Synthesis of novel 2H-spiro[1-benzofuran-3,4′-piperidin]ol scaffolds

Article abstract of DOI:10.1016/j.tetlet.2012.03.005

With the aim to enrich our 'privileged structure'-based library, novel 2H-spiro[1-benzofuran-3,4′-piperidin]ol scaffolds were prepared. The method involved a key intramolecular Heck cyclization which was successfully applied for three series of compounds.

Full text of DOI:10.1016/j.tetlet.2012.03.005

Tetrahedron Letters 53 (2012) 2432–2435
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel 2H-spiro[1-benzofuran-3,40-piperidin]ol scaffolds
Nicolas Leflemme a, , Axel R. Stoit a, Alfio Borghese b
⇑
a Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
b Abbott Healthcare Products B.V., Early Chemical Development, PDS, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
With the aim to enrich our ‘privileged structure’-based library, novel 2H-spiro[1-benzofuran-3,40-piper-
idin]ol scaffolds were prepared. The method involved a key intramolecular Heck cyclization which was
successfully applied for three series of compounds. The desired scaffolds were obtained in overall yields
of 42–53%.
Article history:
Received 18 January 2012
Revised 17 February 2012
Accepted 1 March 2012
Available online 7 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spiro[benzofuran-piperidine]
Scaffold
Privileged structure
Intramolecular Heck reaction
SNAr
The generalization of high-throughput screening (HTS) in drug
discovery has been of significant interest for the design of chemical
libraries with the goal of identifying new lead compounds. Initial
HTS campaigns with random compound libraries—so-called blind
screenings—have resulted in disappointingly low hit rates. Thus,
compound synthesis for merely expanding proprietary compound
stock, without taking any design or filtering criteria into account,
is now considered an inefficient strategy.1 As a consequence, a
clear trend to optimize chemical libraries in terms of size2 and
diversity3 has emerged. Nowadays the design of smaller and fo-
cused libraries is considered a highly promising strategy for hit-
finding in drug discovery.4–6 Concerning the generation of focused
libraries, one of the widely used approaches is to create compound
collections based on ‘privileged structures’.7 Libraries prepared
according to this concept, are considered to provide an ideal source
of new leads.8,9 Scaffolds containing spiropiperidine motifs have
been classified as ‘privileged structures’ owing to their rigid frame-
work and ability to direct functional groups in a well defined
space.10,11 However, when considering the literature, it was found
that the spiro scaffold 2H-spiro[1-benzofuran-3,40-piperidin]ol 1
has received no attention (Fig. 1). With our aim to develop libraries
based on ‘privileged structures’, spirocycle 1 appeared to be an
attractive scaffold for combinatorial chemistry. With two distinct
reactive functionalities for selective substitutions, this scaffold
may easily provide a number of compounds with the high diversity
needed for the development of new, selective compounds.
In this Letter, we report our preliminary results on the synthesis
of 2H-spiro[1-benzofuran-3,40-piperidin]ol scaffold 1 via a syn-
thetic approach involving an intramolecular Heck reaction for the
formation of the spiro core.
While the preparation of 2H-spiro[1-benzofuran-3,40-piperi-
dines] is well documented, the construction of this spirocycle struc-
ture, specifically with a hydroxy or an alkoxy moiety on the aryl
ring, is comparatively less studied. Four potential strategies are
described in the literature (Scheme 1). For both the nucleophilic
aromatic substitution (SNAr)12 and dehydration13,14 strategies, the
major hurdle appeared to be the design of a straightforward meth-
od which could provide the required key intermediates 3 and 4,
respectively. Two other synthetic approaches, both based on key
intermediate 5, were studied by Cheng15,16 for the synthesis of a
morphine fragment. In view of a potential active pharmaceutical
ingredient (API) preparation and to avoid purification issues due
to the use of toxic Sn reagents in the radical cyclization strategy,
we decided to explore the Heck cyclization-based approach16 for
the preparation of 2 (Scheme 1).
In accordance with our strategy, the synthesis of the desired
spiro[benzofuran-piperidin]ols 1a–d required the preparation of
H
N
HO
1
O
⇑
Corresponding author. Tel.: +31 (0) 718879153.
E-mail address: leflemme@hotmail.com (N. Leflemme).
Figure 1. 2H-Spiro[1-benzofuran-3,40-piperidin]ol scaffold 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.005

