Removal of the pyridine directing group from α-substituted N-(pyridin-2-yl)piperidines obtained via directed Ru-catalyzed sp3 C-H functionalization

Article abstract of DOI:10.1021/jo401521y

Two strategies, "hydrogenation-hydride reduction" and "quaternization-hydride reduction", are reported that make use of mild reaction conditions (room temperature) to efficiently remove the N-pyridin-2-yl directing group from a diverse set of C-2-substituted piperidines that were synthesized through directed Ru-catalyzed sp³ C-H functionalization. The deprotected products are obtained in moderate to good overall yields irrespective of the strategy followed, indicating that both methods are generally equally effective. Only in the case of 2,6-disubstituted piperidines, could the "quaternization-hydride reduction" strategy not be used. The "hydrogenation-hydride reduction" protocol was successfully applied to trans- and cis-2-methyl-N-(pyridin-2-yl)-6-undecylpiperidine in a short synthetic route toward (±)-solenopsin A (trans diastereoisomer) and (±)-isosolenopsin A (cis diastereoisomer). The absolute configuration of the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.

Full text of DOI:10.1021/jo401521y

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Article
Removal of the pyridine directing group from alpha-substituted N-(pyridin-2-
yl)piperidines obtained via directed Ru-catalyzed sp3 C-H functionalization
Veerle Smout, Aldo Peschiulli, Stefan Verbeeck, Emily A Mitchell, Wouter Herrebout, Patrick
Bultinck, Christophe M.L. Vande Velde, Didier Berthelot, Lieven Meerpoel, and Bert U. W. Maes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401521y • Publication Date (Web): 06 Sep 2013
Downloaded from http://pubs.acs.org on September 7, 2013
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Removal of the pyridine directing group from α-substituted N-
(pyridin-2-yl)piperidines obtained via directed Ru-catalyzed sp3 C-H
functionalization
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Veerle Smout,a Aldo Peschiulli,a Stefan Verbeeck,a Emily A. Mitchell,a Wouter Herrebout,c
Patrick Bultinck,d Christophe M. L. Vande Velde,e Didier Berthelot,b Lieven Meerpoel,b Bert U.
W. Maes*,a
a
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020
Antwerp, Belgium
* E-mail: bert.maes@uantwerpen.be
b Janssen Research & Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, 2340
Beerse, Belgium
c
Cryospectroscopy, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020
Antwerp, Belgium
d
Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent,
Belgium
e University of Antwerp, Faculty of Applied Engineering, Advanced Reactor Technology, Salesianenlaan
30, 2660 Hoboken, Belgium
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Abstract
Two strategies, ‘hydrogenationꢀhydride reduction’ and ‘quaternizationꢀhydride
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reduction’, are reported that make use of mild reaction conditions (room temperature) to
efficiently remove the Nꢀpyridinꢀ2ꢀyl directing group from a diverse set of Cꢀ2 substituted
piperidines that were synthesized through directed Ruꢀcatalyzed sp3 CꢀH functionalization. The
deprotected products are obtained in moderate to good yields irrespective of the strategy
followed, indicating that both methods are generally equally effective. Only in the case of 2,6ꢀ
disubstituted piperidines, the ‘quaternizationꢀhydride reduction’ strategy could not be used. The
‘hydrogenationꢀhydride reduction’ protocol was successfully applied to trans- and cisꢀ2ꢀmethylꢀ
Nꢀ(pyridinꢀ2ꢀyl)ꢀ6ꢀundecylpiperidine in a short synthetic route towards (±)ꢀsolenopsin A (trans
diastereoisomer) and (±)ꢀisosolenopsin A (cis diastereoisomer). The absolute configuration of
the enantiomers of these fire ant alkaloids could be determined via VCD spectroscopy.
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Introduction
The concept of direct functionalization via transition metalꢀcatalyzed CꢀH activation has
attracted much attention in the last decade.[1] Methods that allow for the direct functionalization
of inert CꢀH bonds are undoubtedly of high synthetic value and have recently become a useful
tool in the synthesis of complex substrates such as pharmaceuticals, natural products and organic
materials.[2] Since CꢀH bonds are ubiquitous in organic molecules, one of the major challenges in
this area is to develop reactions that work with predictable regioselectivity. Both in sp2 and sp3
CꢀH activation, regioselectivity can be achieved with the aid of preꢀexisting or deliberately builtꢀ
in functional groups that coordinate to the metal and position it for a regioselective CꢀH bond
cleavage.[3] The majority of directed CꢀH activation methods reported so far rely on nitrogenꢀ,
sulfurꢀ or phosphorusꢀcontaining directing groups (e.g. pyridine, oxazoline, thioether and
phosphine), which are strongly coordinating and form a thermodynamically stable fiveꢀ or sixꢀ
membered metallacycle with the transition metal in the CꢀH activation step.[3b,4] Weakly
coordinating directing groups like ketones, carboxylic acids, esters, alcohols and ethers on the
other hand have been less actively studied.[3b,5] A stable directing group is often required to make
direct functionalization via CꢀH activation possible, but also has an associated major drawback in
that stable directing groups, when not required in the final target structures, are difficult to
remove after the functionalization step.
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Scheme 1. General concept of using a pyridine directing group in the direct Cꢀ2
functionalization of saturated cyclic amines via transition metalꢀcatalyzed sp3 CꢀH activation.
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Recently, our group has disclosed directed rutheniumꢀcatalyzed (hetero)arylation and alkylation
reactions that, applied to piperidines and related cyclic amines, deliver the corresponding αꢀ
substituted heterocycles.[6] Essential for the success of these Cꢀ2 functionalization reactions is
the presence of a stable pyridine directing group on the nitrogen atom of the cyclic amine. An
ideal directing group should be easily introduced onto the cyclic amine prior to Cꢀ2
functionalization, be perfectly stable under the reaction conditions required for the CꢀH
functionalization process and, finally, be removed in a straightforward manner from the Cꢀ2
substituted reaction product (Scheme 1). When inefficiency at the stage of the removal of the
directing group is encountered, the functionalization process itself loses part of its synthetic
appeal. Nꢀ(pyridinꢀ2ꢀyl) derivatives of cyclic amines can be easily obtained by applying a
BuchwaldꢀHartwig reaction[7] or via nucleophilic aromatic substitution, starting from readily
available cyclic amines and 2ꢀhalopyridines. On the other hand, pyridine removal from the
corresponding αꢀsubstituted reaction products appeared, at the outset of our study, not
straightforward. Nevertheless, we were able to show in a concept reaction the first example of
such an Nꢀ(pyridinꢀ2ꢀyl) group removal by ‘deprotecting’ model substrate 2ꢀphenylꢀNꢀ(pyridinꢀ
2ꢀyl)piperidine (1a) in a oneꢀpot sequential protocol (Scheme 2).[6a,8] The pyridinyl moiety was
first partially reduced via a Pd/Cꢀcatalyzed hydrogenation and subsequent cleavage of the
resulting amidine functionality was achieved by treatment with NH2NH2.[9]
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Scheme 2. Oneꢀpot sequential protocol for the removal of the pyridine group from 2ꢀphenylꢀNꢀ
(pyridinꢀ2ꢀyl)piperidine (1a), a method that has been described previously by our group.
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The use of pyridine to efficiently direct both sp2 and sp3 CꢀH activation is well documented in
the literature.[10] Nevertheless, only in a limited number of reports is its removal from the
functionalized products discussed. Wu and Ackermann (Scheme 3a) reported that orthoꢀarylated
Oꢀ(pyridinꢀ2ꢀyl)phenols can be converted into the corresponding free phenols by a twoꢀstep
protocol involving methylation of the pyridine nitrogen with methyl triflate at 100 °C, followed
by treatment of the Nꢀmethylpyridinium salt with Na in MeOH at 80 °C.[11] The group of
Schnürch (Scheme 3b) applied a threeꢀstep method for the removal of the pyridine group from αꢀ
arylated NꢀbenzylꢀN′
ꢀ(3ꢀmethylpyridinꢀ2ꢀyl)amines.[12] Carbamoylation of the secondary amine
nitrogen is followed by subsequent methylation of the pyridine nitrogen using methyl triflate at 0
°C and hydrolysis of the resulting pyridinium salt at 50 °C, to eventually give Bocꢀprotected αꢀ
arylated benzylic amines. Reaction conditions similar to those originally developed by our group
for 1a were reported by Shibata (Scheme 3c) for αꢀalkylated NꢀalkylꢀN’ꢀ(pyridinꢀ2ꢀyl)amines.[13]
In a threeꢀstep protocol, the corresponding HClꢀsalt of (S)ꢀNꢀ(4ꢀ(4ꢀmethoxyphenyl)butanꢀ2ꢀ
yl)pyridinꢀ2ꢀamine was first formed and then subjected to a PtO2ꢀcatalyzed hydrogenation
reaction at 0 °C, followed by treatment with hydrazine at 75 °C. Although these initial results on
pyridine group removal reported by our group and others are promising, the ‘deprotection’ is
always shown for one ‘model substrate’ which is usually acyclic. In addition, there is only very
limited information on the compatibility of the developed method with functional groups.
Moreover, harsh reaction conditions are sometimes required (e.g. MeOTf and NH2NH2 at higher
temperatures). Herein, we wish to report two strategies that make use of mild reaction conditions
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(room temperature) to efficiently remove the pyridine directing group from a diverse set of Cꢀ2
substituted piperidines that were obtained through directed Ruꢀcatalyzed sp3 CꢀH
functionalization.
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Scheme 3. Removal of the pyridine directing group from reaction products obtained via
transition metalꢀcatalyzed directed sp2 or sp3 CꢀH functionalization.
Results and discussion
The need for a new, efficient and general method became apparent when we applied the
hydrogenation conditions originally developed for 1a (Scheme 2) to more challenging substrates.
