Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Article abstract of DOI:10.1002/ejoc.201900450

An efficient approach towards introducing (cyclo)alkyl substituents at C-2, C-3 or C-4 positions of the piperidine ring was described. The method relied on the straightforward two-step reaction sequence based on the formal sp³–sp³ re

Full text of DOI:10.1002/ejoc.201900450

A Journal of
Accepted Article
Title: Scalable and Straightforward Synthesis of All Isomeric
(Cyclo)alkylpiperidines
Authors: Andrii I. Subota, Anton O. Lutsenko, Bohdan V. Vashchenko,
Dmitriy M. Volochnyuk, Vitalina Levchenko, Yurii V. Dmytriv,
Eduard B. Rusanov, Alina O. Gorlova, Sergey V. Ryabukhin,
and Oleksandr O Grygorenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900450
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900450
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
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Scalable and Straightforward Synthesis of All Isomeric
(Cyclo)alkylpiperidines
Andrii I. Subota,[a,b] Anton O. Lutsenko,[a,c] Bohdan V. Vashchenko,[a,c] Prof.
Dr. Dmitriy M. Volochnyuk,*[b,c] Vitalina Levchenko,[a] Dr. Yurii V. Dmytriv,[a,d] Dr. Eduard B. Rusanov,[b]
Dr. Alina O. Gorlova,[a,b] Dr. Sergey V. Ryabukhin,[c] and Dr. Oleksandr O. Grygorenko*[a,c]
Dedication ((optional))
Abstract: An efficient approach towards introducing (cyclo)alkyl
substituents at C-2, C-3 or C-4 positions of the piperidine ring was
described. The method relied on the straightforward two-step
reaction sequence based on the formal sp3–sp3 retrosynthetic
disconnection. The procedure commenced with selective directed
ortho metalation of 2- and 3-bromopyridine, followed by reaction with
aldehydes or ketones. The optimized methods were developed for
all three isomers of hydroxyalkyl-substituted pyridines, which were
synthesized in 28-84% overall yield (20 examples). Catalytic
hydrogenation of these adducts could be performed selectively with
or without retention of the hydroxyl group in their molecules, so that
either (cyclo)alkylpiperidines (14 examples) or the corresponding
saturated amino alcohols (16 examples) were obtained (28-96% and
82–96% yield, respectively). After minor modifications, the
developed method was also implemented in a flow reactor and a 5 L
autoclave, which allowed for the preparation of up to 0.5 kg of the
representative (cyclo)alkylpiperidines.
surprising therefore, that reliable and robust synthetic
approaches to sp3-enriched conformationally restricted building
blocks are of high demand. Retrosynthetic disconnection of such
building blocks often requires synthetic methods which allow for
the formation of the C–C bonds between two sp3-hybridized
carbon centers. Although such methods are available, they are
much less explored as compared to the corresponding sp2–sp2
or sp2–sp3 C–C couplings.[4–6]
A
promising retrosynthetic idea to introduce (cyclo)-alkyl
substituents into a (hetero)aliphatic core might rely on using the
power of reactions leading to the formation of bonds between
the sp2- and sp3-hybridized carbon atoms.
A prominent
illustration of this idea is given by the case of piperidine
derivatives, where the problem can be reduced to modification of
the pyridine ring with its subsequent hydrogenation (Scheme
1).[7] It should be noted that piperidine is the top nitrogen
heterocyclic ring in drug discovery;[8,9] it is found in a total of 76
unique small-molecule FDA-approved pharmaceuticals. Also,
this core is one of prevalent structural motifs in nature
compounds.[10–12]
Introduction
Recently, the concept of lead-oriented synthesis was proposed
as an opportunity for chemical design to generate compounds
suitable for modern drug discovery in an efficient manner.[1] This
strategy commenced from criteria desirable for high-quality lead
compounds, in particular, increased fraction of sp3 carbon
atoms,[2] as well as limited conformational flexibility.[3] It is not
[a]
[b]
[c]
Andrii I. Subota, Anton O. Lutsenko, Bohdan V. Vashchenko,
Vitalina Levchenko, Dr. Yurii V. Dmytriv, Dr. Alina O. Gorlova, Dr.
Oleksandr O. Grygorenko
Scheme 1. Retrosynthetic disconnection of (cyclo)alkyl-substituted piperidine
derivatives
Enamine Ltd. (www.enamine.net)
Chervonotkatska Street 78, Kyiv 02094, Ukraine
Andrii I. Subota, Prof. Dr. Dmitriy M. Volochnyuk,
Dr. Eduard B. Rusanov, Dr. Alina O. Gorlova,
Institute of Organic Chemistry, National Academy of Sciences of
Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
E-mail: d.volochnyuk@gmail.com (D.M.V.)
Anton O. Lutsenko, Bohdan V. Vashchenko, Prof.
Dr. Dmitriy M. Volochnyuk, Dr. Sergey V. Ryabukhin,
Dr. Oleksandr O. Grygorenko
Piperidine derivatives bearing a single (cyclo)alkyl substituent
became a topic of significant interest as the structural units of
compounds relevant to drug discovery (Figure 1, Table 1). In
particular, the C-2-substituted piperidines or their derivatives
are represented by alkaloids (+)-coniine (1) and perhexiline (2),
as well as marketed drugs piperocaine (3) and cyclomethycaine
(4). Derivatives of other regioisomers can also be found among
marketed pharmaceuticals, e.g. ifenprodil (5) and melperone (6),
as well as compounds that have reached various drug
development phases (e.g. 7–13).
Taras Shevchenko National University of Kyiv
Volodymyrska Street 64, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua (O.O.G.)
[d]
Dr. Yurii V. Dmytriv
Department of Chemical Technology, National Technical University
of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Peremohy Ave.
37, Kyiv 03056, Ukraine
Despite their extensive use in drug discovery, synthetic
accessibility of (cyclo)alkylpiperidines have remained far from
being satisfactory. Although there are many methods which rely
on the modification of a preexisting piperidine ring,[7] we have
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900450
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Figure 1. Some biologically active (cyclo)alkylpiperidines.
Table 1. Total number of (cyclo)alkylpiperidine-derived compounds in various
drug development phases (according to the Reaxys® database, accessed in
March 2019)
Development phase
2-Isomers
3-Isomers
4-Isomers
Marketed
Phase III
Phase II
Phase I
23
2
2
27
4
0
2
2
4
1
1
9
Preclinical
16
18
96
considered retrosynthetic approach shown in Scheme 1 as more
promising synthetic strategy. Indeed, numerous efforts were put
into the development of protocols for hydrogenation of the pyridi-
ne ring in the last decade.[7] Some of them relied on the use of
homogeneous Rh-[13] or Ir-based,[14,15] and metal-free[16–18] cata-
lytic systems; nevertheless, heterogeneous catalysts like Pd-C,
PtO2, Pd(OH)2-C, Rh, or RuO2 often remained more preferable.
Most papers describing synthesis of (cyclo)alkylpiperidines
according to the discussed strategy either relied on readily
available alkyl-pyridines or did not focus on the preparation
thereof.[19–35] Recent works which implied the strategy shown in
Scheme 1 used the Sonogashira cross-coupling,[36,37] Negishi[26]
or Kumada[27] reactions with benzyl organometallics, aldol-type
condensations,[27,38] or reactions of lithiated pyridines with
aromatic aldehydes,[39] carboxylic acids or their derivatives[40,41]
to introduce the substituent at the pyridine ring prior the
hydrogenation (Scheme 2). Therefore, these methods were
limited in the substrate scope.
Scheme 2. Recent syntheses of piperidines according to the strategy shown
in Scheme 1
We have turned our attention to the latter approach[39,40] since it
might be beneficial for the preparation of all regioisomeric
(cyclo)alkylpiperidines provided that the scope of the carbonyl
compounds involved could be extended to other aldehydes and
ketones – readily available starting materials. Taking into
account our preliminary results described in
a previous
communication,[42] as well as the literature data,[42–44] we have
envisaged that the required chemo- and regioselectivity could be
achieved via directed ortho metalation (DOM) of 2- or 3-
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10.1002/ejoc.201900450
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bromopyridines (Scheme 3).[45–48] The bromine atom might serve
as the directed metalation group, which could be easily removed
under reductive conditions. Other modifications necessary for
the preparation of the title compounds included pyridine ring
hydrogenation and deoxygenation; all the aforementioned
transformations could be achieved under reductive reaction
conditions.
smoothly and provided the corresponding pyridine 17c in 63%
yield. Nevertheless, the hydroxyl group was retained upon
hydrogenation under the standard hydrogenation conditions in
the presence of either HCl or Et3N, so that only the
corresponding aminoalcohol 19c could be obtained (61% yield).
Scheme 3. The synthetic approach studied in this work.
Scheme 5. Preparation of aminoalcohols 19
Results and Discussion
Table 2. Directed ortho metallation of 3-bromopyridine (20) at the C-4 atom
As it was described in our previous communication, directed
ortho metalation of 2-bromopyridine (14) using LDA in THF at
–78 °C followed by addition of pre-cooled solution of aldehyde or
ketone 16 (two-fold excess in THF) in one portion at –78 °C led
to the corresponding pyridinyl alkanols 17 in good yield (41–
67%) (Scheme 4).[42] Removal of the directed metalation group,
dehydroxylation at the benzylic position, and reduction of the
pyridine ring were achieved in a single step starting from 17
upon hydrogenation under 40 bar of H2 in the presence of ca. 30
mol% of concentrated aq HCl. This protocol gave the title
compounds 18 after treatment with aq NaOH (45-90% yield).
#
1
2
3
4
5
6
7
8
Metallating agent
LDA
Temperature, °C
Time, min
Yield, %
13
–90
–78
>–75
–78
–78
–78
–85
–95
30
LDA
5
34
LDA
ca. 2
5
0[a]
LDA - TMEDA
LDA - TMEDA
LiTMP[b]
LiTMP
45
10
14[a]
0[a]
ca. 5
25
90
LiTMP
40
72
[a] Significant tar formation was observed [b] TMP - 2,2,6,6-tetramethylpiperidide
Next, we have aimed at the DOM of 3-bromopyridine (20) at the
C-4 position for the preparation of 4-substituted piperidines.[45–47]
First of all, we have tested reaction of 20 with LDA (Table 2,
Entries 1-3); LDA - TMEDA (Entries 4 and 5), and LiTMP
(Entries 6-8); D2O was used as an electrophile to quench the
corresponding organolithium intermediate 21. It was found that
21 was stable below –85 °C (Table 2, Entries 1, 8 and 9); at
higher temperatures, significant tar formation was observed
(Entries 3, 5 and 6). A possible explanation of this result might
include formation of dehydropyridine intermediate followed by its
polymerization; no specific side products could be detected in
Scheme 4. Synthesis of 3-(cyclo)alkylpiperidines 18[42]
Moreover, a possibility to retain the hydroxyl group in the
substrates 17a–c upon the catalytic hydrogenation was also
demonstrated (Scheme 5). The reaction proceeded smoothly in
the presence of 10% Pd-C and 5-fold excess of Et3N in MeOH
under 30 bar of H2 at 80 °C. This procedure gave the
corresponding amino alcohols 19a–c (82–94% yield).
