dichloromethane elution (9:1:0.5) and then recrystallized using
various solvents such as chloroform, ethyl acetate, and methanol.
Preparation of benzyl ethers amino quinuclidine ring
Using the same procedure as for benzyl ethers, amino tropane ring was prepared.
Compounds were purified using single column chromatography using a solvent
dichloromethane-methanol-triethylamine elution (9:1:0.5).

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Conclusions
In conclusion, we have developed a new methodology to generate bicyclic amino benzyl
ethers from different substituted benzyl alcohols and bicyclic amino alcohols (with a ter-
tiary amine) using commercial and low-cost reagents such as chlorotrimethylsilane,
sodium iodide, and sodium hydride in acetonitrile and N,N-dimethylformamide, reflux-
ing under nitrogen. The simple procedure makes it an attractive, selective, and a useful
method to prepare bicyclic amino benzyl ethers from benzyl alcohols and three different
bicyclic amino alcohols.
Disclosure statement
The authors declare that the research was conducted in the absence of any commercial
or financial relatioship that could be construed as a potential conflict of interest.
Funding
ꢀ
ꢀ
We are grateful to the Fondo Nacional de Desarrollo Cientıfico y Tecnologico, Chile
(FONDECYT postdoctoral grant 3170061 to J.J.L. and FONDECYT grant 1130079 to E. G. P.)
and FONDEQUIP grant EQM120021.
ORCID
ꢀ
Jhon J. Lopez
http://orcid.org/0000-0002-2678-3627
http://orcid.org/0000-0002-3777-6297
ꢀ
Edwin G. Perez
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