N. Leflemme et al. / Tetrahedron Letters 53 (2012) 2432–2435
2433
R'
N
R'
N
R'
N
SNAr
Dehydration
R
OH
OH
2
R
O
4
3
OH
F
Radical
cyclization
Heck
cyclization
OMe
X
O
OMe
N
5
R'
Scheme 1. Retrosynthetic approaches based on the literature.
BnO
BnO
Br
BnO
Br
O
Table 1
i
ii
Benzylation and SNAr reactions
OH
OH
Br
i
Br
F
Br
O
N
9
10
8b
ii
HO
BnO
BnO
Scheme 2. Alternative pathway for the synthesis of 8b. Reagents and conditions: (i)
Br2, CHCl3, rt, 2 h, 72%; (ii) 4-picolyl chloride hydrochloride, K2CO3, CH3CN, reflux,
18 h, 81%.
F
N
6a-d
Entry
7a-d
8a-d
6a–d
Product
Yielda
(%)
Product
Yielda
controlled (higher than 0 °C) during the addition of the reducing
agent, small amounts of by-products could be detected due to a
decoupling reaction.24 Finally, compounds 12a–d were converted
into the corresponding benzyl carbamates 13a–d using benzyl
chloroformate in excess (4.5 equiv were required for total conver-
sion),25 or into 14 using ethyl chloroformate (Table 2).
(%)
1
2
3
4
2-Bromo-3-fluorophenol
3-Bromo-4-fluorophenol
4-Bromo-3-fluorophenol
3-Bromo-2-fluorophenol
7a
7b
7c
7d
98
95
8a
8b
8c
8d
71
12
83
77
b
—
97
Reagents and conditions: (i) BnBr, K2CO3, acetone, reflux 4 h; (ii) pyridine-4-
For the intramolecular Heck reaction, we first used the condi-
tions described by Cheng for the morphine fragment synthesis.16
When a solution of 12c in THF was heated in a sealed vessel to
120 °C in the presence of Pd(OAc)2 (10 mol %), PPh3 (40 mol %),
and Ag2CO3 (2 equiv), only unidentifiable products were obtained.
However, with the neutral carbamate 13c the expected product
was obtained with 75% conversion (Table 3, entry 1). Considering
this initial promising result, we next focused our efforts on finding
the conditions that provided improved conversions with catalytic
reagents requiring smaller quantities, to minimize purification is-
sues. Despite the use of other ligands, solvents, or higher temper-
atures, the reactions did not exceed 75% conversion (entries 2–5).
We attributed the incomplete conversions to catalyst decomposi-
tion and the formation of inert palladium black.26 To circumvent
this problem the Herrmann–Beller palladacycle was used as a cat-
alyst which is described as a highly effective source of Pd(0), even
at high temperatures.27 Its reactivity has been attributed to the
slow release of Pd(0) into the reaction medium, thus maintaining
a constant level of the active catalytic species.28 We were pleased
to observe that the use of this catalyst in conjunction with Ag2CO3
led to complete conversion and with a good isolated yield (entry 9).
Moreover, the amounts of catalyst and base used could be reduced
to 4 mol % and 1.05 equiv, respectively, giving the same yield (en-
try 11).
methanol, NaH, NMP, 100 °C, 2 h.
a
Isolated yields after column chromatography.
Compound 7c is commercially available.
b
the corresponding pyridine intermediates 8a–d (Table 1). Recently,
several articles have described a straightforward method for the
preparation of aromatic ethers and desymmetrized resorcinol
derivatives via a SNAr reaction of substituted aryl fluorides by me-
tal alkoxides.17–21 This methodology was applied for the prepara-
tion of 8a–d, starting from commercially available bromo-
fluorophenols 6a–d. The benzyl protected phenols 7a–d were then
reacted with the sodium alkoxide of pyridine-4-methanol. After
two hours at 100 °C in NMP,19 complete conversion of 7a,c,d had
occurred and products 8a,c,d were isolated in good yields (Table
1). The low isolated yield (12%) obtained for the formation of 8b
(entry 2, Table 1) is in agreement with previous observations in
which this reaction proceeds poorly with para-substituted com-
pounds.18,19 Even with the addition of two extra equivalents of
the sodium alkoxide, higher temperatures (until reflux)19 or in a
toluene/DMPU solvent system,18 the reaction never reached
completion.
An alternative two-step methodology was envisaged for the
preparation of 8b. First, 4-benzyloxyphenol 9 was brominated fol-
lowing the procedure of Dodsworth22,23 and the intermediate 10
was converted into 8b by reaction with 4-picolyl chloride (Scheme
2).
Intermediate pyridinium salts 11a–d were easily prepared in
90–99% yields (Table 2) by N-benzylation of the corresponding
pyridine derivatives 8a–d. The subsequent reduction step was
achieved with NaBH4 to give regioselectively 1,2,3,6-tetrahydro-
pyridines 12a–d in excellent yields. No other reduction products
were found. However, when the temperature was not carefully
The optimized conditions were then applied to the other sub-
strates (Table 4) and similar results were obtained, except for the
formation of 15a. When applied to 13a, the reaction conditions ap-
peared to be totally inefficient, the starting material was recovered
in 75% yield and product 15a could not be detected (entry 1). This
disappointing result appeared to be in accordance with the well
known sensitivity of the Heck reaction to both steric hindrance
and electron donating aryl group effects.29 Removal of the benzyl
and Cbz groups in conjunction with the double bond reduction