Full conversion of the Cꢀ2 phenylated piperidine 1a to the corresponding Nꢀ(tetrahydropyridinꢀ2ꢀ
yl)amine 2 was previously accomplished by making use of a Pd/Cꢀcatalyzed hydrogenation in
the presence of HCl. However, when the same hydrogenation conditions were applied to 4ꢀketalꢀ
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2ꢀphenyl-N-(pyridinꢀ2ꢀyl)piperidine (1b), incomplete conversion to the desired Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine 4 was observed (Table 1, entry 1). Moreover, hydrolysis of the
ketal functionality occurred as a major side reaction and a small amount of acyclic Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine 5 was formed as a result of undesired cleavage of the benzylic C2ꢀ
N bond. Clearly, novel hydrogenation conditions were required in order to develop a pyridine
removal method that is applicable to a broad range of Cꢀ2 arylated Nꢀ(pyridinꢀ2ꢀyl)piperidine
derivatives.
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Table 1. Optimization of the transition metalꢀcatalyzed hydrogenation of 2ꢀarylꢀN-(pyridinꢀ2ꢀ
yl)piperidines with 4ꢀketalꢀ2ꢀphenyl-N-(pyridinꢀ2ꢀyl)piperidine (1b) as model substrate.a
LC-MS Yieldh [%]
Entry
Catalyst
Acid
Solvent
T
T
1b/4/5
22/19/2i
1/1/98
86/8/6
95/5/0
52/48/0
0/4/0j
Pd/Cb
Pd/Cc
Pd/Cc
HClf (6.0 eq.)
AcOH (6.0 eq.)
AcOH (6.0 eq.)
AcOH (6.0 eq.)
AcOH (6.0 eq.)
HClg (6.0 eq.)
HClg (1.2 eq.)
HClg (1.2 eq.)
iꢀPrOH (3.6 mL)
iꢀPrOH (10 mL)
iꢀPrOH (10 mL)
EtOH (5 mL)
r.t.
50 °C
r.t.
16 h
16 h
16 h
18 h
18 h
18 h
18 h
8 h
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2
3
4
5
6
7
8
d
PtO2
r.t.
Pt/Ce
Pt/Ce
Pt/Ce
Pt/Ce
EtOH (5 mL)
r.t.
EtOH (2.6 mL)
EtOH (4.5 mL)
EtOH (4.5 mL)
r.t.
r.t.
0/92/0k
0/100/0
r.t.
a All reactions were performed on a 0.5 mmol scale under 1 atm H2 pressure in the presence of the mentioned catalyst (10 mol%
or 0.05 mmol of metal [Pd or Pt]), acid and solvent, using the indicated temperature (T) and time (t). b Pd/C with 10% Pdꢀbasis. c
e
f
g
h
Pd/C with 5% Pdꢀbasis. d PtO2 with 83% Ptꢀcontent. Pt/C with 5% Ptꢀbasis. HCl 6.0 M in iꢀPrOH. HCl 1.25 M in EtOH.
Uncorrected LCꢀMS yields. i 52% side products with a hydrolyzed ketal functionality were detected. j A complex mixture of side
products was formed. MS indicates that the ketal functionality is hydrolyzed or completely removed. Additional cleavage of the
C2ꢀN benzylic bond and/or reduction of the C2ꢀphenyl ring was also detected. k 8% side product with additional reduction of the
C2ꢀphenyl ring was detected.
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Earlier work in our laboratory had shown that 1ꢀ(pyridinꢀ2ꢀyl)ꢀ4ꢀpiperidinone ethylene ketal, the
nonꢀphenylated derivative of 1b, could be fully converted to the corresponding Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine without side product formation by performing a Pd/Cꢀcatalyzed
hydrogenation at 50 °C in the presence of an excess of weak acid (AcOH) instead of HCl.[6a]
Unfortunately, when these hydrogenation conditions were applied to 4ꢀketalꢀ2ꢀphenylꢀNꢀ
(pyridinꢀ2ꢀyl)piperidine (1b), nearly complete conversion to the undesired acyclic Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine 5 was observed (entry 2). At room temperature, the majority of the
starting material 1b remained and a mixture of the desired compound 4 and the C2ꢀN benzylic
cleaved compound 5 was obtained (entry 3). As it is documented that Pd has the tendency to
induce hydrogenolysis at benzylic positions,[14] we reasoned that the formation of side product 5
might be prevented by using another transition metal to catalyze the hydrogenation. Since Pt is
used for the reduction of pyridines without affecting benzylic positions,[15] we attempted the
hydrogenation step in the presence of catalytic amounts of PtO2, unfortunately without a positive
outcome (entry 4). Gratifyingly, in the presence of Pt/C as the catalyst, a reasonable conversion
to the desired Nꢀ(tetrahydropyridinꢀ2ꢀyl)amine 4 could be obtained at room temperature (entry
5). Since our goal was to develop a mild pyridine removal method, we preferred to keep the
reaction at room temperature and tried to fully convert 1b to 4 by switching again to the stronger
acid HCl to mediate the Pt/Cꢀcatalyzed hydrogenation. To our delight, we found that the ketal
functionality stayed intact when only a small excess of HCl was used (1.2 eq. instead of 6.0 eq.)
and we could obtain the desired compound 4 in 92% LCꢀMS yield (entries 6 and 7). Because
additional reduction of the phenyl ring starts taking place after 18 h, we shortened the reaction
time to 8 h and found the Nꢀ(tetrahydropyridinꢀ2ꢀyl)amine 4 to be formed chemoselectively in
100% LCꢀMS yield (entry 8).
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The remaining amidine functionality in compound 4 can be reduced by subjecting it to the
previously established conditions that make use of NH2NH2 and, in this way, the deprotected
product 3b was obtained in 80% overall isolated yield (Scheme 4a). Because of the hazardous
nature of hydrazine as a reagent (especially at higher temperatures), we continued our search for
a milder and more generally applicable alternative for the second step of our ‘deprotection’
protocol. Unfortunately, attempts to cleave the amidine group with nucleophilic reagents such as
NaOtꢀBu or NH3 ꢀ even at temperatures up to 120 °C ꢀ failed. As mentioned above, the imine
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moiety of the remaining amidine in compound 4 is not reduced if the Pt/Cꢀcatalyzed
hydrogenation is performed for a longer time, but instead undesired reduction of the phenyl ring
takes place. Also, when the hydrogenation was carried out at a higher H2 pressure (10 atm
instead of 1 atm), 1b could not be directly converted to the corresponding deprotected product
3b. Again, the amidine bond is not reduced and the reaction stops at the stage of the Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine 4.
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Scheme 4. Pyridine group removal via oneꢀpot sequential reactions involving a) Pt/Cꢀcatalyzed
hydrogenation followed by hydrazinolysis and b) Nꢀmethylpyridinium formation followed by
hydrazinolysis.
Since compound 4 is formed as its hydrochloride salt, it occurred to us that a simple reduction of
the protonated amidine with NaBH4 could deliver the desired free piperidine (Scheme 5a).[16]
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Indeed, protonation reduces the electron density of the amidine and makes it more prone to
nucleophilic attack by a reducing agent. In this way, an unstable aminal is formed which
decomposes in situ, delivering the deprotected product 3b in 71% overall isolated yield.
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Scheme 5. Optimized reaction conditions for removing the pyridine group from 4ꢀketalꢀ2ꢀ
phenylꢀNꢀ(pyridinꢀ2ꢀyl)piperidine (1b) via a) the oneꢀpot sequential ‘hydrogenationꢀhydride
reduction’ strategy and b) the oneꢀpot sequential ‘quaternizationꢀhydride reduction’ strategy.
Along with the ‘hydrogenationꢀhydride reduction’ strategy shown in Scheme 5a, an alternative
route was developed based on the formation of an Nꢀmethylpyridinium salt. As depicted in
Scheme 5b, this ‘quaternizationꢀhydride reduction’ strategy relies on the use of a methylating
agent to form Nꢀmethylpyridinium salt 6, which is then reduced by NaBH4. This concept of
quaternizationꢀhydride reduction is well documented in literature,[17] but has never been applied
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before to 2ꢀaminopyridine systems like 1b. Treatment of 1b with a slight excess of methyl
triflate in acetonitrile at room temperature produced the desired pyridinium salt (6)
quantitatively. Compound 6 was then easily reduced at room temperature by adding NaBH4 to
yield an unstable aminal, which in situ decomposes to the deprotected piperidine derivative. The
free amine 3b was isolated in 77% overall yield. Whereas the amidine bond in Nꢀ
(tetrahydropyridinꢀ2ꢀyl)amine 4 (obtained after hydrogenation of 1b) can be cleaved with
NH2NH2 instead of NaBH4 (Scheme 4a), only 9% of the desired deprotected product 3b could be
isolated when Nꢀmethylpyridinium salt 6 (obtained after methylation of 1b) was treated with
NH2NH2 in iꢀPrOH at 120 °C for 2.5 h (Scheme 4b). Importantly, both the ‘hydrogenationꢀ
hydride reduction’ and the ‘quaternizationꢀhydride reduction’ strategy are oneꢀpot sequential
procedures consisting of two steps, meaning that only limited (filtration) or even no workꢀup is
performed after the first step of the protocols.
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Having established two different strategies, we explored their scope (Scheme 6). Both the
‘hydrogenationꢀhydride reduction’ and the ‘quaternizationꢀhydride reduction’ approach were
found effective in removing the pyridine directing group from a variety of substituted piperidines
(1) that were obtained via directed Ruꢀcatalyzed sp3 CꢀH functionalization.[6] Since both methods
consist of two sequential reaction steps, the results displayed in Scheme 6 have to be considered
as overall isolated yields, indicating that moderate to excellent conversions/yields are achieved in
each step of the protocols. Only in a few cases, one method proved superior over the other (3c,
3f, 3k). Functional groups on a Cꢀ2 aryl substituent are tolerated by both methodologies and no
real electronic effects can be noticed when comparing the results obtained for compounds 3bꢀe.
It is noteworthy that the 4ꢀCl substituent in 3e is also compatible with the hydrogenation strategy
as no significant hydrodechlorination was observed. 2,4ꢀ and 2,5ꢀDisubstituted piperidine
derivatives could be smoothly deprotected using either of both strategies (3bꢀe, 3k and 3j).