1
the reaction mixture by LC-MS and/or H NMR. Treatment of 20
with LDA at –90 °C for 30 min resulted in low conversion to the
target product 22 (13%). Therefore, a stronger base (namely, in
situ generated LiTMP) was applied below –85 °C (Entries 7 and
8). The best results were obtained when 20 was treated with
N-Boc-piperidin-4-one was also studied in the aforementioned
reaction sequence. It was found that the first step proceeded
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LiTMP at –85 °C for 25 min; in this case, the deuterated
derivative 22 was formed in an excellent yield (90%, Entry 7).
These optimized conditions were applied for preparation of 4-
substituted 3-bromopyridines 23 via reaction of 21 with simple
aliphatic ketones (41-74% yield, Table 3, Entries 1-6), N-Boc-
respectively. As in the case of 3-substituted isomers,[42] the best
results were obtained in the case of non-enolizable aldehydes,
i.e. benzaldehyde (Entry 15). In the case of the least electro-
philic cycloheptanone or acetophenone, the corresponding
products 23 were obtained in modest yields; a considerable tar
formation was observed which might be addressed to
dehydropyridine formation.
Table 3. DOM of 3-bromopyridine (20) at the C-4 position
Regioselectivity of the reaction was confirmed by X-Ray
diffraction studies, which were performed with the product 23b
(Figure 2).
#
Carbonyl
compound [a]
R1
R2
Product
Yield, %
1
2
3
Me
Me
23a
23b
23c
57
74
51
(CH2)3
(CH2)4
Figure 2. Molecular structure of the compound 23b. Thermal ellipsoids are
shown at 50% probability.
4
5
(CH2)5
(CH2)6
23d
23e
59
59
Catalytic reduction of the products 23 was optimized for the
selective preparation of either (cyclo)alkylpiperidines 24 or
amino alcohols 25. In all cases, the hydrogenation was
performed in the presence of 10% Pd-C in MeOH under 60 bar
of H2 at 80°C for 18 h (Table 4). It was found that in the absence
of any additives, the products 24c and 25c were formed at ca.
2:1 ratio (Entry 1). Therefore, the concentration of HCl or Et3N
was varied to achieve selectivity in the hydrogenation of the
substrates 23b, 23c and 23l (Entries 2-13). It was found that
using 5- to 10-fold excess of 10 M aq HCl as an additive resulted
in a predominant formation of deoxygenated products 24HCl
(Entries 3, 7 and 12); while in the presence of 3- to 5-fold excess
of Et3N, aminoalcohols 25 formed exclusively (Entries 5, 9 and
13).
6
(CH2)7
23f
41
7
8
1-Boc-azetidin-3-yl
1-Boc-pyrrolidin-3-yl
23g
23h
67
54
9
1-Boc-piperidin-4-yl
23i
23j
51
28
10
Ph
Me
Et
Me
H
11
23k
23l
68
70
74
73
84
Table 4. Optimization of the reaction conditions for the preparation of
piperidines 24 and 25
12
H
13
i-Pr
t-Bu
Ph
H
23m
23n
23o
14 [b])
15 [с]
H
H
#
Pyridine 23
Conditions
Yield, % [a]
[a] Unless noted otherwise, 2.2-fold excess of the electrophile was used [b] 1.5-
fold excess of aldehyde [с] 1.1-fold excess of aldehyde
24
25
1
2
3
4
No additives
aq HCl (2 eq)
aq HCl (5 eq)
Et3N (3 eq)
67
33
amino ketones (51-67% yield, Entries 7-9), acetophenone (28%
yield, Entry 10) as well as various aldehydes (68-84% yield,
Entries 11-15). The proposed method worked well with all the
electrophilic substrates studied. Typically, 2.2-fold excess of
carbonyl compound 16 was used for the preparation of 23a–m
(Entries 1-13); meanwhile, only 1.5-fold and 1.1-fold excess was
sufficient for the synthesis of 23n (Entry 14) and 23o (Entry 15),
>98
>99
6
<2
traces
94
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10.1002/ejoc.201900450
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moreover, compound 24n bearing a tert-butyl group could not be
obtained at all (Entry 14). Hydrogenation of 23n at these
conditions resulted in an exclusive formation of amino alcohol
25n (91% yield).
Expectedly, the method was not successful with Boc derivatives
23g–i due to instability of moiety in acidic media; complex
mixtures were obtained in these cases. Attempts to replace the
Boc moiety with trifluoroacetyl or mesyl groups were also
unfruitful.
For the preparation of amino alcohols 25, the reduction of 23
was performed in the presence of 5-fold excess of Et3N, which
gave the target products 25 in all cases studied (88–96% yield).
Finally, the strategy shown in Scheme 3 was evaluated for the
case of 2-(cyclo)alkylpiperidines. It was found that metalation of
20 with organozinc[49,50] or magnesium agents[51] occurred
selectively at the C-2 position of the pyridine ring (Table 6, Entry
1).[48] The corresponding intermediate 26a was formed via the
reaction of 20 with TMPZnClLiCl at 25 °C for 24 h. Quenching of
26a with D2O gave the corresponding deuterated derivative 27 in
80% yield (Entry 2).
5
Et3N (5 eq)
traces
38
>99
62
6
aq HCl (2 eq)
aq HCl (5 eq)
aq HCl (10 eq)
Et3N (3 eq)
7
64
36
8
71
29
9
traces
66
>99
34
10
11
12
13
aq HCl (1 eq)
aq HCl (2 eq)
aq HCl (5 eq)
Et3N (5 eq)
73
27
74
26
traces
>99
[a] Yield by 1H NMR and LCMS/GCMS
Thus, to prepare piperidine derivatives 24a–oHCl, hydroge-
nation of the compounds 23a–o was performed in the presence
of 10-fold excess of 10 M aq HCl (51-96% yield) (Table 5).
Table 5. Synthesis of 4-(cyclo)alkylpiperidines 24 and 25
Table 6. DOM of 3-bromopyridine 20 at the C-2 position
#
23[a]
R1
R2
Product 24
(Yield, %)[b]
Product 25
(Yield, %)[c]
1
2
3
4
5
6
23a
23b
23c
23d
23e
23f
Me
Me
(CH2)3
(CH2)4
(CH2)5
(CH2)6
(CH2)7
24a (62)
24b (51)
24c (95)
24d (91)
24e (96)
24f (96)
N/A
25b (91)
25c (95)
25d (96)
25e (96)
N/A
#
1
Metallating
agent
E+
source
Temperature,
°C
Time,h
2
Yield,
%
(TMP)2Zn
TMPLi2LiCl,
TMEDA, 1.1 eq
D2O
25
60
2
3
4
5
6
7
8
TMPZnClLiCl,
1.0 eq
D2O
25
24
24
1
80
0
1-Boc-
azetidin-3-yl
7
8
9
23g
23h
23i
–
–
–
25g (89)
25h (91)
25i (91)
TMPZnClLiCl,
1.0 eq
PhCHO
D2O
25
1-Boc-
pyrrolidin-3-yl
TMPMgClLiCl,
1.0 eq
–40
4
1-Boc-
piperidin-4-yl
TMPMgClLiCl,
1.0 eq
D2O
–25
0.67
0.5
1
18
40
50
50 [a]
10
11
12
13
14
15
23j
Ph
Me
H
24j (92)
N/A
23k
23l
Me
Et
24k (83)
24l (63)
N/A
TMPMgClLiCl,
1.5 eq
D2O
–25 to –5
0 to 15
25
H
25l (88)
25m (91)
25n (94)
25o (94)
TMPMgClLiCl,
1.5 eq
D2O
23m
23n
23o
i-Pr
t-Bu
Ph
H
24m (28)
25n (91)[d]
24o (95)
H
TMPMgClLiCl,
1.5 eq
D2O
1
H
[a] The reaction was accompanied by significant tar formation
[a] See Table 4 for the reaction scheme [b] 10-fold excess of 10 M aq HCl was
used as an additive [c] 5-fold excess of Et3N was used as an additive [d] Amino
alcohol 25n was obtained instead of 24n
Unfortunately, the organozinc intermediate 26a had insufficient
reactivity towards aldehydes (i.e. benzaldehyde, Entry 3). It was
envisaged that organomagnesium species 26b generated in situ
by treatment of 20 with TMPMgClLiCl would be more suitable
for the subsequent reaction with carbonyl compounds (Entries
4–8).
It should be noted that steric factor was important for the
deoxygenation process: isopropyl-substituted derivative 24m
could be synthesized from 23m in only 28% yield (Entry 13);
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The most fruitful results were obtained using 1.5-fold excess of
metallating agent at 0–15 °C (Entry 7). At higher temperature,
the reaction was accompanied by significant tar formation (Entry
8). The optimized conditions mentioned above (Table 6, Entry 7)
were applied for the reaction of 26b with PhCHO, and the
corresponding derivative 28f was isolated in 74% yield (Table 7,
Entry 6).
All attempts to extend this method towards aliphatic ketones (i.e.
acetone and cyclobutanone) were unfruitful - only traces of 28a
and 28b were detected in the crude reaction mixtures obtained
(Entries 1 and 2). Nevertheless, aliphatic aldehydes appeared to
be suitable for such transformation, providing the corresponding
3-bromo-2-hydroxyalkylpyridines 28c-f in 52–81% yield (Entries
3–5).
Catalytic hydrogenation of the products 28 was performed using
the optimized procedures described above for the 4-isomers 23
(Table 8). In the presence of HCl, the method worked well with
relatively unhindered pyridine derivatives 28c and 28f, providing
the target 2-alkylpiperidines 29cHCl and 29fHCl in 88% and
92% yield, respectively.
In the case of sterically constrained derivatives 28d and 28e,
only the corresponding amino alcohols 30d and 30e were
formed at these conditions (91% and 92% yield, respectively).
As it was expected, the corresponding derivatives 30d and 30e
were obtained in 91 and 93% yield, respectively, when the
hydrogenation of 28d and 28e was performed in the presence of
Et3N.