2434
N. Leflemme et al. / Tetrahedron Letters 53 (2012) 2432–2435
Table 2
Pyridium salt formation, partial reduction and carbamate preparation
Br
i
Br
O
Br
O
8a-d
ii
iii
BnO
BnO
BnO
O
Br
N+
Bn
N
N
13a-d (R=Bn)
14 (R=Et)
CO2R
Yielda (%)
Bn
11a-d
12a-d
Entry
Reactant
Product
Yielda (%)
Product
Yielda (%)
Product
1
2
3
4
5
8a
8b
8c
8d
11a
11b
11c
11d
90
97
99
97
12a
12b
12c
12d
98
94
90
98
13a
13b
13c
13d
14b
86
98
94
85
97
Reagents and conditions: (i) BnBr, acetone, reflux, 18 h; (ii) NaBH4, MeOH, ꢀ5 °C, 2 h; (iii) For the preparation of 13a–d: benzyl chloroformate, KHCO3, CH2Cl2, rt, 18 h; for the
preparation of 14: ethyl chloroformate, KHCO3, DCE, reflux, 2 h.
a
Isolated yield after column chromatography.
Prepared from 12d.
b
Table 3
Intramolecular Heck cyclization reaction starting from 13c under various conditions
CO2Bn
Br
N
BnO
O
N
BnO
CO2Bn
13c
O
15c
Entry
Catalyst (mol %)
Ligand (mol %)
Base (equiv)
Solvent
T (°C)
Conversiona (%)
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
PPh3 (40)
PPh3 (15)
PPh3 (15)
PCy3 (15)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
Ag2CO3 (2)
n-BuNOAc (2)
MeNCy2 (4)
K2CO3 (2)
THF
120
120
140
140
140
140
140
140
140
140
140
75
25
55
72
75
63
44
100
100
76
ndc
nd
nd
nd
54
nd
nd
0d
DMF
DMF
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Pd(OAc)2 (5)
PCy3 (15)
Herrmann–Beller (5)
Herrmann–Beller (5)
Herrmann–Beller (5)
Herrmann–Beller (5)
Herrmann–Beller (2.5)
Herrmann–Beller (4)
—
—
—
—
—
—
9
10
11
Ag2CO3 (1.25)
Ag2CO3 (1.05)
Ag2CO3 (1.05)
87
nd
86
100
a
b
c
Conversion was determined by LC–MS, using an internal standard after reaction for 18 h.
Isolated yield.
Not determined.
d
Complete conversion observed, but only a mixture of unidentifiable products was obtained.
Table 4
Heck cyclization and protecting group cleavage
CO2R
H
N
.HCl
N
i
ii
13a-d (R=Bn)
14 (R=Et)
HO
BnO
O
1a-d
O
ii
15a-d (R=Bn)
16 (R=Et)
CO2Et
N
iii
O
17
HO
Entry
Reactant
Product
Yielda (%)
Product
Yielda (%)
1
2
3
4
5
13a
13b
13c
13d
14
15a
15b
15c
15d
16
0b
1a
1b
1c
1d
1d
—
86
83
81
81
98
91
0
92c
Reagents and conditions: (i) Herrmann–Beller catalyst (4 mol %), Ag2CO3 (1.05 equiv), NMP, 140 °C, 18 h; (ii) H2, 10% Pd/C, MeOH/EtOAc/HCl, rt, 18 h; (iii) AcOH/HCl 12 N,
reflux, 18 h.
a
Isolated yield after column chromatography.
13a recovered in 75% yield.
First step 16 to 17: 94%; second step 17 to 1d: 98%.
b
c

N. Leflemme et al. / Tetrahedron Letters 53 (2012) 2432–2435
2435
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generated 1b–c in excellent yields (entries 2 and 3). Surprisingly,
when 15d was hydrogenated, only unidentifiable products were
obtained. This issue was overcome using a two-step procedure
starting from the corresponding ethyl carbamate 16 (entry 5).
In conclusion, an efficient strategy has been developed for the
preparation of novel 2H-spiro[1-benzofuran-3,40-piperidin]-5-ol
(7 steps, 42%), 6-ol (6 steps, 53%), and 7-ol (8 steps, 51%) 1b–d from
commercially available starting materials. The amounts of catalyst
and base used during the spirocyclization reaction were reduced to
very acceptable levels. Unfortunately, the Heck conditions could
not be applied for the synthesis of 15a. Work is still in progress
to solve this issue. The scaffolds 1b–d have been used in our ‘priv-
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.03.005. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
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