However, with 2,6ꢀdisubstituted piperidines, the corresponding deprotected products could not
be obtained by implementing the ‘quaternizationꢀhydride reduction’ strategy (3hꢀi). The
methylation step proceeds smoothly, but the subsequent hydride reduction step does not occur.
Hydride addition by NaBH4 presumably suffers from steric hindrance caused by the Cꢀ6
substituent. Interestingly, the stereo information of the diastereomerically pure compounds 3hꢀk
is preserved throughout the ‘deprotection’ process, irrespective whether the ‘hydrogenationꢀ
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Scheme 6. Removal of the pyridine directing group from αꢀsubstituted Nꢀ(pyridinꢀ2ꢀ
yl)piperidines (1).
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9
R'
'Hydrogenation-hydride
reduction' strategy (H)a
R'
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N
R
N
H
R
'Quaternization-hydride
reduction' strategy (Q)b
N
3
1
O
O
O
O
O
O
N
H
N
H
N
H
OMe
CO2Me
3b
3c
3d
Ha - 71%
Qb - 77%
Ha,c - 72%
Qb - 31%[18]
Ha,c - 43%
Qb - 57%
O
O
OMe
N
H
N
H
N
H
Cl
3e
3a
3f
Ha,d - 67%
Qb - 69%
Ha,h - 40%
Qb,g,h - 62%
Ha - 42%
Qb - 24%[19]
N
Me
N
Ph
N
H
H
H
3g
3h
3i
Ha,c,e - 72%
Qb,g - 87%
Ha,f,h - 55%
Qb,f,g - 0%
Ha,c,f - 14%
Qb,f,g - 0%
CO2Me
F3C
Me
N
N
H
N
H
N
H
3j
3k
3l
Ha,c,e,h - 81%
Qb,h - 61%
Ha,c - 28%[20]
Qb - 60%
Ha - 19%
Qb - 76%
O
O
N
H
C6H13
3m
Ha,c,f - 70%
Qb - 76%
a
The reactions were performed on a 0.5 mmol scale under 1 atm H2 pressure in the presence of Pt/C (10 mol%; Pt/C with 5% Ptꢀ
basis used; 10 mol% refers to the amount of Ptꢀmetal), HCl (1.2 eq.; HCl 1.25 M in EtOH used) and EtOH (4.5 mL) at room
temperature for 8 h. After filtration of the catalyst and evaporation of the volatiles, MeOH (5 mL) and NaBH4 (4.0 eq.) were
b
added and the reaction mixture was stirred at 0 °C for 15 min. The reactions were performed on a 0.5 mmol scale in the
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presence of methyl triflate (1.2 eq.) and acetonitrile (1 mL) at 0 °C going to room temperature over 5 min. After this time, MeOH
(5 mL) and NaBH4 (5.0 eq.) were added and stirring was continued at 0 °C for 15 min. c A longer reaction time was needed in the
d
hydrogenation step. The reaction was stopped after 7 h hydrogenation. e Complete conversion to the deprotected product upon
hydrogenation. A subsequent reduction step with NaBH4 was not necessary. f 6.0ꢀ10.0 eq. NaBH4 were used in the reduction step.
g 2.4ꢀ3.6 eq. methyl triflate were used in the quaternization step. h Isolated as the respective HClꢀsalt due to the volatile nature of
the free amine.
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hydride reduction’ or ‘quaternizationꢀhydride reduction’ strategy is followed. Remarkably, 3g
and 3j are immediately obtained after hydrogenation and no subsequent reduction with NaBH4 is
needed. This indicates that hydrogenation of the pyridine moiety to a hexahydropyridinꢀ2ꢀyl
occurred, followed by spontaneous cleavage of the unstable aminal formed. To our delight,
heteroaryls of the azole type are also compatible with the developed methodology as exemplified
for an αꢀ(Nꢀmethyl)indolꢀ2ꢀyl substituent which gave a high yield when applying the
‘quaternizationꢀhydride reduction’ strategy (3l). On the contrary, the desired deprotected product
3l could only be isolated in 19% yield via the ‘hydrogenationꢀhydride reduction’ protocol.
Indeed, protonation can occur on the pyridinyl and pyrrolyl moiety, thus allowing hydrogenation
of both rings (observed in LCꢀMS) and leading to a low yield for target compound 3l.
Gratifyingly, next to Cꢀ2 aryl and heteroaryl groups, also an αꢀalkyl substituent is tolerated by
either of the two strategies. Comparably to the αꢀphenylated model substrate 3b, both protocols
gave excellent isolated yields of αꢀhexylated piperidine 3m. All reactions displayed in Scheme 6
were performed with 0.5 mmol of a Nꢀ(pyridinꢀ2ꢀyl)piperidine substrate 1. The feasibility to
scaleꢀup the newly developed synthetic methods to 2.5 mmol was tested on model substrate 1b.
The resulting isolated yields for the corresponding free amine 3b (‘hydrogenationꢀhydride
reduction’ strategy: 73%, ‘quaternizationꢀhydride reduction’ strategy: 81%) were comparable to
those obtained on a 0.5 mmol scale.
To further showcase the potential of the newly developed mild pyridine removal methods, we
wondered if we could apply them in a synthetic route towards enantiomerically pure solenopsin
A and isosolenopsin A (9) (Scheme 7).[21] These alkaloids were originally isolated from fire ants
and consist of a 2,6ꢀdialkylated piperidine ring. The αꢀundecylated product 8 was synthesized
from racemic 2ꢀmethylꢀNꢀ(pyridinꢀ2ꢀyl)piperidine 7 via a directed Ruꢀcatalyzed sp3 CꢀH
alkylation procedure recently established by our group.[6b] 2ꢀMethylꢀNꢀ(pyridinꢀ2ꢀyl)ꢀ6ꢀ
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undecylpiperidine (8) was then separated into its four stereoisomers (transꢀ8a, transꢀ8b, cisꢀ8a
and cisꢀ8b) by preparative SFC (Super critical Fluid Chromatography). Subsequent removal of
the Nꢀ(pyridinꢀ2ꢀyl) group using the ‘quaternizationꢀhydride reduction’ strategy did not give any
9, which is in agreement with our findings on 2,6ꢀdisubstituted piperidines 3h and 3i (Scheme 6).
When the ‘hydrogenationꢀhydride reduction’ protocol was applied to enantiomerically pure 2ꢀ
methylꢀNꢀ(pyridinꢀ2ꢀyl)ꢀ6ꢀundecylpiperidines 8, the corresponding ‘deprotected’ products
(solenopsins transꢀ9a, transꢀ9b and isosolenopsins cisꢀ9a, cisꢀ9b) were isolated in moderate to
good yields.
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Scheme 7. Synthesis of solenopsin A and isosolenopsin A (9).
The stereo information of enantiomerically pure piperidines 8 is preserved throughout the
pyridine removal process, as was observed earlier for diastereomers 3hꢀk (Scheme 6). The
absolute configuration of 2ꢀmethylꢀ6ꢀundecylpiperidines 9 was determined by VCD (Vibrational
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9
Circular Dichroism) spectroscopy. In this way, transꢀ9a and transꢀ9b could be identified as
(2S,6S)ꢀ and (2R,6R)ꢀsolenopsin A, while the isosolenopsins cisꢀ9a and cisꢀ9b were found to
have a (2S,6R)ꢀ and (2R,6S)ꢀconfiguration, respectively. The structure of transꢀ9b was
additionally confirmed by Xꢀray crystallographic analysis of the corresponding HClꢀsalt (Figure
1). To the best of our knowledge, this is the first reported Xꢀray structure for solenopsin A.
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Figure 1. Xꢀray structure of (2R,6R)ꢀsolenopsin A•HCl (transꢀ9b•HCl).
Conclusion
We have developed two novel synthetic strategies requiring mild reaction conditions (room
temperature) to remove the Nꢀpyridinꢀ2ꢀyl directing group from a diverse set of αꢀsubstituted
piperidines that were synthesized through directed Ruꢀcatalyzed sp3 CꢀH functionalization. The
reaction products are obtained in moderate to good overall yields irrespective whether the
‘hydrogenationꢀhydride reduction’ or ‘quaternizationꢀhydride reduction’ strategy is followed,
indicating that both methods are equally effective. Only in the case of 2,6ꢀdisubstituted
piperidines, the ‘quaternizationꢀhydride reduction’ protocol could not be used. There are no
significant electronic effects and the stereo information in diastereomerically and
enantiomerically pure compounds is preserved throughout the ‘deprotection’ processes. The
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‘hydrogenationꢀhydride reduction’ method was successfully applied in a short synthetic route
towards fire ant alkaloids involving a directed sp3 CꢀH alkylation reaction.
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Experimental section
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General considerations ꢀ Reagents and solvents were used as purchased without further
purification. NaBH4 was available as granules. Methyl trifluoromethanesulfonate was delivered
in 10 g ampules. αꢀSubstituted Nꢀ(pyridinꢀ2ꢀyl)piperidines 1a, 1b and 1fꢀm have already been
described in former publications from our group and their synthesis and characterization will not
be reported here.[6] Preparative HPLC and preparative SFC were performed as described below.
Flash chromatography was carried out using an automated chromatography system. Proton
Nuclear Magnetic Resonance spectra were recorded on a 400 MHz spectrometer in CDCl3 or d6-
DMSO; resonances are reported as chemical shifts (δ) in parts per million (ppm) with
tetramethylsilane (TMS) as reference; splitting is reported as s = singlet, d = doublet, t = triplet, q
= quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets,
td = triplet of doublets, tt = triplet of triplets, qd = quartet of doublets and m = multiplet;
coupling constants (J) are given in Hertz (Hz); the number of protons per signal is represented as
nH. Carbon NMR spectra were recorded on the same instrument (100 MHz) with total proton
decoupling. High resolution mass spectrometry samples were prepared by dissolving 0.1ꢀ5.0 mg
of the compound in MeOH/H2O ꢀ 80/20 containing 0.1% formic acid, in such a way that a
concentration of 10ꢀ6ꢀ10ꢀ5 mol/L was obtained. 10 ꢁL of the samples were injected and
electrosprayed through the nanoelectrospray source. The latter was operated in positive ion mode
at an electrospray potential of 1.5 kV. Samples were injected with an interval of 3 min and
positive ion mode accurate mass spectra were acquired. The MS was calibrated prior to use with
a 0.2% H3PO4 solution. The spectra were lock mass corrected using the known mass of the
nearest H3PO4 cluster or the phthalate background ions. All analytes are detected as protonated
molecules.