It is interesting to note that in all cases studied, the products
30d–f were obtained with moderate to good diastereoselectivity
(dr 3.3:1 to 22:1). To establish relative stereochemistry of the
major diastereomer, X-Ray diffraction studies were performed
with tert-butyl substituted derivative 30e. Unfortunately, the
crystal structure of sufficient quality could not be obtained in this
case. Therefore, adduct of 30e with hexafluoroacetone was
obtained. The unit cell of the resulting product contained two
enantiomeric molecules of zwitterionic derivative 31 (Figure 3)
per one molecule of hexafluoroacetone hydrate. These data
confirmed that the major diastereomer of the product 30e is (R*)-
2,2-dimethyl-1-((S*)-piperidin-2-yl)propan-1-ol.
Table 7. Synthesis of 2-substituted 3-bromopyridines 28
#
1
2
Reagent 16
R1
R2
Product
28a
Yield, %
traces
Me
Me
(CH2)3
28b
traces
3
4
5
6
Me
i-Pr
t-Bu
Ph
H
H
H
H
28c
28d
28e
28f
52
53
81
74
Figure 3. (a) Molecular structure of the compound 31 (only one enantiomer –
(R)-2,2-dimethyl-1-((S)-piperidin-2-yl)propan-1-ol
– is shown) (b) Relative
configuration of the compound 30e (major diastereomer). Thermal ellipsoids
are shown at 50% probability.
Table 8. Synthesis of piperidines 29 and 30
Next, we have tested the possibility for the scale up of the
procedures proposed on a kilogram scale; the compounds 17a
and 17b were selected to illustrate this. First of all, scaling up of
the lithiation step upon flow conditions was envisaged.[52–56] The
preliminary experiments were performed using 0.5 M THF
solution of 14, 1 M THF solution of LDA and 2 M THF solution of
acetone (the general flow set up is shown in Scheme 6, the
reactor volumes were 200 mL and 100 mL, respectively). The
temperature varied from −70 °C to −30 °C; and the residence
times changed from 5 to 20 min (1, reactor 1), and from 2 to 10
min (2, reactor 2) (Table 9). It was found that the optimal
temperature was –50 °C with residence times 1 = 20 min and
2 = 8.6 min (Entry 4), which gave 17a in 72% yield.
#
28
R
Product 29
Product 30
(Yield, %, dr) a)
(Yield, %, dr) b)
1
2
28c
28d
Me
29c (88)
N/A
30d (91,
dr 3.3:1) c)
30d (91,
dr 4.6:1)
i-Pr
30e (92,
dr 18:1) c)
30e (93,
dr 22:1)
3
4
28e
28f
t-Bu
Furthermore, less expensive and more accessible 2-chloro-
pyridine (31) was tested upon the optimized conditions (Entry 4)
instead of 2-bromopyridine (14). In this case, the yield
decreased only slightly (66%, Entry 7); thus, chloro derivative 31
was used for subsequent three-fold scale up due to more
Ph
29f (92)
N/A
a) 10-fold excess of 10 M aq HCl was used as an additive b) 5-fold excess of
Et3N was used as an additive c) Amino alcohol 30 was obtained instead of 29
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10.1002/ejoc.201900450
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Scheme 6. General flow setup for the synthesis of 32a and 32b
Table 9. Optimization of the flow reaction conditions.
#
1
2
3
4
5
6
7
Pyridine
14
Temperature, °C
1, min
10
2, min
4.3
Yield, %
38
Conclusions
–70
–70
–50
–50
–30
–30
–50
14
20
8.6
43
Directed ortho metalation of 2- and 3-bromopyridines, followed
by reaction with carbonyl compounds and subsequent catalytic
hydrogenation is scalable and straightforward approach to all
isomeric (cyclo)alkyl-substituted piperidines. In the case of 3-
substituted piperidines, lithiation of 2-bromopyridine with LDA at
–78 C was the key step of the synthesis. To obtain the
corresponding 4- and 2-regioisomers, the use of LiTMP at –85
C and TMPMgClLiCl at 0 C, respectively, appeared to be
necessary. The resulting organometallic species reacted
smoothly with aliphatic and aromatic aldehydes and ketones
(except the 2-metallated derivative which was not reactive
enough towards ketones), and the corresponding adducts were
isolated in 28–84% yields (20 examples).
The pyridine derivatives thus obtained could be transformed into
the corresponding (cyclo)alkyl-substituted piperidines upon
catalytic hydrogenation in acidic media. In this case, three
reactions (removal of the directed metalation group, dehydro-
xylation at the benzylic position, and reduction of the pyridine
ring) occurred in one step. The procedure was efficient with
most of the substrates studied (28–96% yields, 14 examples). In
the case of sterically hindered substrates, the deoxygenation
process did not occur, so that the corresponding amino alcohols
were obtained. Also, the method did not work with acid-sensitive
compounds.
14
10
4.3
45
14
20
8.6
72
14
10
4.3
36
14
20
8.6
28
31
20
8.6
66
favorable environmental factor (E-factor). After minor additional
modification, the optimized conditions (1 = 17 min and 2 = 7.5
min) were finally applied in a flow reactor with 600 mL and 300
mL reaction volumes (Scheme 5): the 63% preparative yield was
achieved with 61 g/h production rate. Accordingly, 1.2 kg of the
target pyridine 32a was obtained after 20 h of reactor operation.
In the case of cyclobutanone, the compound 32b was obtained
in 74% yield on the 380 g scale after 5 h operation time.
Subsequent hydrogenation of 32a and 32b was also tested in
the flow variant.[57] For this purpose, the H-Cube Mini system
with 5% Pd/C ThalesNano CatCart were used. Taking into
account the desired reagent molar ratio (31:H2 = 1:5), as well as
H-Cube Mini H2 production rate (25 mL/min) together with
minimal flow rate (0.3 mL/min), the fruitful results could be
obtained only at the concentration of 32a less than 0.025 M (10
M aq HCl (5 eq), MeOH, 50 °C, 80 bar). Unfortunately, these
values were ineffective for further scale up. Therefore, the
hydrogenation of 32a (0.29 M MeOH solution, 4 L) was
performed in a 5 L autoclave in the presence of 10 M aq HCl (5
eq) under 50 atm of H2 at 50 °C for 18 h, and 10% Pd-C (13
mol%) was used as catalyst. This protocol gave the target
compound 18a in 78% yield on 116 g scale after vacuum
distillation. This experiment was repeated in four additional runs,
and the results appeared to be highly reproducible, so that 0.5
kg of 18a could be prepared. The same conditions were used in
the case of 32b, and the corresponding piperidine 18b was
synthesized in 71% yield.
A possibility to retain the hydroxyl group upon the catalytic
hydrogenation was also demonstrated: this was the case when
the reaction was performed in the presence of Et3N. In this case,
the corresponding (piperidin-2-, -3-, or -4-yl)alkanols were
obtained in excellent yields (82–96%, 16 examples) in all cases
studied. It should be noted that 2-regioisomers were obtained
with significant regioselectivity; the relative stereochemistry of
the products was confirmed by X-Ray diffraction studies.
The method could be extended for a kilogram-scale production
of the target products using a flow reactor for the first step, and a
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
mmol) in THF (7.0 mL) was added in one portion at this temperature. The
solution was stirred for 15 min at –85 °C, and saturated aq NaHCO3 (25
mL) was added. The resulting mixture was stirred for 5 min, and the
solution was diluted with EtOAc (80 mL). The organic layer was
separated, washed with H2O (25 mL), dried over Na2SO4 and evaporated
in vacuo.
5 L autoclave for the hydrogenation; this allowed obtaining
0.5 kg of a representative compound (3-isopropylpiperidine).
Experimental Section
The solvents were purified according to the standard procedures.[58]
Compounds 14, 15a–m and 31 were available from Enamine Ltd. Melting
points were measured on MPA100 OptiMelt automated melting point
system. Analytical TLC was performed using Polychrom SI F254 plates.
Column chromatography was performed using silica gel (230–400 mesh)
as the stationary phase. 1H and 13C NMR spectra were recorded on a
Bruker 170 Avance 500 spectrometer (at 500 MHz for 1H NMR, 126 MHz
for 13C NMR and 470 MHz for 19F NMR) and Varian Unity Plus 400
spectrometer (at 400 MHz for 1H NMR, 101 MHz for 13C NMR and 376
MHz for 19F NMR). NMR chemical shifts are reported in ppm (δ scale)
downfield from TMS as an internal standard and are referenced using
residual NMR solvent peaks at 7.26 and 77.16 ppm for 1H and 13C in
CDCl3, 2.50 and 39.52 ppm for 1H and 13C in DMSO-d6. Coupling
constants (J) are shown in Hz. Spectra are reported as follows: chemical
shift (δ, ppm), multiplicity, integration, coupling constants (Hz). Elemental
analyses were performed at the Laboratory of Organic Analysis,
Department of Chemistry, National Taras Shevchenko University of Kyiv.
Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument
(chemical ionization (CI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)). The flow hydrogenation was
tested using ThalesNano H-Cube MiniTM system. CCDC 1904528 (23b)
and CCDC 1904529 (adduct of 30e with hexafluoroacetone) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
2-(3-Bromopyridin-4-yl)propan-2-ol (23a). The com-pound was purified
by column chromatography on silica gel using hexanes – EtOAc (1:1) as
eluent. Rf = 0.20. Yield 6.31 g (57% from acetone (6.45 g, 111 mmol));
white solid; mp 67–69 °C. 1H NMR (500 MHz, CDCl3) δ 8.64 (s, 1H), 8.44
(d, J = 5.1 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 3.30 (s, 1H), 1.73 (s, 6H).
13C NMR (126 MHz, CDCl3) δ 155.6, 153.4, 148.5, 122.0, 118.7, 72.9,
28.5. LC/MS (CI): m/z = 216/218 [M+H]+. Anal. Calcd. for C8H10BrNO: C
44.47; H 4.66; N 6.48; Br 36.98. Found: C 44.38; H 4.82; N 6.78; Br
37.12.
1-(3-Bromopyridin-4-yl)cyclobutanol (23b). The compound was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.21. Yield 4.30 g (74% from cyclobutanone (3.92 g,
56.0 mmol)); yellowish solid; mp 83–85 °C. 1H NMR (500 MHz, CDCl3) δ
8.65 (d, J = 4.5 Hz, 1H), 8.46 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 5.1, 2.5
Hz, 1H), 3.41 – 3.25 (m, 1H), 2.68 – 2.62 (m, 2H), 2.50 – 2.44 (m, 2H),
2.19 (dtdd, J = 18.2, 9.0, 7.1, 2.0 Hz, 1H), 1.75 – 1.68 (m, 1H). 13C NMR
(126 MHz, CDCl3) δ 153.0, 151.6, 148.6, 121.7, 120.1, 77.9, 34.8, 14.3.