General procedure 1 ꢀ A 100 mL roundꢀbottom flask was charged with the appropriate Nꢀ
(pyridinꢀ2ꢀyl)piperidine (10.0 mmol) and arylboronate ester (40.0 mmol, 4.0 eq.), [Ru3(CO)12]
(511 mg, 0.8 mmol, 8 mol%) and 3ꢀethylꢀ3ꢀpentanol (1.38 mL, 10.0 mmol, 1.0 eq.). The roundꢀ
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bottom flask was fitted with a reflux condenser and the reaction mixture was then heated to
reflux ꢀ the temperature of the oil bath being set at 153 °C ꢀ under magnetic stirring for 24 h.
After this time, the reaction mixture was cooled down and volatiles were removed under reduced
pressure. To the residue were added 20 g of a commercially available ruthenium scavenger
(Siliabond® DMT, Silicycle), along with 300 mL CH2Cl2. The resulting suspension was stirred
at r.t. for 60 h (overweekend). Subsequently, the solids were removed by filtration through
dicalite, the pad was washed with CH2Cl2 (4 x 50 mL) and the combined filtrate was evaporated
to dryness. The residue ꢀ being a mixture of monoarylated and diarylated products ꢀ was purified
by prep HPLC to obtain the desired monoarylated product.
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7-(4-Methoxyphenyl)-8-(pyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (1c) ꢀ Prepared as per
general procedure 1, starting from 8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (2.20 g, 10.0
mmol), [Ru3(CO)12] (511 mg, 0.8 mmol, 8 mol%), 2ꢀ(4ꢀmethoxyphenyl)ꢀ5,5ꢀdimethylꢀ1,3,2ꢀ
dioxaborinane (8.80 g, 40.0 mmol, 4.0 eq.) and 3ꢀethylꢀ3ꢀpentanol (1.38 mL, 10.0 mmol, 1.0
eq.). The crude product was purified by prep HPLC on C18 silica, eluting with (0.25%
NH4HCO3 solution in H2O)/CH3CN, to give 1c as a yellow semiꢀsolid in 27% (868 mg) yield. 1H
NMR (400 MHz, CDCl3) δ 8.15 (ddd, J = 5.0, 1.9, 0.8 Hz, 1H), 7.33 (ddd, J = 8.7, 7.1, 1.9 Hz,
1H), 7.18 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.54 (ddd, J = 7.1, 5.0, 0.8 Hz, 1H), 6.46
(d, J = 8.7 Hz, 1H), 5.31 (t, J = 5.8 Hz, 1H), 4.40 (dt, J = 13.8, 4.3 Hz, 1H), 3.97ꢀ3.81 (m, 4H),
3.74 (s, 3H), 3.52 (ddd, J = 13.8, 9.9, 4.3 Hz, 1H), 2.35 (dd, J = 14.0, 5.8 Hz, 1H), 2.16 (dd, J =
14.0, 5.8 Hz, 1H), 1.96ꢀ1.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.0, 158.2, 147.9, 137.4,
132.2, 127.3, 113.8, 112.9, 107.8, 107.5, 64.3, 64.0, 55.2, 54.9, 40.2, 38.9, 34.7; HRMS (ESI):
+
Calculated for C19H23N2O3 [M+H]+: 327.1703, Observed: 327.1700.
Methyl 4-(8-(pyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)benzoate (1d) ꢀ Prepared as
per general procedure 1, starting from 8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (2.20 g,
10.0 mmol), [Ru3(CO)12] (511 mg, 0.8 mmol, 8 mol%), methyl 4ꢀ(5,5ꢀdimethylꢀ1,3,2ꢀ
dioxaborinanꢀ2ꢀyl)benzoate (9.92 g, 40.0 mmol, 4.0 eq.) and 3ꢀethylꢀ3ꢀpentanol (1.38 mL, 10.0
mmol, 1.0 eq.). The crude product was purified by prep HPLC on C18 silica, eluting with (0.25%
NH4HCO3 solution in H2O)/CH3CN, to give 1d as a yellow semiꢀsolid in 15% (528 mg) yield.
1H NMR (400 MHz, CDCl3) δ 8.14 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.38
(ddd, J = 8.8, 7.1, 1.9 Hz, 1H), 7.34 (d, J = 8.3 Hz, 2H), 6.57 (ddd, J = 7.1, 4.9, 0.8 Hz, 1H), 6.51
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(d, J = 8.8 Hz, 1H), 5.57 (t, J = 5.5 Hz, 1H), 4.32 (dt, J = 13.6, 4.2 Hz, 1H), 3.98ꢀ3.88 (m, 2H),
3.87 (s, 3H), 3.85ꢀ3.76 (m, 2H), 3.52 (ddd, J = 13.6, 10.5, 4.2 Hz, 1H), 2.39 (dd, J = 13.9, 5.5
13
Hz, 1H), 2.20 (dd, J = 13.9, 5.5 Hz, 1H), 1.96ꢀ1.82 (m, 2H); C NMR (100 MHz, CDCl3) δ
167.0, 158.8, 148.0, 147.9, 137.5, 129.7, 128.3, 126.3, 113.2, 107.6, 107.3, 64.3, 64.1, 55.1, 51.9,
9
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+
40.6, 38.4, 34.5; HRMS (ESI): Calculated for C20H23N2O4 [M+H]+: 355.1652, Observed:
355.1648.
7-(4-Chlorophenyl)-8-(pyridin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (1e) ꢀ Prepared as per
general procedure 1, starting from 8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (2.20 g, 10.0
mmol), [Ru3(CO)12] (511 mg, 0.8 mmol, 8 mol%), 2ꢀ(4ꢀchlorophenyl)ꢀ5,5ꢀdimethylꢀ1,3,2ꢀ
dioxaborinane (8.98 g, 40.0 mmol, 4.0 eq.) and 3ꢀethylꢀ3ꢀpentanol (1.38 mL, 10.0 mmol, 1.0
eq.). The crude product was purified by prep HPLC on C18 silica, eluting with (0.25%
1
NH4HCO3 solution in H2O)/CH3CN, to give 1e as a yellow oil in 16% (521 mg) yield. H NMR
(400 MHz, CDCl3) δ 8.15 (ddd, J = 5.0, 1.8, 0.7 Hz, 1H), 7.39 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H),
7.31ꢀ7.19 (m, 4H), 6.58 (ddd, J = 7.2, 5.0, 0.7 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 5.44 (t, J = 5.6
Hz, 1H), 4.30 (dt, J = 13.5, 4.6 Hz, 1H), 3.99ꢀ3.79 (m, 4H), 3.49 (ddd, J = 13.5, 10.6, 4.6 Hz,
13
1H), 2.34 (dd, J = 13.9, 5.6 Hz, 1H), 2.17 (dd, J = 13.9, 5.6 Hz, 1H), 1.95ꢀ1.82 (m, 2H); C
NMR (100 MHz, CDCl3) δ 158.8, 147.9, 140.6, 137.6, 132.0, 128.4, 127.8, 113.3, 107.8, 107.3,
+
64.3, 64.1, 54.7, 40.5, 38.5, 34.5; HRMS (ESI): Calculated for C18H20ClN2O2 [M+H]+:
331.1208, Observed: 331.1211.
‘Hydrogenation-hydride reduction’ strategy, general procedure 2 ꢀ Step 1: A 50 mL
hydrogenation tube was charged with the appropriate Cꢀ2 functionalized N-(pyridinꢀ2ꢀ
yl)piperidine (0.5 mmol) and Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%). Under N2, EtOH (4.5
mL) was added. To the resulting black suspension, HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2
eq.) was added and the reaction mixture was subsequently flushed twice with H2. The reaction
mixture was then stirred under H2 at r.t. for 7ꢀ24 h. After this time, the solids were removed by
filtration through dicalite, the pad was washed with CH2Cl2 (5 x 20 mL), and the combined
filtrate was evaporated to dryness. Step 2: The residue of step 1 was dissolved in MeOH (5 mL)
and the resulting solution was cooled to 0 °C using an ice/waterꢀbath. NaBH4 (2.0ꢀ4.0 mmol, 4.0ꢀ
8.0 eq.) was added portionwise (ca. 10 mg each portion) to the cooled solution under magnetic
stirring, avoiding intense evolution of H2 and keeping the temperature constant at 0 °C. After
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complete addition of NaBH4, the reaction mixture was stirred further at 0 °C for 15 min. After
this time, the volatiles were removed in vacuo. The residue was purified by straight phase or
reversed phase flash chromatography to obtain the desired Cꢀ2 functionalized piperidine as either
the free base or the corresponding HClꢀsalt.
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‘Quaternization-hydride reduction’ strategy, general procedure 3 ꢀ Step 1: A 50 mL roundꢀ
bottom flask was charged with the appropriate Cꢀ2 functionalized Nꢀ(pyridinꢀ2ꢀyl)piperidine (0.5
mmol) and CH3CN (1 mL). The resulting solution was cooled to 0 °C using an ice/waterꢀbath.
Under N2, iceꢀcold methyl trifluoromethanesulfonate (0.6ꢀ1.8 mmol, 1.2ꢀ3.6 eq.) was added
dropwise over 1 min under magnetic stirring. After complete addition of the methyl triflate, the
ice/waterꢀbath was removed and stirring of the reaction mixture was continued at r.t. for 5 min.
Step 2: After this time, MeOH (5 mL) was added and the reaction mixture was again cooled to 0
°C using an ice/waterꢀbath. NaBH4 (2.5ꢀ5.0 mmol, 5.0ꢀ10.0 eq.) was added portionwise (ca. 10
mg each portion) to the cooled solution under magnetic stirring, avoiding intense evolution of H2
and keeping the temperature constant at 0 °C. After complete addition of NaBH4, the reaction
mixture was stirred further at 0 °C for 15 min. After this time, volatiles were removed in vacuo.
The residue was purified by straight phase or reversed phase flash chromatography to obtain the
desired Cꢀ2 functionalized piperidine as either the free base or the corresponding HClꢀsalt.
7-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (3b) ꢀ Prepared as per general procedure 2, using in
step 1 (8 h reaction time): 7ꢀphenylꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (1b, 148
mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in
EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol,
4.0 eq.). The crude product was purified by straight phase flash chromatography on NH silica,
eluting with a heptane/EtOAc gradient (from 100% heptane up to heptane/EtOAc ꢀ 85/15), to
obtain 3b as a colorless oil in 71% (77 mg) yield. Alternatively prepared as per general
procedure 3, using in step 1: 7ꢀphenylꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (1b, 148
mg, 0.5 mmol), CH3CN (1 mL) and methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2
eq.), and in step 2: MeOH (5 mL) and NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was
purified by straight phase flash chromatography on NH silica, eluting with a heptane/EtOAc
gradient (from 100% heptane up to heptane/EtOAc ꢀ 9/1), to obtain 3b as a colorless oil in 77%
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(84 mg) yield. H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.35 (m, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.24
(tt, J = 7.4, 1.8 Hz, 1H), 4.03ꢀ3.91 (m, 4H), 3.85 (dd, J = 11.9, 2.6 Hz, 1H), 37 (ddd, J = 11.8,
4.8, 2.4 Hz, 1H), 2.99 (td, J = 12.1, 3.3 Hz, 1H), 1.87 (dt, J = 12.9, 2.6 Hz, 1H), 1.79ꢀ1.71 (m,
13
3H); C NMR (100 MHz, CDCl3) δ 144.0, 128.5, 127.3, 126.7, 107.9, 64.4, 64.2, 59.4, 44.5,
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43.6, 35.3; HRMS (ESI): Calculated for C13H18NO2 [M+H]+: 220.1332, Observed: 220.1331.
7-(4-Methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (3c) ꢀ Prepared as per general
procedure 2, using in step 1 (10.5 h reaction time): 7ꢀ(4ꢀmethoxyphenyl)ꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀ
dioxaꢀ8ꢀazaspiro[4.5]decane (1c, 163 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10
mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2:
MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol, 4.0 eq.). The crude product was purified by
straight phase flash chromatography on NH silica, eluting with a heptane/EtOAc gradient (from
100% heptane up to heptane/EtOAc ꢀ 9/1), to obtain 3c as a pale yellow oil in 72% (90 mg)
yield. Alternatively prepared as per general procedure 3, using in step 1: 7ꢀ(4ꢀmethoxyphenyl)ꢀ8ꢀ
(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (1c, 163 mg, 0.5 mmol), CH3CN (1 mL) and
methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and
NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by straight phase flash
chromatography on HP silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100%
CH2Cl2 up to CH2Cl2/(NH3 7 N in MeOH) ꢀ 92/8), to obtain 3c as a pale yellow oil in 31% (38
1
mg) yield. H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H),
4.03ꢀ3.92 (m, 4H), 3.81 (dd, J = 11.3, 2.8 Hz, 1H), 3.79 (s, 3H), 3.16 (ddd, J = 11.8, 4.8, 2.7 Hz,
1H), 2.98 (td, J = 11.8, 4.2 Hz, 1H), 1.95 (br s, 1H), 1.85 (dt, J = 12.8, 2.8 Hz, 1H), 1.80ꢀ1.72
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 136.0, 127.8, 113.9, 107.9, 64.4, 64.2, 58.8, 55.3,
44.4, 43.6, 35.2; HRMS (ESI): Calculated for C14H20NO3 [M+H]+: 250.1438, Observed:
+
250.1432.
Methyl 4-(1,4-dioxa-8-azaspiro[4.5]decan-7-yl)benzoate (3d) ꢀ Prepared as per general
procedure 2, using in step 1 (12 h reaction time): methyl 4ꢀ(8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀ
azaspiro[4.5]decanꢀ7ꢀyl)benzoate (1d, 177 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10
mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2:
MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol, 4.0 eq.). The crude product was purified by
straight phase flash chromatography on HP silica, eluting with a CH2Cl2/(NH3 7 N in MeOH)
gradient (from 100% CH2Cl2 up to CH2Cl2/(NH3 7 N in MeOH) ꢀ 96/4), to obtain 3d as a pale
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yellow oil in 43% (60 mg) yield. Alternatively prepared as per general procedure 3, using in step
1: methyl 4ꢀ(8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decanꢀ7ꢀyl)benzoate (1d, 114 mg, 0.32
mmol), CH3CN (1 mL) and methyl trifluoromethanesulfonate (44 ꢂL, 0.39 mmol, 1.2 eq.), and
in step 2: MeOH (5 mL) and NaBH4 (61 mg, 1.6 mmol, 5.0 eq.). The crude product was purified
by reversed phase flash chromatography on C18 silica, eluting with a H2O/CH3CN gradient
(from 100% H2O up to H2O/CH3CN ꢀ 8/2), to obtain 3d as a colorless oil in 57% (51 mg) yield.
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 4.05ꢀ3.94 (m,
4H), 3.92 (dd, J = 12.4, 2.9 Hz, 1H), 3.90 (s, 3H), 3.19 (ddd, J = 11.7, 4.8, 2.6 Hz, 1H), 3.00 (td,
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J = 11.7, 4.8 Hz, 1H), 1.87 (dt, J = 12.8, 2.6 Hz, 1H), 1.84ꢀ1.73 (m, 4H); C NMR (100 MHz,
CDCl3) δ 169.0, 149.1, 129.9, 129.2, 126.7, 107.7, 64.5, 64.3, 59.2, 52.1, 44.4, 43.7, 35.3;
+
HRMS (ESI): Calculated for C15H20NO4 [M+H]+: 278.1387, Observed: 278.1385.
7-(4-Chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (3e) ꢀ Prepared as per general procedure
2, using in step 1 (7 h reaction time): 7ꢀ(4ꢀchlorophenyl)ꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀ
azaspiro[4.5]decane (1e, 165 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%),
EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5
mL) and NaBH4 (76 mg, 2.0 mmol, 4.0 eq.). The crude product was purified by straight phase
flash chromatography on HP silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from
100% CH2Cl2 up to CH2Cl2/(NH3 7 N in MeOH) ꢀ 99/1), to obtain 3e as a yellow oil in 67% (86
mg) yield. Alternatively prepared as per general procedure 3, using in step 1: 7ꢀ(4ꢀchlorophenyl)ꢀ
8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (1e, 165 mg, 0.5 mmol), CH3CN (1 mL) and
methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and
NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by straight phase flash
chromatography on HP silica, eluting with 100% CH2Cl2, to obtain 3e as a yellow oil in 69% (87
1
mg) yield. H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.26 (m, 4H), 4.03ꢀ3.93 (m, 4H), 3.83 (dd, J =
11.9, 2.5 Hz, 1H), 3.16 (ddd, J = 11.7, 4.4, 2.6 Hz, 1H), 2.97 (td, J = 11.7, 5.5 Hz, 1H), 1.94 (br
s, 1H), 1.83 (dt, J = 12.8, 2.5 Hz, 1H), 1.79ꢀ1.69 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5,
132.9, 128.6, 128.1, 107.7, 64.4, 64.3, 58.7, 44.3, 43.7, 35.2; HRMS (ESI): Calculated for
+
C13H17ClNO2 [M+H]+: 254.0942, Observed: 254.0943.
2-Phenylpiperidine•HCl (3a•HCl) ꢀ Prepared as per general procedure 2, using in step 1 (8 h
reaction time): 2ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)piperidine (1a, 119 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195
mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2
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eq.), and in step 2: MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol, 4.0 eq.). The crude product was
purified by reversed phase flash chromatography on C18 silica, eluting with a H2O/CH3CN
gradient (from 100% H2O up to H2O/CH3CN ꢀ 3/7). The fractions containing the desired product
3a were combined and 0.5 mL of HCl 1.25 M in EtOH was added. After 1 min stirring, volatiles
were removed in vacuo. To the remaining colorless oil, Et2O (10 mL) was added and
crystallization of the resulting emulsion was induced upon stirring. Subsequently, volatiles were
removed under reduced pressure to obtain 3a•HCl as a white solid (m.p. = 192 °C) in 40% (40
mg) yield. Alternatively prepared as per general procedure 3, using in step 1: 2ꢀphenylꢀ1ꢀ
(pyridinꢀ2ꢀyl)piperidine (1a, 119 mg, 0.5 mmol), CH3CN (1 mL) and methyl
trifluoromethanesulfonate (136 ꢂL, 1.2 mmol, 2.4 eq.), and in step 2: MeOH (5 mL) and NaBH4
(95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by reversed phase flash
chromatography on C18 silica, eluting with a H2O/CH3CN gradient (from 100% H2O up to
H2O/CH3CN ꢀ 2/8). The fractions containing the desired product 3a were combined and 0.5 mL
of HCl 1.25 M in EtOH was added. After 1 min stirring, volatiles were removed in vacuo. To the
remaining colorless oil, Et2O (10 mL) was added and crystallization of the resulting emulsion
was induced upon stirring. Subsequently, volatiles were removed under reduced pressure to
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obtain 3a•HCl as a white solid (m.p. = 193 °C) in 62% (62 mg) yield. H NMR (400 MHz, d6ꢀ
DMSO) δ 9.47 (br s, 1H), 9.21 (br s, 1H), 7.59 (dd, J = 8.1, 1.5 Hz, 2H), 7.46ꢀ7.37 (m, 3H),
4.23ꢀ4.16 (m, 1H), 3.31 (br d, J = 12.8 Hz, 1H), 3.06ꢀ2.98 (m, 1H), 1.91ꢀ1.76 (m, 5H), 1.69ꢀ1.53
(m, 1H); 13C NMR (100 MHz, d6ꢀDMSO) δ 136.6, 127.4 (two overlapping signals), 126.1, 58.3,
43.5, 29.1, 21.2, 20.0; HRMS (ESI): Calculated for C11H16N+ [M+H]+: 162.1277, Observed:
162.1285.