LC/MS (CI): m/z = 228/230 [M+H]+. Anal. Calcd. for C9H10BrNO: C 47.39;
H 4.42; N 6.14; Br 35.03. Found: C 47.51; H 4.63; N 6.18; Br 35.09.
1-(3-Bromopyridin-4-yl)cyclopentanol (23c). The compound was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.25. Yield 3.12 g (51% from cyclopentanone (4.71 g,
56.0 mmol)); beige solid; mp 68–70 °C. 1H NMR (500 MHz, CDCl3) δ
8.66 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 2.77 (s,
1H), 2.42 – 2.34 (m, 2H), 2.05 – 1.97 (m, 4H), 1.95 – 1.87 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 153.4, 148.4, 145.7, 122.4, 119.7, 83.2, 39.5,
24.3. LC/MS (CI): m/z = 242/244 [M+H]+. Anal. Calcd. for C10H12BrNO: C
49.61; H 5.00; N 5.79; Br 33.00. Found: C 49.92; H 4.69; N 5.94; Br
32.89.
tert-Butyl
4-(2-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxy-
late (17c). n-BuLi (22.0 mL, 2.5 M in hexanes, 54.5 mmol) was added
dropwise to a cooled to –78 °С solution of diisopropylamine (5.77 g, 8.00
mL, 57.0 mmol) in THF (150 mL) under argon atmosphere. The mixture
was stirred at –78 °C for 1 h, and a solution of 2-bromopyridine 14 (7.17
g, 45.4 mmol) in THF (70 mL) was added dropwise over 20 min. The
reaction mixture was stirred at –78 °С for 90 min, and precooled (–78 °С)
solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.95 g, 50.0 mmol) in
THF (15 mL) was added in one portion. The mixture was stirred at –
78 °С for 80 min and saturated aq NaHCO3 (70 mL) was added at –78°С.
The resulting mixture was warmed up to rt and diluted with EtOAc (300
mL). The organic phase was separated, washed with saturated aq
NaHCO3 (2×150 mL) and brine (200 mL), dried over Na2SO4, and
evaporated in vacuo. The compound was purified by column
chromatography on silica gel using hexanes – EtOAc (2:1) as eluent.
Rf = 0.47. Yield 10.3 g (63%); white solid; mp 162–164 °C. 1H NMR (500
MHz, CDCl3) δ 8.27 (dd, J = 4.6, 1.8 Hz, 1H), 7.88 (dd, J = 7.8, 1.8 Hz,
1H), 7.29 (dd, J = 7.8, 4.6 Hz, 1H), 4.17 – 3.98 (m, 2H), 3.34 – 3.18 (m,
2H), 3.12 (s, 1H), 2.36 – 2.25 (m, 2H), 1.98 (d, J = 13.5 Hz, 2H), 1.47 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 154.8, 148.4, 142.0, 140.3, 136.0,
123.0, 79.7, 71.5, 64.9, 35.0, 28.5. LC/MS (CI): m/z = 357/359 [M+H]+.
Anal. Сalcd. for C15H21BrN2O3: C 50.43; H 5.93; N 7.84; Br 22.37. Found:
C 50.54; H 6.26; N 8.12; Br 22.27.
1-(3-Bromopyridin-4-yl)cyclohexanol (23d). The compound was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.27. Yield 3.83 g (59% from cyclohexanone (5.50 g,
56.0 mmol)); yellowish solid; mp 112–114 °C. 1H NMR (500 MHz, CDCl3)
δ 8.65 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.64 (d, J = 5.2 Hz, 1H), 2.68 (s,
1H), 2.33 (td, J = 13.5, 4.2 Hz, 2H), 1.82 – 1.74 (m, 5H), 1.72 – 1.66 (m,
2H), 1.38 – 1.30 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 155.1, 153.9,
148.7, 122.2, 119.0, 74.0, 34.5, 25.0, 21.6. LC/MS (CI): m/z = 256/258
[M+H]+. Anal. Calcd. for C11H14BrNO: C 51.58; H 5.51; N 5.47; Br 31.20.
Found: C 51.62; H 5.32; N 5.58; Br 31.44.
1-(3-Bromopyridin-4-yl)cycloheptanol (23e). The compound was
purified by column chromatography on silica gel using hexanes – EtOAc
(1:1) as eluent. Rf = 0.29. Yield 4.03 g (59% from cycloheptanone (6.28 g,
56.0 mmol)); white solid; mp 114–116 °C. 1H NMR (500 MHz, CDCl3) δ
8.66 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 2.53 (ddd,
J = 14.8, 10.9, 2.2 Hz, 3H), 1.91 – 1.81 (m, 4H), 1.77 – 1.72 (m, 2H),
1.69 – 1.62 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 156.7, 153.8, 148.6,
121.7, 118.9, 77.5, 38.9, 27.9, 22.2. LC/MS (CI): m/z = 270/272 [M+H]+.
Anal. Calcd. for C12H16BrNO: C 53.35; H 5.97; N 5.18; Br 29.58. Found:
C 53.02; H 5.69; N 5.15; Br 29.37.
Representative procedure for the preparation of pyridines 23a–o
(given for 23b). n-BuLi (11.2 mL, 2.5 M in hexanes, 28.0 mmol) was
added dropwise to the solution of TMP (4.00 g, 28.3 mmol) in THF (50
mL) at –40 °C. The reaction mixture was warmed up to –5°C, stirred for
15 min., then cooled to –85 °C, and 3-bromopyridine (20) (4.00 g, 25.3
mmol) in THF (10 mL) was added dropwise. The resulting mixture was
stirred at –85 °C for 25 min, and a solution of cyclobutanone (3.92 g, 56.0
1-(3-Bromopyridin-4-yl)cyclooctanol (23f). The compound was purified
by column chromatography on silica gel using hexanes – EtOAc (1:1) as
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
eluent. Rf = 0.29. Yield 2.97 g (41% from cyclooctanone (7.06 g, 56.0
mmol)); yellowish solid; mp 137–139 °C. 1H NMR (500 MHz, CDCl3) δ
8.67 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 2.66 (s,
1H), 2.59 (dd, J = 15.1, 9.5 Hz, 2H), 1.98 (dq, J = 15.5, 7.5 Hz, 2H), 1.88
– 1.82 (m, 1H), 1.76 (dd, J = 15.1, 9.5 Hz, 2H), 1.65 – 1.52 (m, 7H). 13C
NMR (126 MHz, CDCl3) δ 156.6, 153.9, 148.6, 122.1, 118.9, 77.0, 34.5,
27.9, 23.2, 20.9. LC/MS (CI): m/z = 284/286 [M+H]+. Anal. Calcd. for
C13H18BrNO: C 54.94; H 6.38; N 4.93; Br 28.12. Found: C 54.91; H 6.10;
N 4.65; Br 27.77.
1H), 4.01 (s, 1H), 1.43 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
154.4, 151.2, 148.3, 121.7, 119.7, 68.0, 23.3. LC/MS (CI): m/z = 202/204
[M+H]+. Anal. Calcd. for C7H8BrNO: C 41.61; H 3.99; N 6.93; Br 39.55.
Found: C 42.00; H 3.93; N 6.77; Br 39.91.
1-(3-Bromopyridin-4-yl)propan-1-ol (23l). The compound was purified
by column chromatography on silica gel using hexanes – EtOAc (1:2) as
eluent. Rf = 0.43. Yield 3.80 g (70% from propanal (3.25 g, 56.0 mmol));
1
yellowish oil. H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.38 (d, J = 5.0
Hz, 1H), 7.50 (d, J = 5.0 Hz, 1H), 4.91 (dd, J = 7.8, 4.1 Hz, 1H), 3.84 (br
s, 1H), 1.82 (dqd, J = 14.8, 7.4, 4.1 Hz, 1H), 1.64 (dp, J = 14.8, 7.4 Hz,
1H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 153.3, 151.3,
148.1, 122.4, 120.1, 72.9, 30.0, 9.9. LC/MS (CI): m/z = 216/218 [M+H]+.
Anal. Calcd. for C8H10BrNO: C 44.47; H 4.66; N 6.48; Br 36.98. Found: C
44.15; H 4.56; N 6.57; Br 37.08.
tert-Butyl 3-(3-bromopyridin-4-yl)-3-hydroxyazetidine-1-carboxylate
(23g). The compound was purified by column chromatography on silica
gel using EtOAc as eluent. Rf = 0.38. Yield 5.58 g (67% from the
corresponding N-Boc-amino ketone (9.58 g, 56.0 mmol)); white solid; mp
1
117–119 °C. H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.47 (d, J = 5.1
Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 4.90 (s, 1H), 4.47 (d, J = 9.8 Hz, 2H),
4.19 (d, J = 9.8 Hz, 2H), 1.41 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
156.3, 153.0, 148.8, 148.4, 122.4, 120.3, 80.3, 72.0, 61.2, 28.3. LC/MS
(CI): m/z = 329/331 [M+H]+. Anal. Calcd. for C13H17BrN2O3: C 47.43; H
5.21; N 8.51; Br 24.27. Found: C 47.78; H 4.88; N 8.59; Br 23.99.