2-(2-Methoxyphenyl)piperidine (3f) ꢀ Prepared as per general procedure 2, using in step 1 (8 h
reaction time): 2ꢀ(2ꢀ(2ꢀmethoxyphenyl)piperidinꢀ1ꢀyl)pyridine (1f, 134 mg, 0.5 mmol), Pt/C (5%
Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6
mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol, 4.0 eq.). The crude
product was purified by reversed phase flash chromatography on C18 silica, eluting with a
H2O/CH3CN gradient (from 100% H2O up to H2O/CH3CN ꢀ 2/8), to obtain 3f as a pale yellow
oil in 42% (41 mg) yield. Alternatively prepared as per general procedure 3, using in step 1: 2ꢀ
(2ꢀ(2ꢀmethoxyphenyl)piperidinꢀ1ꢀyl)pyridine (1f, 134 mg, 0.5 mmol), CH3CN (1 mL) and
methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and
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NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by reversed phase flash
chromatography on C18 silica, eluting with a H2O/CH3CN gradient (from 100% H2O up to
1
H2O/CH3CN ꢀ 4/6), to obtain 3f as a pale yellow oil in 24% (23 mg) yield. H NMR (400 MHz,
d6ꢀDMSO) δ 7.42 (dd, J = 7.7, 1.5 Hz, 1H), 7.17 (td, J = 7.7, 1.5 Hz, 1H), 6.93 (d, J = 7.7 Hz,
1H), 6.90 (td, J = 7.7, 1.5 Hz, 1H), 3.84 (br d, J = 10.6 Hz, 1H), 3.77 (s, 3H), 3.04 (br d, J = 11.0
Hz, 1H), 2.67ꢀ2.58 (m, 1H), 2.10 (br s, 1H), 1.78ꢀ1.68 (m, 2H), 1.56ꢀ1.49 (m, 1H), 1.47ꢀ1.31 (m,
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2H), 1.23ꢀ1.11 (m, 1H); C NMR (100 MHz, d6ꢀDMSO) δ 155.9, 133.8, 127.3, 126.4, 120.3,
110.5, 55.3, 54.3, 47.3, 33.5, 25.8, 25.3; HRMS (ESI): Calculated for C12H18NO+ [M+H]+:
192.1383, Observed: 192.1393.
2-Phenyl-1,2,3,4-tetrahydroquinoline (3g) ꢀ Prepared as per general procedure 2, using in step
1 (14 h reaction time): 2ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1,2,3,4ꢀtetrahydroquinoline (1g, 143 mg, 0.5
mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH
(0.5 mL, 0.6 mmol, 1.2 eq.). There was no need to perform a subsequent reduction step, since
complete conversion to the desired product 3g occurred in step 1. After purification of the crude
product by straight phase flash chromatography on HP silica, eluting with 100% CH2Cl2, 3g was
obtained as a pale yellow oil in 72% (75 mg) yield. Alternatively prepared as per general
procedure 3, using in step 1: 2ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)ꢀ1,2,3,4ꢀtetrahydroquinoline (1g, 143 mg,
0.5 mmol), CH3CN (1 mL) and methyl trifluoromethanesulfonate (136 ꢂL, 1.2 mmol, 2.4 eq.),
and in step 2: MeOH (5 mL) and NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was
purified by straight phase flash chromatography on HP silica, eluting with 100% CH2Cl2, to
obtain 3g as a pale yellow oil in 87% (91 mg) yield. 1H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.29 (m,
4H), 7.28ꢀ7.22 (m, 1H), 7.01ꢀ6.95 (m, 2H), 6.63 (td, J = 7.4, 1.1 Hz, 1H), 6.48 (d, J = 7.4 Hz,
1H), 4.38 (dd, J = 9.1, 3.3 Hz, 1H), 3.96 (br s, 1H), 2.88 (ddd, J = 16.5, 10.6, 5.5 Hz, 1H), 2.69
(td, J = 16.5, 4.8 Hz, 1H), 2.12ꢀ2.04 (m, 1H), 2.00ꢀ1.90 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
143.8, 143.7, 128.2, 127.5, 126.4, 125.8, 125.5, 119.8, 116.1, 112.9, 55.2, 29.9, 25.3; HRMS
(ESI): Calculated for C15H16N+ [M+H]+: 210.1277, Observed: 210.1280.
Trans-2-methyl-6-phenylpiperidine•HCl (3h•HCl) ꢀ Prepared as per general procedure 2,
using in step 1 (8 h reaction time): 2ꢀ(transꢀ2ꢀmethylꢀ6ꢀphenylpiperidinꢀ1ꢀyl)pyridine (transꢀ1h,
126 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25
M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (132 mg, 3.5
mmol, 7.0 eq.). The crude product was purified by reversed phase flash chromatography on C18
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silica, eluting with a H2O/CH3CN gradient (from 100% H2O up to H2O/CH3CN ꢀ 3/7). The
fractions containing the desired product 3h were combined and 0.5 mL of HCl 1.25 M in EtOH
was added. After 1 min stirring, volatiles were removed in vacuo. To the remaining colorless oil,
Et2O (10 mL) was added and crystallization of the resulting emulsion was induced upon stirring.
Subsequently, volatiles were removed under reduced pressure to obtain 3h•HCl as a white solid
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(m.p. = 256 °C) in 55% (58 mg) yield. H NMR (400 MHz, d6ꢀDMSO) δ 9.86 (br s, 1H), 9.10
(br s, 1H), 7.65 (dd, J = 8.4, 1.8 Hz, 2H), 7.46ꢀ7.36 (m, 3H), 4.45ꢀ4.38 (m, 1H), 3.66 (br s, 1H),
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2.13ꢀ2.04 (m, 1H), 1.90ꢀ1.75 (m, 3H), 1.70ꢀ1.54 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H); C NMR
(100 MHz, d6ꢀDMSO) δ 136.5, 127.3, 127.2, 126.3, 51.8, 47.4, 29.3, 25.0, 16.1, 13.0; HRMS
(ESI): Calculated for C12H18N+ [M+H]+: 176.1434, Observed: 176.1432.
Trans-2,6-diphenylpiperidine (3i) ꢀ Prepared as per general procedure 2, using in step 1 (10 h
reaction time): 2ꢀ(transꢀ2,6ꢀdiphenylpiperidinꢀ1ꢀyl)pyridine (transꢀ1i, 157 mg, 0.5 mmol), Pt/C
(5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6
mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (151 mg, 4.0 mmol, 8.0 eq.). The crude
product was purified by straight phase flash chromatography on HP silica, eluting with a
CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to CH2Cl2/(NH3 7 N in MeOH) ꢀ
95/5), to obtain 3i as a pale yellow oil in 14% (17 mg) yield. 1H NMR (400 MHz, CDCl3) δ 7.43
(br d, J = 7.3 Hz, 4H), 7.36 (t, J = 7.3 Hz, 4H), 7.25 (tt, J = 7.3, 1.5 Hz, 2H), 4.12 (dd, J = 6.6,
4.4 Hz, 2H), 2.05ꢀ1.89 (m, 4H), 1.87 (br s, 1H), 1.74ꢀ1.67 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 144.3, 128.5, 126.8, 126.6, 54.8, 31.5, 20.8; HRMS (ESI): Calculated for C17H20N+ [M+H]+:
238.1590, Observed: 238.1593.
Trans-2-phenyl-5-(trifluoromethyl)piperidine•HCl (3j•HCl) ꢀ Prepared as per general
procedure 2, using in step 1 (24 h reaction time): 2ꢀ(transꢀ2ꢀphenylꢀ5ꢀ(trifluoromethyl)piperidinꢀ
1ꢀyl)pyridine (transꢀ1j, 153 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH
(4.5 mL) and HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.). There was no need to perform a
subsequent reduction step, since complete conversion to the desired product 3j occurred in step
1. After purification of the crude product by reversed phase flash chromatography on C18 silica,
eluting with a H2O/CH3CN gradient (from 100% H2O up to H2O/CH3CN ꢀ 4/6), the fractions
containing the desired product were combined and 0.5 mL of HCl 1.25 M in EtOH was added.
After 1 min stirring, volatiles were removed in vacuo to obtain 3j•HCl as a white solid (m.p. =
229 °C) in 81% (108 mg) yield. Alternatively prepared as per general procedure 3, using in step
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CH3CN (1 mL) and methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2:
MeOH (5 mL) and NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by
reversed phase flash chromatography on C18 silica, eluting with a H2O/CH3CN gradient (from
100% H2O up to H2O/CH3CN ꢀ 4/6). The fractions containing the desired product 3j were
combined and 0.5 mL of HCl 1.25 M in EtOH was added. After 1 min stirring, volatiles were
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removed in vacuo to obtain 3j•HCl as a white solid (m.p. = 229 °C) in 61% (81 mg) yield. H
NMR (400 MHz, d6ꢀDMSO) δ 10.24 (br s, 1H), 9.75 (br s, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 2H),
7.49ꢀ7.39 (m, 3H), 4.36 (br s, 1H), 3.47 (app d, J = 8.4 Hz, 1H), 3.26ꢀ35 (m, 2H), 2.13ꢀ2.03 (m,
13
3H), 1.82ꢀ1.71 (m, 1H); C NMR (100 MHz, d6ꢀDMSO) δ 137.1, 128.9, 128.8, 127.5, 126.3 (q,
J = 279.6 Hz), 58.8, 42.3 (q, J = 3.6 Hz), 36.4 (q, J = 29.7 Hz), 28.4, 21.8 (q, J = 1.8 Hz); HRMS
(ESI): Calculated for C12H15F3N+ [M+H]+: 230.1151, Observed: 230.1147.