1-(3-Bromopyridin-4-yl)-2-methylpropan-1-ol (23m). The compound
was purified by column chromatography on silica gel using hexanes –
EtOAc (1:1) as eluent. Rf = 0.31. Yield 4.10 g (74% from isobutyr-
aldehyde (4.00 g, 56.0 mmol)); yellowish oil. 1H NMR (500 MHz, CDCl3)
δ 8.55 (s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 5.0 Hz, 1H), 4.82 (d,
J = 4.8 Hz, 1H), 3.31 (s, 1H), 2.05 (pd, J = 6.9, 4.8 Hz, 1H), 1.01 (d, J =
6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 152.4,
151.4, 147.9, 123.2, 120.7, 76.1, 33.2, 19.5, 15.9. LC/MS (CI): m/z =
230/232 [M+H]+. Anal. Calcd. for C9H12BrNO: C 46.98; H 5.26; N 6.09; Br
34.73. Found: C 46.96; H 5.07; N 5.77; Br 35.06.
tert-Butyl 3-(3-bromopyridin-4-yl)-3-hydroxypyrroli-dine-1-carboxy-
late (23h). The compound existed as a mixture of rotamers (ca. 1:1). The
compound was purified by column chromatography on silica gel using
EtOAc as eluent. Rf = 0.40. Yield 4.70 g (54% from the corresponding N-
Boc-amino ketone (10.4 g, 56.0 mmol)); yellowish oil. 1H NMR (500 MHz,
CDCl3) δ 8.66 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 5.1 Hz, 1H),
4.21 (s, 1H), 3.93 (d, J = 12.1 Hz, 1H), 3.85 – 3.72 (m, 1H), 3.71 – 3.62
(m, 1H), 3.62 – 3.59 (m, 1H), 2.72 (q, J = 10.4 Hz, 1H), 2.21 – 2.12 (m,
1H), 1.42 (d, J = 9.4 Hz, 9H). 13C NMR (126 MHz, CDCl3) δ 154.6 and
154.5, 153.5, 150.0 and 149.9, 148.5, 122.9, 119.6 and 119.5, 80.4 and
79.5, 79.9, 56.9 and 56.4, 44.6 and 44.3, 37.0 and 36.5, 28.5. LC/MS
(CI): m/z = 343/345 [M+H]+. Anal. Calcd. for C14H19BrN2O3: C 48.99; H
5.58; N 8.16; Br 23.28. Found: C 49.11; H 5.87; N 8.10; Br 23.15.
1-(3-Bromopyridin-4-yl)-2,2-dimethylpropan-1-ol (23n). The compo-
und was purified by column chromatography on silica gel using hexanes
– EtOAc (2:1) as eluent. Rf = 0.29. Yield 4.53 g (73% from pivalaldehyde
(3.44 g, 40.0 mmol)); white solid; mp 112–114 °C. 1H NMR (500 MHz,
CDCl3) δ 8.55 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H),
4.89 (s, 1H), 3.25 (s, 1H), 0.99 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
151.5, 150.9, 147.4, 124.6, 122.3, 77.9, 37.1, 25.8. LC/MS (CI): m/z =
244/246 [M+H]+. Anal. Calcd. for C10H14BrNO: C 49.20; H 5.78; N 5.74;
Br 32.73. Found: C 49.06; H 6.07; N 6.13; Br 32.56.
tert-Butyl 4-(3-bromopyridin-4-yl)-4-hydroxypiperi-dine-1-carboxy-
late (23i). The compound was purified by column chromatography on
silica gel using EtOAc as eluent. Rf = 0.42. Yield 4.62 g (51% from the
corresponding N-Boc-amino ketone (11.1 g, 56.0 mmol)); white solid; mp
(3-Bromopyridin-4-yl)(phenyl)methanol (23o). The compound was
purified by treating with boiling hexane, then cooling to rt; hexane was
decanted and solid was crystallized from EtOH - hexane. Yield 5.62 g
(84% from benzaldehyde (2.98 g, 28.0 mmol)); white solid; mp 133–
135 °C. 1H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 8.42 (d, J = 5.1 Hz,
1H), 7.68 (d, J = 5.1 Hz, 1H), 7.39 – 7.34 (m, 3H), 7.34 – 7.28 (m, 2H),
6.04 (s, 1H), 3.98 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 151.7, 151.6,
148.3, 140.8, 128.7, 128.4, 127.4, 122.8, 120.7, 73.9. LC/MS (CI): m/z =
264/266 [M+H]+. Anal. Calcd. for C12H10BrNO: C 54.57; H 3.82; N 5.30;
Br 30.25. Found: C 54.39; H 3.68; N 5.41; Br 30.10.
1
162–164 °C. H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.43 (d, J = 5.2
Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 4.14 – 3.96 (m, 2H), 3.42 – 3.34 (m,
1H), 3.30 – 3.11 (m, 2H), 2.49 – 2.35 (m, 2H), 1.74 (d, J = 13.5 Hz, 2H),
1.44 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 154.8, 153.9, 153.5, 148.8,
122.1, 118.9, 79.8, 72.4, 40.0, 34.1, 28.5. LC/MS (CI): m/z = 357/359
[M+H]+. Anal. Calcd. for C15H21BrN2O3: C 50.43; H 5.93; N 7.84; Br 22.37.
Found: C 50.56; H 5.62; N 7.99; Br 22.50.
1-(3-Bromopyridin-4-yl)-1-phenylethanol (23j). The compound was
purified by treating with boiling hexane, then cooling to rt; hexane was
decanted, and the solid was crystallized from EtOH - hexane. Yield 2.05
g (28% from acetophenone (6.72 g, 56.0 mmol)); beige solid; mp 145–
147 °C. 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 8.54 (d, J = 5.1 Hz,
1H), 7.86 (d, J = 5.1 Hz, 1H), 7.35 – 7.30 (m, 3H), 7.29 – 7.26 (m, 2H),
3.59 – 3.39 (m, 1H), 2.01 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 154.4,
153.5, 148.5, 145.0, 128.5, 127.7, 126.0, 122.7, 120.2, 76.5, 27.9.
LC/MS (CI): m/z = 278/280 [M+H]+. Anal. Calcd. for C13H12BrNO: C
56.14; H 4.35; N 5.04; Br 28.73. Found: C 55.83; H 4.69; N 5.13; Br
28.78.
Representative procedure for the preparation of pyridines 28c–f
(given for 28e). 3-Bromopyridine (20) (8.00 g, 50.6 mmol) was added
dropwise to TMPMgClLiCl (66.0 mL, 1.3 M in THF, 85.8 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 3 h, then pivalaldehyde (8.40
g, 97.5 mmol) was added in one portion. The mixture was stirred at rt for
1.5 h, then saturated aq NH4Cl (50 mL) was added, and EtOAc (150 mL)
was added in 15 min. Organic layer was separated, washed with H2O (25
mL), dried over Na2SO4 and evaporated in vacuo.
1-(3-Bromopyridin-2-yl)ethanol (28c). The compound was purified by
column chromatography on silica gel using hexanes – EtOAc (2:1) as
eluent. Rf = 0.28. Yield 5.31 g (52% from acetaldehyde (4.29 g, 97.5
mmol)); yellowish oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 4.6 Hz,
1H), 7.83 (d, J = 7.9 Hz, 1H), 7.10 (dd, J = 7.9, 4.6 Hz, 1H), 5.10 (p, J =
6.7 Hz, 1H), 4.38 (d, J = 7.7 Hz, 1H), 1.45 (d, J = 6.7 Hz, 3H). 13C NMR
1-(3-Bromopyridin-4-yl)ethanol (23k). The compound was purified by
column chromatography on silica gel using CHCl3 – MeOH (30:1) as
eluent. Rf = 0.24. Yield 3.49 g (68% from acetaldehyde (2.47 g, 56.0
1
mmol)); white solid; mp 72–74 °C. H NMR (400 MHz, CDCl3) δ 8.49 (s,
1H), 8.37 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 5.1 Hz, 1H), 5.10 (q, J = 6.5 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
(101 MHz, CDCl3) δ 160.9, 146.9, 140.8, 123.7, 118.5, 67.8, 23.3. LC/MS
(CI): m/z = 202/204 [M+H]+. Anal. Calcd. for C7H8BrNO: C 41.61; H 3.99;
N 6.93; Br 39.55. Found: C 41.34; H 3.94; N 6.80; Br 39.66.
4-Cyclobutylpiperidin-1-ium chloride (24bHCl). After extraction, the
organic layers were combined and evaporated in vacuo. The crude
compound was purified by distillation in vacuo, bp 89–91 °C / 12 mmHg.
Then, the obtained base was dissolved in hexanes, and 4 M HCl in 1,4-
dioxane (20 mL) was added at rt. The precipitate formed was filtered,
washed with hexanes (310 mL) and dried on air. Yield 1.96 g (51%
from 23b (5.00 g, 21.9 mmol)); gray powder; mp 223–225 °C. 1H NMR
(400 MHz, DMSO-d6) δ 9.12 (s, 2H), 3.17 (dt, J = 12.9, 3.3 Hz, 2H), 2.74
(td, J = 12.2, 2.3 Hz, 2H), 2.05 – 1.88 (m, 3H), 1.80 (hept, J = 9.4 Hz, 1H),
1.72 – 1.54 (m, 5H), 1.47 – 1.37 (m, 1H), 1.21 (qd, J = 12.9, 3.8 Hz, 2H).
13C NMR (126 MHz, DMSO-d6) δ 43.4, 40.6, 39.6, 26.0, 25.8, 17.9.
LC/MS (CI): m/z = 140 [M+H–HCl]+. Anal. Calcd. for C9H18ClN: C 61.52;
H 10.33; N 7.97; Cl 20.18. Found: C 61.65; H 10.68; N 7.98; Cl 20.33.
1-(3-Bromopyridin-2-yl)-2-methylpropan-1-ol (28d). The compound
was purified by column chromatography on silica gel using hexanes –
EtOAc (4:1) as eluent. Rf = 0.40. Yield 6.22
g
(53% from
1
isobutyraldehyde (7.03 g, 97.5 mmol)); yellowish oil. H NMR (400 MHz,
CDCl3) δ 8.46 (d, J = 4.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.07 (dd, J =
7.6, 4.6 Hz, 1H), 4.82 (dd, J = 8.3, 3.4 Hz, 1H), 4.11 (d, J = 8.3 Hz, 1H),
2.15 (pd, J = 6.8, 3.4 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.67 (d, J = 6.8
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 159.6, 146.5, 140.7, 123.5, 119.4,
75.3, 32.9, 20.2, 15.0. LC/MS (CI): m/z = 230/232 [M+H]+. Anal. Calcd.
for C9H12BrNO: C 46.98; H 5.26; N 6.09; Br 34.73. Found: C 46.68; H
5.22; N 6.11; Br 34.33.
4-Cyclopentylpiperidin-1-ium chloride (24cHCl). Yield 3.83 g (95%
from 23c (5.00 g, 21.0 mmol)); white crystals; mp 226–228°C. 1H NMR
(400 MHz, D2O) δ 4.65 (s, 2H), 3.28 (d, J = 11.8 Hz, 2H), 2.82 (t, J = 12.4
Hz, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.69 – 1.58 (m, 2H), 1.54 – 1.41 (m,
3H), 1.42 – 1.34 (m, 2H), 1.34 – 1.20 (m, 3H), 1.09 – 0.94 (m, 2H). 13C
NMR (126 MHz, D2O) δ 44.8, 44.2, 38.8, 29.7, 27.5, 24.8. LC/MS (CI):
m/z = 154 [M+H–HCl]+. Anal. Calcd. for C10H20ClN: C 63.31; H 10.63; N
7.38; Cl 18.68. Found: C 63.22; H 10.58; N 7.34; Cl 19.00.
1-(3-Bromopyridin-2-yl)-2,2-dimethylpropan-1-ol (28e). The compo-
und was purified by column chromatography on silica gel using hexanes
– EtOAc (4:1) as eluent. Rf = 0.40. Yield 10.0 g (81% from pivalaldehyde
(8.40 g, 97.5 mmol)); white solid; mp 46–48 °C. 1H NMR (400 MHz,
CDCl3) δ 8.49 (d, J = 4.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.05 (dd, J =
8.1, 4.7 Hz, 1H), 4.85 (d, J = 7.9 Hz, 1H), 3.64 (d, J = 9.7 Hz, 1H), 0.95 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 159.3, 146.8, 140.5, 123.5, 121.2,
77.3, 38.0, 26.1, 26.0, 26.0, 26.0, 25.9. LC/MS (CI): m/z = 244/246
[M+H]+. Anal. Calcd. for C10H14BrNO: C 49.20; H 5.78; N 5.74; Br 32.73.
Found: C 49.13; H 5.38; N 5.50; Br 32.74.
4-Cyclohexylpiperidin-1-ium chloride (24dHCl). Yield 2.90 g (91%
from 23d (4.00 g, 15.6 mmol)); white solid; mp 231–233 °C 1H NMR (400
MHz, DMSO-d6) δ 8.90 (d, J = 67.1 Hz, 2H), 3.21 (d, J = 12.4 Hz, 2H),
2.75 (t, J = 12.4 Hz, 2H), 1.85 – 1.51 (m, 7H), 1.49 – 1.25 (m, 3H), 1.25 –
0.98 (m, 4H), 1.00 – 0.78 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 43.9,
42.1, 39.0, 29.8, 26.6, 26.4, 26.0. LC/MS (CI): m/z = 168 [M+H–HCl]+.
Anal. Calcd. for C11H22ClN: C 64.84; H 10.88; N 6.87; Cl 17.4. Found: C
64.99; H 10.55; N 6.81; Cl 17.41.
(3-Bromopyridin-2-yl)(phenyl)methanol (28f). The compound was
purified by column chromatography on silica gel using hexanes – EtOAc
(4:1) as eluent. Rf = 0.25. Yield 9.88 g (74% from benzaldehyde (10.3 g,
97.5 mmol)); white solid; mp 56–58 °C. 1H NMR (500 MHz, CDCl3) δ 8.60
(d, J = 4.6 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.32
(t, J = 7.6 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.17 (dd, J = 8.1, 4.6 Hz, 1H),
6.00 (d, J = 7.2 Hz, 1H), 5.27 (d, J = 7.6 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 158.6, 146.7, 141.7, 141.1, 128.4, 127.8, 127.7, 124.0, 119.9,
4-Cycloheptylpiperidin-1-ium chloride (24eHCl). Yield 3.10 g (96%
from 23e (4.00 g, 14.8 mmol)); white solid; mp > 200 °C. 1H NMR (400
MHz, DMSO-d6) δ 8.99 (d, J = 61.2 Hz, 2H), 3.21 (d, J = 12.1 Hz, 2H),
2.74 (t, J = 10.4 Hz, 2H), 1.67 – 1.53 (m, 6H), 1.53 – 1.28 (m, 10H), 1.27
– 1.17 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 43.9, 43.3, 40.3, 30.9,
28.3, 26.9, 25.7. LC/MS (CI): m/z = 182 [M+H–HCl]+. Anal. Calcd. for
C12H24ClN: C 66.18; H 11.11; N 6.43; Cl 16.28. Found: C 65.87; H 11.41;
N 6.13; Cl 16.66.
73.5. LC/MS (CI): m/z
=
246/248 [M+H–H2O]+. Anal. Calcd. for
C12H10BrNO: C 54.57; H 3.82; N 5.30; Br 30.25. Found: C 54.19; H 3.68;
N 5.32; Br 30.24.
Representative procedure for the preparation of amines 24 and 29
(given for 24c). Pd-C (10%, 2.30 g) and 10 M aq HCl (10.5 mL, 105
mmol) were added to a stirred solution of 23c (5.00 g, 21.0 mmol) in
MeOH (300 mL). The solution was hydrogenated in autoclave at 80°C for
18 h under H2 (60 bar). Then, the reaction mixture was evaporated in
vacuo, the residue was diluted with 10% aq NaOH (50 mL). The mixture
was extracted with hexanes (350 mL), organic layers were combined
and dried over Na2SO4. Unless noted otherwise, 4 M HCl in 1,4-dioxane
(20 mL) was added, the precipitate formed was filtered, washed with
hexanes and dried on air.
4-Cyclooctylpiperidin-1-ium chloride (24fHCl). Yield 3.11 g (96% from
23f (4.00 g, 14.1 mmol)); white solid; mp > 200 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.94 (s, 2H), 3.21 (d, J = 12.1 Hz, 2H), 2.75 (t, J = 11.3 Hz,
2H), 1.80 – 1.60 (m, 4H), 1.61 – 1.45 (m, 6H), 1.46 – 1.30 (m, 8H), 1.29 –
1.18 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 43.9, 41.1, 40.3, 29.5,
26.9, 26.6, 26.0, 25.9. LC/MS (CI): m/z = 196 [M+H–HCl]+. Anal. Calcd.
for C13H26ClN: C 67.36; H 11.31; N 6.04; Cl 15.29. Found: C 67.58; H
11.68; N 6.12; Cl 15.65.
4-Isopropylpiperidin-1-ium chloride (24aHCl). After extraction, the
organic layers were combined and evaporated in vacuo. The crude
compound was purified by distillation in vacuo, bp 58–60 °C / 12 mmHg.
Then, the obtained base was dissolved in hexanes, and 4 M HCl in 1,4-
dioxane (20 mL) was added at rt. The precipitate formed was filtered,
washed with hexanes (310 mL) and dried on air. Yield 2.05 g (62% from
23a (4.40 g, 20.4 mmol)); white crystals; mp 247–249 °C. 1H NMR (400
MHz, D2O) δ 4.65 (s, 2H), 3.31 (d, J = 12.2 Hz, 2H), 2.82 (t, J = 12.2 Hz,
2H), 1.81 (d, J = 11.5 Hz, 2H), 1.38 (hept, J = 6.7 Hz, 1H), 1.33 – 1.20 (m,
3H), 0.76 (d, J = 6.7 Hz, 6H). 13C NMR (126 MHz, D2O) δ 44.5, 39.5,
31.4, 25.6, 18.7. LC/MS (CI): m/z = 128 [M+H–HCl]+. GC/MS (CI): m/z =
127 [M–HCl]+. Anal. Calcd. for C8H18ClN: C 58.70; H 11.08; N 8.56; Cl
21.66. Found: C 58.62; H 10.77; N 8.85; Cl 21.29.
4-(1-Phenylethyl)piperidin-1-ium chloride (24jHCl). Yield 3.35 g (92%
from 23j (4.50 g, 16.2 mmol)); white solid; mp 192–194 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.74 (d, J = 168.5 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H),
7.22 – 7.13 (m, 3H), 3.26 (d, J = 12.8 Hz, 1H), 3.13 (d, J = 12.8 Hz, 1H),
2.79 (t, J = 11.3 Hz, 1H), 2.69 (t, J = 11.3 Hz, 1H), 2.49 – 2.43 (m, 1H),
1.92 (dt, J = 13.9, 3.2 Hz, 1H), 1.68 (dtt, J = 12.0, 7.9, 3.2 Hz, 1H), 1.41 –
1.32 (m, 2H), 1.27 – 1.20 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 145.6, 128.7, 127.9, 126.6, 44.5, 43.6, 43.6, 39.7,
27.2, 26.7, 19.0. LC/MS (CI): m/z = 190 [M+H–HCl]+. Anal. Calcd. for
C13H20ClN: C 69.16; H 8.93; N 6.20; Cl 15.7. Found: C 68.81; H 9.27; N
6.15; Cl 16.03.
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
4-Ethylpiperidin-1-ium chloride (24kHCl). After extraction, the organic
layers were combined and evaporated in vacuo. The crude compound
was purified by distillation in vacuo, bp 49–51 °C / 12 mmHg. Then, the
obtained base was dissolved in hexanes, and 4 M HCl in 1,4-dioxane (20
mL) was added at rt. The precipitate formed was filtered, washed with
hexanes (310 mL) and dried on air. Yield 3.67 g (83% from 23k (6.00 g,
29.7 mmol)); white crystals; mp 179–181 °C. 1H NMR (400 MHz, DMSO-
d6) δ 9.14 (s, 2H), 3.18 (dt, J = 12.4, 2.9 Hz, 2H), 2.76 (td, J = 12.4, 2.9
Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.47 – 1.26 (m, 3H), 1.22 (p, J = 7.4
Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 43.5,
35.2, 28.8, 28.4, 11.3. LC/MS (CI): m/z = 114 [M+H–HCl]+. GC/MS (EI):
m/z = 113 [M–HCl]+. Anal. Calcd. for C7H16ClN: C 56.18; H 10.78; N 9.36;
Cl 23.69. Found: C 55.96; H 10.98; N 9.58; Cl 23.39.
2-Ethylpiperidin-1-ium chloride (29c). Yield 2.10 g (88% from 28c
(3.20 g, 15.8 mmol)); white solid; mp 177–179 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.63 (d, J = 132.3 Hz, 2H), 3.19 (d, J = 12.6 Hz, 1H), 2.96 –
2.86 (m, 1H), 2.85 – 2.75 (m, 1H), 1.84 (d, J = 13.3 Hz, 1H), 1.77 – 1.68
(m, 2H), 1.68 – 1.61 (m, 1H), 1.61 – 1.52 (m, 1H), 1.53 – 1.45 (m, 1H),
1.45 – 1.36 (m, 1H), 1.36 – 1.26 (m, 1H), 0.90 (td, J = 7.5, 4.3 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ 57.5, 44.3, 27.8, 26.4, 22.3, 22.1, 9.9.
LC/MS (CI): m/z = 114 [M+H–HCl]+. Anal. Calcd. for C7H16ClN: C 56.18;
H 10.78; N 9.36; Cl 23.69. Found: C 56.52; H 10.46; N 9.34; Cl 23.39.