Cis-methyl 2-phenylpiperidine-4-carboxylate (3k) ꢀ Prepared as per general procedure 2, using
in step 1 (10 h reaction time): cisꢀmethyl 2ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)piperidinꢀ4ꢀcarboxylate (cisꢀ
1k, 148 mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl
1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (76 mg,
2.0 mmol, 4.0 eq.). The crude product was purified by straight phase flash chromatography on
HP silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to
CH2Cl2/(NH3 7 N in MeOH) ꢀ 9/1), to obtain 3k as a pale yellow oil in 28% (30 mg) yield.
Alternatively prepared as per general procedure 3, using in step 1: cisꢀmethyl 2ꢀphenylꢀ1ꢀ
(pyridinꢀ2ꢀyl)piperidinꢀ4ꢀcarboxylate (cisꢀ1k, 148 mg, 0.5 mmol), CH3CN (1 mL) and methyl
trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4
(95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by reversed phase flash
chromatography on C18 silica, eluting with a H2O/CH3CN gradient (from 100% H2O up to
1
100% CH3CN), to obtain 3k as a colorless oil in 60% (66 mg) yield. H NMR (400 MHz, d6ꢀ
DMSO) δ 7.36 (dd, J = 7.0, 1.5 Hz, 2H), 7.30 (t, J = 7.0 Hz, 2H), 7.23 (tt, J = 7.0, 1.5 Hz, 1H),
3.58 (s, 3H), 3.56 (dd, J = 11.3, 2.2 Hz, 1H), 3.09 (ddd, J = 11.7, 4.1, 2.6 Hz, 1H), 2.66 (td, J =
12.1, 2.6 Hz, 1H), 2.56 (tt, J = 12.1, 3.7 Hz, 1H), 1.93ꢀ1.87 (m, 1H), 1.84ꢀ1.77 (m, 1H), 1.46 (qd,
J = 12.6, 4.1 Hz, 1H), 1.35 (q, J = 12.1 Hz, 1H); 13C NMR (100 MHz, d6ꢀDMSO) δ 174.8, 145.2,
+
128.1, 126.8, 126.5, 59.9, 51.4, 45.7, 41.6, 37.3, 28.2; HRMS (ESI): Calculated for C13H18NO2
[M+H]+: 220.1332, Observed: 220.1329.
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1-Methyl-2-(piperidin-2-yl)-1H-indole (3l) ꢀ Prepared as per general procedure 2, using in step
1 (8 h reaction time): 1ꢀmethylꢀ2ꢀ(1ꢀ(pyridinꢀ2ꢀyl)piperidinꢀ2ꢀyl)ꢀ1Hꢀindole (1l, 146 mg, 0.5
mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in EtOH
(0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (76 mg, 2.0 mmol, 4.0
eq.). The crude product was purified by reversed phase flash chromatography on C18 silica,
eluting with a H2O/CH3CN gradient (from 100% H2O up to H2O/CH3CN ꢀ 2/8), to obtain 3l as
an offꢀwhite solid (m.p. = 69 °C) in 19% (20 mg) yield. Alternatively prepared as per general
procedure 3, using in step 1: 1ꢀmethylꢀ2ꢀ(1ꢀ(pyridinꢀ2ꢀyl)piperidinꢀ2ꢀyl)ꢀ1Hꢀindole (1l, 146 mg,
0.5 mmol), CH3CN (1 mL) and methyl trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.),
and in step 2: MeOH (5 mL) and NaBH4 (95 mg, 2.5 mmol, 5.0 eq.). The crude product was
purified by reversed phase flash chromatography on C18 silica, eluting with a H2O/CH3CN
gradient (from 100% H2O up to H2O/CH3CN ꢀ 2/8), to obtain 3l as a white solid (m.p. = 69 °C)
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in 70% (75 mg) yield. H NMR (400 MHz, d6ꢀDMSO) δ 7.48 (d, J = 7.7 Hz, 1H), 7.40 (d, J =
7.7 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.33 (s, 1H), 3.84ꢀ3.74 (m, 4H),
3.05 (br d, J = 12.1 Hz, 1H), 2.70 (br t, J = 11.5 Hz, 1H), 2.07 (br s, 1H), 1.94ꢀ1.86 (m, 2H),
13
1.65ꢀ1.39 (m, 4H); C NMR (100 MHz, d6ꢀDMSO) δ 142.8, 135.8, 125.7, 119.2, 118.4, 117.5,
107.9, 96.2, 52.0, 45.5, 30.7, 28.4, 24.8, 23.5; HRMS (ESI): Calculated for C14H19N2 [M+H]+:
+
215.1543, Observed: 215.1544.
7-Hexyl-1,4-dioxa-8-azaspiro[4.5]decane (3m) ꢀ Prepared as per general procedure 2, using in
step 1 (16 h reaction time): 7ꢀhexylꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀazaspiro[4.5]decane (3m, 152
mg, 0.5 mmol), Pt/C (5% Pt ꢀ 195 mg, 0.05 mmol, 10 mol%), EtOH (4.5 mL) and HCl 1.25 M in
EtOH (0.5 mL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4 (113 mg, 3.0 mmol,
6.0 eq.). The crude product was purified by straight phase flash chromatography on HP silica,
eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to CH2Cl2/(NH3 7 N
in MeOH) ꢀ 9/1), to obtain 3m as a pale yellow oil in 70% (80 mg) yield. Alternatively prepared
as per general procedure 3, using in step 1: 7ꢀhexylꢀ8ꢀ(pyridinꢀ2ꢀyl)ꢀ1,4ꢀdioxaꢀ8ꢀ
azaspiro[4.5]decane (3m, 152 mg, 0.5 mmol), CH3CN (1 mL) and methyl
trifluoromethanesulfonate (68 ꢂL, 0.6 mmol, 1.2 eq.), and in step 2: MeOH (5 mL) and NaBH4
(95 mg, 2.5 mmol, 5.0 eq.). The crude product was purified by straight phase flash
chromatography on HP silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100%
CH2Cl2 up to CH2Cl2/(NH3 7 N in MeOH) ꢀ 9/1), to obtain 3m as a pale yellow oil in 76% (86
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mg) yield. H NMR (400 MHz, CDCl3) δ 3.98ꢀ3.93 (m, 4H), 3.07 (ddd, J = 12.3, 4.8, 2.2 Hz,
1H), 2.83 (td, J = 12.4, 3.3 Hz, 1H), 2.74ꢀ2.68 (m, 1H), 1.76ꢀ1.59 (m, 3H), 1.38ꢀ1.24 (m, 12H),
0.87 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 108.0, 64.3, 64.1, 54.6, 44.0, 42.3, 37.0,
35.8, 31.8, 29.4, 25.8, 22.6, 14.1; HRMS (ESI): Calculated for C13H26NO2 [M+H]+: 228.1958,
+
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Observed: 228.1957.
2-(2-Methyl-6-undecylpiperidin-1-yl)pyridine (8) ꢀ An 80 mL stainless steel autoclave was
charged with 2ꢀ(2ꢀmethylpiperidinꢀ1ꢀyl)pyridine 7 (881 mg, 5 mmol), [Ru3(CO)12] (320 mg, 0.5
mmol, 10 mol%), 3,4,5ꢀtrifluorobenzoic acid (88 mg, 0.5 mmol, 10 mol%), 2,4ꢀdimethylꢀ3ꢀ
pentanol (3.5 mL, 25 mmol, 5 eq.) and 1ꢀundecene (10.3 mL, 50 mmol, 10 eq.). The reactor was
purged with N2, sealed tight, and heated at 140 °C for 48 h. After this time, the content was
transferred to a roundꢀbottom flask and evaporated to dryness. The crude product was purified by
straight phase flash chromatography on silica gel, eluting with a heptane/EtOAc gradient (from
heptane/EtOAc ꢀ 99/1 to heptane/EtOAc ꢀ 9/1), to obtain the diastereomeric mixture 8 (trans/cis
3:5) as a pale yellow oil in 75% (1.24 g) yield. Pure transꢀ and cisꢀenantiomers (transꢀ8a, transꢀ
8b and cisꢀ8a, cisꢀ8b) were obtained by separating the diastereomeric mixture 8 via prep SFC (1.
eluting with CO2, iꢀPrOH with 0.2% iꢀPrNH2, giving transꢀ8b, cisꢀ8a and a mixture of transꢀ8a
and cisꢀ8b; 2. eluting with iꢀPrOH with 0.4% iꢀPrNH2, giving transꢀ8a and impure cisꢀ8b; 3.
1
eluting with CO2, EtOH with 0.4% iꢀPrNH2, giving cisꢀ8b). Transꢀ8a and transꢀ8b: H NMR
(400 MHz, CDCl3) δ 8.20 (ddd, J = 5.1, 2.0, 0.7 Hz, 1H), 7.42 (ddd, J = 8.7, 7.0, 2.0 Hz, 1H),
6.54 (ddd, J = 7.0, 5.1, 0.8 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 4.16ꢀ4.08 (m, 1H), 3.85ꢀ3.79 (m,
1H), 2.04ꢀ1.89 (m, 2H), 1.85ꢀ1.78 (m, 1H), 1.75ꢀ1.60 (m, 3H), 1.58ꢀ1.43 (m, 2H), 1.26 (br s,
13
18H), 1.21 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 158.9,
148.0, 136.6, 112.0, 109.3, 53.1, 47.0, 31.9, 31.8, 29.7, 29.7, 29.6, 29.6, 29.6, 29.3, 28.6, 27.0,
24.2, 22.7, 19.6, 14.5, 14.1; HRMS (ESI): Calculated for C22H39N2 [M+H]+: 331.3108,
+
1
Observed: 331.3119. Cisꢀ8a and cisꢀ8b: H NMR (400 MHz, CDCl3) δ 8.17 (ddd, J = 4.8, 2.2,
0.9 Hz, 1H), 7.40 (ddd, J = 8.7, 7.0, 2.2 Hz, 1H), 6.51ꢀ6.46 (m, 2H), 4.63ꢀ4.55 (m, 1H), 4.21 (br
s, 1H), 1.84ꢀ1.68 (m, 3H), 1.67ꢀ1.55 (m, 3H), 1.53ꢀ1.39 (m, 2H), 1.26 (br s, 18H), 1.17 (d, J =
6.8 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 148.1, 137.1, 111.2,
106.4, 50.5, 45.3, 33.2, 32.0, 31.0, 29.9, 29.7 (four overlapping signals), 29.4, 28.0, 27.3, 22.7,
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+
18.9, 14.8, 14.1; HRMS (ESI): Calculated for C22H39N2 [M+H]+: 331.3108, Observed:
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331.3119.