2-(1-Hydroxy-2-methylpropyl)piperidin-1-ium chloride (30d). Yield
2.80 g (91% from 28d (2.80 g, 12.1 mmol)); dr 3.3:1; white solid; mp
1
179–181 °C. H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.03 (s, 1H),
5.32 (d, J = 6.4 Hz, 0.76H) and 5.31 (d, J = 6.4 Hz, 0.23H), 3.33 – 3.30
(m, 1H), 3.16 – 3.04 (m, 2H), 2.86 (t, J = 12.7 Hz, 1H), 1.78 – 1.71 (m,
1H), 1.70 – 1.64 (m, 2H), 1.62 – 1.54 (m, 2H), 1.53 – 1.44 (m, 2H), 0.93
(d, J = 6.4 Hz, 2.30H) and 0.92 (d, J = 6.4 Hz, 0.70H), 0.80 (d, J = 6.4 Hz,
2.30H) and 0.79 (d, J = 6.4 Hz, 0.70H). 13C NMR (126 MHz, DMSO-d6)) δ
75.3, 58.1, 44.5, 30.2, 22.3, 21.9, 21.5, 20.0, 19.1. LC/MS (CI): m/z = 158
[M+H–HCl]+. Anal. Calcd. for C9H20ClNO: C 55.80; H 10.41; N 7.23; Cl
18.30. Found: C 55.45; H 10.58; N 6.88; Cl 18.11.
4-Propylpiperidin-1-ium chloride (24lHCl). After extraction, the organic
layers were combined and evaporated in vacuo. The crude compound
was purified by distillation in vacuo, bp 58–60 °C / 12 mmHg. Then, the
obtained base was dissolved in hexanes, and 4 M HCl in 1,4-dioxane (20
mL) was added at rt. The precipitate formed was filtered, washed with
hexanes (310 mL) and dried on air. Yield 2.39 g (63% from 23l (5.00 g,
23.1 mmol)); white crystals; mp 193–195 °C. 1H NMR (400 MHz, DMSO-
d6) δ 9.29 – 8.98 (m, 2H), 3.17 (d, J = 12.2 Hz, 2H), 2.77 (dt, J = 8.1, 3.2
Hz, 2H), 1.73 (d, J = 13.1 Hz, 2H), 1.58 – 1.45 (m, 1H), 1.35 (td, J = 13.1,
3.2 Hz, 2H), 1.29 – 1.22 (m, 2H), 1.21 – 1.13 (m, 2H), 0.85 (t, J = 7.1 Hz,
3H). 13C NMR (126 MHz, DMSO-d6) δ 43.5, 38.3, 33.1, 28.8, 19.4, 14.5.
LC/MS (CI): m/z = 128 [M+H–HCl]+. GC/MS (EI): m/z = 127 [M–HCl]+.
Anal. Calcd. for C8H18ClN: C 58.70; H 11.08; N 8.56; Cl 21.66. Found: C
58.59; H 11.36; N 8.83; Cl 21.94.
2-(1-Hydroxy-2,2-dimethylpropyl)piperidin-1-ium chlo-ride (30e). The
crude product was extracted with EtOAc (2x80 mL). Organic layers
combined, dried over Na2SO4 and evaporated. Residue was dissolved in
MeOH, aq saturated HCl was added to pH = 3–4 and evaporated. The
major diastereomer was purificated by recrystallization from t-BuOMe –
EtOH. Yield 2.33 g (92% from 28e (3.00 g, 12.3 mmol)); dr 18:1; white
solid; mp > 200 °C (dec). 1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 2H),
5.16 (s, 1H), 3.35 (d, J = 5.5 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 3.15 (d, J
= 12.4 Hz, 1H), 2.94 (dt, J = 12.7, 6.2 Hz, 1H), 1.76 – 1.66 (m, 3H), 1.63
– 1.54 (m, 2H), 1.53 – 1.46 (m, 1H), 0.89 (s, 9H). 13C NMR (126 MHz,
DMSO-d6) δ 77.6, 58.5, 44.8, 35.2, 27.3, 23.4, 22.1, 21.9. LC/MS (CI):
m/z = 172 [M+H–HCl]+. Anal. Calcd. for C10H22ClNO: C 57.82; H 10.67; N
6.74; Cl 17.06. Found: C 57.53; H 10.39; N 6.74; Cl 17.45.
4-Isobutylpiperidin-1-ium chloride (24mHCl). After extraction, the
organic layers were combined and evaporated in vacuo. The crude
compound was purified by distillation in vacuo, bp 67–69 °C / 12 mmHg.
Then, the obtained base was dissolved in hexanes, and 4 M HCl in 1,4-
dioxane (20 mL) was added at rt. The precipitate formed was filtered,
washed with hexanes (310 mL) and dried on air. Yield 1.30 g (28%
1
from 23m (6.00 g, 26.1 mmol)); white crystals; mp 232–234 °C H NMR
(400 MHz, DMSO-d6) δ 9.05 (d, J = 82.4 Hz, 2H), 3.17 (d, J = 12.9 Hz,
2H), 2.79 (q, J = 12.1 Hz, 2H), 1.72 (d, J = 13.9 Hz, 2H), 1.62 (hept, J =
6.7 Hz, 1H), 1.59 – 1.51 (m, 1H), 1.28 (qd, J = 12.9, 3.7 Hz, 2H), 1.06 (t,
J = 6.7 Hz, 2H), 0.84 (d, J = 6.7 Hz, 6H). 13C NMR (126 MHz, DMSO-d6)
δ 45.5, 43.5, 31.2, 29.0, 24.5, 23.1. LC/MS (CI): m/z = 142 [M+H–HCl]+.
Anal. Calcd. for C9H20ClN: C 60.83; H 11.34; N 7.88; Cl 19.95. Found: C
60.83; H 11.43; N 8.03; Cl 19.98.
2-Benzylpiperidin-1-ium chloride (29f). Yield 2.66 g (92% from 28f
(3.64 g, 13.8 mmol)); white solid; mp 141–143 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.84 (s, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.28 – 7.14 (m, 3H),
3.33 – 3.25 (m, 1H), 3.23 (d, J = 13.0 Hz, 1H), 3.12 (dd, J = 13.3, 4.7 Hz,
1H), 2.87 (td, J = 11.8, 3.2 Hz, 1H), 2.74 (dd, J = 13.3, 9.4 Hz, 1H), 1.74
– 1.63 (m, 3H), 1.60 (d, J = 14.0 Hz, 1H), 1.47 – 1.30 (m, 2H). 13C NMR
(126 MHz, DMSO-d6) δ 136.6, 129.7, 129.1, 127.3, 57.2, 44.3, 39.3, 27.7,
22.2, 21.9. LC/MS (CI): m/z = 176 [M+H–HCl]+. Anal. Сalcd. for
C12H18ClN: C 68.07; H 8.57; N 6.62; Cl 16.74. Found: C 67.81; H 8.93; N
6.24; Cl 16.85.
2,2-Dimethyl-1-(piperidin-4-yl)propan-1-ol (25n). The crude product
was extracted with EtOAc (280 mL). Organic layers combined, dried
over Na2SO4 and evaporated. Yield 1.56 g (91% from 23n (2.44 g, 10.0
mmol)); white solid; mp 142–144 °C. 1H NMR (500 MHz, DMSO-d6) δ
4.20 (s, 1H), 2.88 (d, J = 11.8 Hz, 2H), 2.81 (s, 1H), 2.49 – 2.36 (m, 2H),
2.13 (s, 1H), 1.57 – 1.47 (m, 2H), 1.45 – 1.38 (m, 1H), 1.36 – 1.23 (m,
2H), 0.85 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 81.7, 47.3, 46.9, 38.7,
36.1, 33.9, 28.5, 27.4. LC/MS (CI): m/z = 172 [M+H]+. Anal. Calcd. for
C10H21NO: C 70.12; H 12.36; N 8.18. Found: C 70.39; H 12.03; N 8.18.
Representative procedure for the preparation of 19, 25 and 30. Pd-C
(10%, 0.60 g) and Et3N (2.51 g, 3.45 mL, 24.8 mmol) were added to a
stirred solution of 23c (1.20 g, 4.96 mmol) in MeOH (100 mL).The
mixture was hydrogenated in autoclave at 80°C for 18 h under H2 (30
bar). Then, the reaction mixture was evaporated in vacuo, 5% aq NaOH
(10 mL) was added to the residue and the mixture was extracted with
EtOAc (250 mL). Organic layers were combined, dried over Na2SO4 and
evaporated in vacuo. The residue was diluted with hexanes (30 mL), the
precipitate formed was filtered, washed with hexanes (310 mL), and
dried on air.
4-Benzylpiperidin-1-ium chloride (24oHCl). Yield 3.81 (95% from 23o
(5.00 g, 18.9 mmol)); white solid; mp 181–183 °C. 1H NMR (500 MHz,
DMSO-d6) δ 9.01 (d, J = 135.0 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.23 –
7.08 (m, 3H), 3.18 (d, J = 12.7 Hz, 2H), 2.75 (q, J = 11.9 Hz, 2H), 2.56 –
2.51 (m, 2H), 1.78 (ttt, J = 10.9, 7.1, 3.5 Hz, 1H), 1.72 – 1.59 (m, 2H),
1.47 – 1.28 (m, 2H). 13C NMR (126 MHz, DMSO-d6δ 139.9, 129.5, 128.7,
126.5, 43.4, 42.1, 35.4, 28.6. LC/MS (CI): m/z = 176 [M+H–HCl]+. Anal.
Calcd. for C12H18ClN: C 68.07; H 8.57; N 6.62; Cl 16.74. Found: C 67.80;
H 8.65; N 6.95; Cl 16.45.
2-(Piperidin-3-yl)propan-2-ol (19a). Yield 0.98 g (82% from 17a (1.80 g,
8.33 mmol)); beige solid; mp 73–75 °C. 1H NMR (500 MHz, CDCl3) δ
3.17 (d, J = 11.3 Hz, 1H), 2.97 (dt, J = 11.8, 3.5 Hz, 1H), 2.55 (ddd, J =
13.8, 8.5, 2.7 Hz, 2H), 2.25 – 1.99 (m, 2H), 1.86 – 1.81 (m, 1H), 1.76 (dp,
J = 11.4, 3.5 Hz, 1H), 1.49 – 1.41 (m, 2H), 1.30 (td, J = 11.8, 4.0 Hz, 1H),
1.18 (d, J = 9.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 71.9, 48.2, 47.5,
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
46.9, 28.1, 26.8, 26.4, 26.2. LC/MS (CI): m/z = 144 [M+H]+. Anal. Calcd.
for C8H17NO: C 67.09; H 11.96; N 9.78. Found: C 67.41; H 12.33; N 9.51.