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2(S)-Methyl-6(S)-undecylpiperidine, (2S,6S)-solenopsin A (trans-9a) ꢀ Step 1: A 50 mL
hydrogenation tube was charged with transꢀ8a (63 mg, 0.19 mmol) and Pt/C (5% Ptꢀbasis ꢀ 74.5
mg, 0.019 mmol, 10 mol%). Under N2, EtOH (4.8 mL) was added. To the resulting black
suspension, HCl 1.25 M in EtOH (0.2 mL, 0.23 mmol, 1.2 eq.) was added and the reaction
mixture was subsequently flushed twice with H2. The reaction mixture was then stirred under H2
at r.t. for 24 h. After this time, the solids were removed by filtration through a syringe filter unit
(PTFE membrane) using CH2Cl2 (30 mL) as solvent, and the filtrate was evaporated to dryness.
Step 2: The residue of step 1 was dissolved in MeOH (5 mL) and the resulting solution was
cooled to 0 °C using an ice/waterꢀbath. NaBH4 (58 mg, 1.5 mmol, 8.0 eq.) was added
portionwise (ca. 10 mg each portion) to the cooled solution under magnetic stirring, avoiding
intense evolution of H2 and keeping the temperature constant at 0 °C. After complete addition of
NaBH4, the reaction mixture was stirred further at 0 °C for 15 min. After this time, the volatiles
were removed in vacuo. The residue was purified by straight phase flash chromatography on HP
silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to
CH2Cl2/(NH3 7 N in MeOH) ꢀ 9/1). The resulting pale yellow solid was treated with 1% aq.
NaOH (3 mL) to remove any residual salts formed during purification. Subsequent extractive
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workꢀup (3 x 3 mL CH2Cl2) yielded the free base as a pale yellow oil in 35% (17 mg) yield. H
NMR (400 MHz, CDCl3) δ 3.11ꢀ3.03 (m, 1H), 2.91ꢀ2.85 (m, 1H), 1.68ꢀ1.37 (m, 6H), 1.26 (br s,
13
20H), 1.07 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 50.9,
45.9, 34.0, 32.9, 31.9, 30.7, 29.8, 29.7, 29.7, 29.6 (two overlapping signals), 29.4, 26.5, 22.7,
21.2, 19.6, 14.1; HRMS (ESI): Calculated for C17H36N+ [M+H]+: 254.2842, Observed: 254.2846.
2(R)-Methyl-6(R)-undecylpiperidine, (2R,6R)-solenopsin A (trans-9b) ꢀ Step 1: A 50 mL
hydrogenation tube was charged with transꢀ8b (70 mg, 0.21 mmol) and Pt/C (5% Ptꢀbasis ꢀ 83
mg, 0.021 mmol, 10 mol%). Under N2, EtOH (4.8 mL) was added. To the resulting black
suspension, HCl 1.25 M in EtOH (0.2 mL, 0.25 mmol, 1.2 eq.) was added and the reaction
mixture was subsequently flushed twice with H2. The reaction mixture was then stirred under H2
at r.t. for 20 h. After this time, the solids were removed by filtration through a syringe filter unit
(PTFE membrane) using CH2Cl2 (30 mL) as solvent, and the filtrate was evaporated to dryness.
Step 2: The residue of step 1 was dissolved in MeOH (5 mL) and the resulting solution was
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cooled to 0 °C using an ice/waterꢀbath. NaBH4 (64 mg, 1.7 mmol, 8.0 eq.) was added
portionwise (ca. 10 mg each portion) to the cooled solution under magnetic stirring, avoiding
intense evolution of H2 and keeping the temperature constant at 0 °C. After complete addition of
NaBH4, the reaction mixture was stirred further at 0 °C for 15 min. After this time, the volatiles
were removed in vacuo. The residue was purified by straight phase flash chromatography on HP
silica, eluting with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to
CH2Cl2/(NH3 7 N in MeOH) ꢀ 9/1). The resulting pale yellow solid was treated with 1% aq.
NaOH (3 mL) to remove any residual salts formed during purification. Subsequent extractive
workꢀup (3 x 3 mL CH2Cl2) yielded the free base as a pale yellow oil in 36% (19 mg) yield. The
spectral data of transꢀ9b were in accordance with those reported above for transꢀ9a.
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2(S)-Methyl-6(R)-undecylpiperidine, (2S,6R)-isosolenopsin A (cis-9a) ꢀ Step 1: A 50 mL
hydrogenation tube was charged with cisꢀ8a (165 mg, 0.5 mmol) and Pt/C (5% Ptꢀbasis ꢀ 195
mg, 0.05 mmol, 10 mol%). Under N2, EtOH (4.5 mL) was added. To the resulting black
suspension, HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.) was added and the reaction
mixture was subsequently flushed twice with H2. The reaction mixture was then stirred under H2
at r.t. for 32 h. After this time, the solids were removed by filtration through dicalite, the pad was
washed with CH2Cl2 (5 x 20 mL), and the combined filtrate was evaporated to dryness. Step 2:
The residue of step 1 was dissolved in MeOH (5 mL) and the resulting solution was cooled to 0
°C using an ice/waterꢀbath. NaBH4 (227 mg, 6 mmol, 12.0 eq.) was added portionwise (ca. 10
mg each portion) to the cooled solution under magnetic stirring, avoiding intense evolution of H2
and keeping the temperature constant at 0 °C. After complete addition of NaBH4, the reaction
mixture was stirred further at 0 °C for 15 min. After this time, the volatiles were removed in
vacuo. The residue was purified by straight phase flash chromatography on HP silica, eluting
with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to CH2Cl2/(NH3 7 N in
MeOH) ꢀ 9/1). The resulting pale yellow solid was treated with 1% aq. NaOH (10 mL) to remove
any residual salts formed during purification. Subsequent extractive workꢀup (3 x 10 mL
1
CH2Cl2) yielded the free base as a pale yellow oil in 56% (72 mg) yield. H NMR (400 MHz,
CDCl3) δ 2.66ꢀ2.58 (m, 1H), 2.51ꢀ2.44 (m, 1H), 1.80ꢀ1.72 (m, 1H), 1.66ꢀ1.55 (m, 2H), 1.38ꢀ1.22
13
(m, 21H), 1.06 (d, J = 6.3 Hz, 3H), 1.08ꢀ0.92 (m, 2H), 0.88 (t, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3) δ 57.2, 52.5, 37.5, 34.5, 32.3, 31.9, 29.9, 29.7, 29.6, 29.6 (two overlapping
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signals), 29.4, 26.0, 24.9, 23.1, 22.7, 14.1; HRMS (ESI): Calculated for C17H36N+ [M+H]+:
254.2842, Observed: 254.2846.
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2(R)-Methyl-6(S)-undecylpiperidine, (2R,6S)-isosolenopsin A (cis-9b) ꢀ Step 1: A 50 mL
hydrogenation tube was charged with cisꢀ8b (165 mg, 0.5 mmol) and Pt/C (5% Ptꢀbasis ꢀ 195
mg, 0.05 mmol, 10 mol%). Under N2, EtOH (4.5 mL) was added. To the resulting black
suspension, HCl 1.25 M in EtOH (0.5 mL, 0.6 mmol, 1.2 eq.) was added and the reaction
mixture was subsequently flushed twice with H2. The reaction mixture was then stirred under H2
at r.t. for 24 h. After this time, the solids were removed by filtration through dicalite, the pad was
washed with CH2Cl2 (5 x 20 mL), and the combined filtrate was evaporated to dryness. Step 2:
The residue of step 1 was dissolved in MeOH (5 mL) and the resulting solution was cooled to 0
°C using an ice/waterꢀbath. NaBH4 (227 mg, 6 mmol, 12.0 eq.) was added portionwise (ca. 10
mg each portion) to the cooled solution under magnetic stirring, avoiding intense evolution of H2
and keeping the temperature constant at 0 °C. After complete addition of NaBH4, the reaction
mixture was stirred further at 0 °C for 15 min. After this time, the volatiles were removed in
vacuo. The residue was purified by straight phase flash chromatography on HP silica, eluting
with a CH2Cl2/(NH3 7 N in MeOH) gradient (from 100% CH2Cl2 up to CH2Cl2/(NH3 7 N in
MeOH) ꢀ 9/1). The resulting pale yellow solid was treated with 1% aq. NaOH (10 mL) to remove
any residual salts formed during purification. Subsequent extractive workꢀup (3 x 10 mL
CH2Cl2) yielded the free base as a pale yellow oil in 62% (78 mg) yield. The spectral data of cisꢀ
9b were in accordance with those reported above for cisꢀ9a.
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Acknowledgments
This work was financially supported by the University of Antwerp (BOF, IOF), the Fund for
Scientific Research ꢀ Flanders (FWO), the Hercules Foundation and Janssen Research &
Development, a division of Janssen Pharmaceutica N.V. The authors would like to thank
François Sommen, Gaston Diels, Thomas Storr and Carl Mensch for their contribution. We also
thank Dr. Sergey Sergeyev for valuable discussions and Prof. Matthias Zeller of Youngstown
State University for the collection of Xꢀray datasets. The diffractometer was funded by NSF
grant 0087210, Ohio Board of Regents grant CAPꢀ491, and YSU.
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