1.57 – 1.38 (m, 4H), 1.37 (s, 9H), 1.18 – 1.06 (m, 2H). 13C NMR (126
MHz, CDCl3) δ 156.5, 79.6, 72.0, 60.5, 46.4, 43.4, 28.4, 26.1. LC/MS
(CI): m/z = 257 [M+H]+. Anal. Calcd. for C13H24N2O3: C 60.91; H 9.44; N
10.93. Found: C 60.53; H 9.31; N 11.12.
1-(Piperidin-3-yl)cyclobutan-1-ol (19b). Yield 1.38 g (85% from 17b
(2.40 g, 10.5 mmol)); beige solid; mp 110–112 °C. 1H NMR (500 MHz,
CDCl3) δ 2.99 (s, 1H), 2.97 (dd, J = 11.9, 2.5 Hz, 1H), 2.90 (dd, J = 11.9,
5.9 Hz, 1H), 2.85 – 2.76 (m, 2H), 2.74 (s, 1H), 2.21 – 2.10 (m, 2H), 2.05
– 1.94 (m, 2H), 1.90 (dq, J = 11.9, 5.9 Hz, 1H), 1.79 (ddt, J = 15.2, 10.0,
4.6 Hz, 1H), 1.71 – 1.57 (m, 3H), 1.53 – 1.41 (m, 2H). 13C NMR (126
MHz, CDCl3) δ 78.4, 47.3, 47.0, 41.2, 35.7, 34.0, 25.0, 24.2, 12.1. LC/MS
(CI): m/z = 156 [M+H]+. Anal. Calcd. for C9H17NO: C 69.63; H 11.04; N
9.02. Found: C 69.44; H 10.81; N 9.13.
tert-Butyl 3-hydroxy-3-(piperidin-4-yl)pyrrolidine-1-carboxylate (25h).
The compound existed as a mixture of rotamers (ca. 1:1) Yield 1.79 g
1
(91% from 23h (2.50 g, 7.28 mmol)); white solid; mp 72–74 °C. H NMR
(400 MHz, CDCl3) δ 3.56 – 3.37 (m, 3H), 3.34 – 3.16 (m, 2H), 3.14 – 3.07
(m, 2H), 2.57 (t, J = 11.6 Hz, 2H), 1.95 – 1.67 (m, 4H), 1.65 – 1.46 (m,
3H), 1.43 (s, 9H), 1.29 – 1.25 (m, 1H). 13C NMR (126 MHz, CDCl3) δ
154.8 and 154.7, 81.6 and 80.6, 79.2, 57.0 and 56.8, 46.6 and 46.5, 44.9
and 44.4, 44.3, 36.2 and 35.7, 28.5, 27.7 and 27.4. LC/MS (CI): m/z =
271 [M+H]+. Anal. Calcd. for C14H26N2O3: C 62.19; H 9.69; N 10.36.
Found: C 62.03; H 9.71; N 10.65.
tert-Butyl 4'-hydroxy-[3,4'-bipiperidine]-1'-carboxylate (19c). Yield
0.75 g (94% from 17c (1.00 g, 2.80 mmol)); white solid; mp 151–153 °C.
1H NMR (500 MHz, CDCl3) δ 3.85 (s, 2H), 3.10 (d, J = 13.0 Hz, 2H), 3.01
(dd, J = 11.9, 3.4 Hz, 1H), 2.88 – 2.79 (m, 2H), 2.69 (ddd, J = 11.9, 8.3,
3.4 Hz, 1H), 1.83 (dtt, J = 13.8, 6.8, 4.2 Hz, 1H), 1.67 (ddt, J = 11.8, 7.6,
3.9 Hz, 1H), 1.63 – 1.47 (m, 4H), 1.48 – 1.39 (m, 13H), 1.35 (tq, J = 7.6,
3.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 154.8, 79.2, 71.2, 47.7, 47.1,
44.5, 35.9, 34.7, 28.5, 25.2, 25.1. LC/MS (CI): m/z = 285 [M+H]+. Anal.
Calcd. for C15H28N2O3: C 63.35; H 9.92; N 9.85. Found: C 63.06; H 9.52;
N 9.72.
tert-Butyl 4-hydroxy-[4,4'-bipiperidine]-1-carboxylate (25i). Yield 1.81
g (91% from 23i (2.50 g, 7.00 mmol)); white solid; mp 133–135 °C. 1H
NMR (400 MHz, DMSO-d6) δ 4.01 (s, 1H), 3.70 (d, J = 12.5 Hz, 2H), 3.01
– 2.88 (m, 4H), 2.35 (t, J = 11.6 Hz, 2H), 1.54 (d, J = 11.6 Hz, 2H), 1.38
(s, 9H), 1.36 – 1.20 (m, 5H), 1.17 – 1.04 (m, 3H). 13C NMR (126 MHz,
CDCl3) δ 154.8, 79.3, 71.0, 47.3, 46.9, 39.5, 33.9, 28.5, 26.8. LC/MS
(CI): m/z = 285 [M+H]+. Anal. Calcd. for C15H28N2O3: C 63.35; H 9.92; N
9.85. Found: C 63.29; H 9.91; N 9.87.
1-(Piperidin-4-yl)cyclobutan-1-ol (25b). Yield 1.71
g (91% from
23b(1.15 g, 5.00 mmol)); white solid; mp 166–168 °C. 1H NMR (500 MHz,
CDCl3) δ 3.20 (d, J = 12.4 Hz, 2H), 2.60 (td, J = 12.4, 2.6 Hz, 2H), 2.36 (s,
2H), 2.18 – 2.12 (m, 2H), 1.93 (ddd, J = 12.4, 9.9, 7.4 Hz, 2H), 1.88 –
1.77 (m, 1H), 1.70 (d, J = 12.9 Hz, 2H), 1.59 – 1.47 (m, 2H), 1.31 (qd, J =
12.4, 4.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 77.2, 46.6, 43.8, 33.6,
25.9, 12.3. LC/MS (CI): m/z = 156 [M+H]+. Anal. Calcd. for C9H17NO: C
69.63; H 11.04; N 9.02. Found: C 69.51; H 11.41; N 9.30.
1-(Piperidin-4-yl)propan-1-ol (25l). Yield 0.82 g (88% from 23l (1.40g,
6.48 mmol)); white solid; mp 97–99 °C. 1H NMR (400 MHz, CDCl3) δ 3.21
(ddd, J = 9.0, 5.7, 3.5 Hz, 1H), 3.15 – 2.99 (m, 2H), 2.53 (d, J = 11.9 Hz,
4H), 1.75 (dt, J = 12.8, 2.9 Hz, 1H), 1.58 – 1.46 (m, 2H), 1.44 – 1.30 (m,
2H), 1.29 – 1.11 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 76.7, 46.4, 41.7, 29.4, 28.2, 26.7, 10.1. LC/MS (CI): m/z = 144
[M+H]+. Anal. Calcd. for C8H17NO: C 67.09; H 11.96; N 9.78. Found: C
66.94; H 11.66; N 10.11.
1-(Piperidin-4-yl)cyclopentan-1-ol (25c). Yield 0.82 g (95% from 23c
(1.20 g, 4.96 mmol)); white solid; mp 138–140 °C. 1H NMR (500 MHz,
CDCl3) δ 3.12 (d, J = 11.9 Hz, 2H), 2.58 (t, J = 11.9 Hz, 2H), 1.84 – 1.76
(m, 2H), 1.68 (d, J = 11.9 Hz, 2H), 1.62 – 1.51 (m, 6H), 1.49 (s, 2H), 1.44
– 1.31 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 84.3, 47.0, 46.1, 37.6, 28.4,
23.6. LC/MS (CI): m/z = 170 [M+H]+. Anal. Calcd. for C10H19NO: C 70.96;
H 11.31; N 8.28. Found: C 70.74; H 11.30; N 7.98.
2-Methyl-1-(piperidin-4-yl)propan-1-ol (25m). Yield 0.62 g (91% from
23m (1.00 g, 4.34 mmol)); yellowish solid; mp 121–123 °C. 1H NMR (500
MHz, CDCl3) δ 3.15 – 3.07 (m, 2H), 3.04 (t, J = 5.7 Hz, 1H), 2.58 (qd, J =
12.4, 2.7 Hz, 2H), 2.34 (s, 2H), 1.84 (dq, J = 13.1, 2.7 Hz, 1H), 1.76 (pd,
J = 6.9, 5.0 Hz, 1H), 1.57 – 1.47 (m, 2H), 1.34 – 1.20 (m, 2H), 0.92 (d, J
= 6.9 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
80.2, 46.5, 46.4, 39.1, 29.8, 29.5, 28.3, 19.9, 16.2. LC/MS (CI): m/z = 158
[M+H]+. Anal. Calcd. for C9H19NO: C 68.74; H 12.18; N 8.91. Found: C
69.07; H 11.99; N 8.62.
1-(Piperidin-4-yl)cyclohexan-1-ol (25d). Yield 0.76 g (96% from 23d
(1.12 g, 4.37 mmol)); white solid; mp 113–115 °C. 1H NMR (400 MHz,
CDCl3) δ 3.14 (d, J = 12.2 Hz, 2H), 2.55 (t, J = 11.4 Hz, 2H), 2.17 (s, 2H),
1.71 (d, J = 11.4 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.53 – 1.46 (m, 5H), 1.38
– 1.26 (m, 5H), 1.18 – 1.10 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 72.4,
46.9, 46.6, 34.2, 26.6, 25.9, 21.8. LC/MS (CI): m/z = 184 [M+H]+. Anal.
Calcd. for C11H21NO: C 72.08; H 11.55; N 7.64. Found: C 72.29; H 11.64;
N 7.25.
2,2-Dimethyl-1-(piperidin-4-yl)propan-1-ol (25n). Yield 0.80 g (94%
from 23n (1.22 g, 5.00 mmol)); white solid; mp 142–144 °C. 1H NMR
(500 MHz, DMSO-d6) δ 4.21 (s, 1H), 2.88 (d, J = 9.1 Hz, 2H), 2.81 (s,
1H), 2.50 – 2.37 (m, 2H), 2.15 (s, 1H), 1.57 – 1.47 (m, 2H), 1.45 – 1.38
(m, 1H), 1.36 – 1.25 (m, 2H), 0.85 (s, 9H). 13C NMR (126 MHz, DMSO-
d6) δ 81.7, 47.3, 46.9, 38.7, 36.1, 33.9, 28.5, 27.4. LC/MS (CI): m/z = 172
[M+H]+. Anal. Calcd. for C10H21NO: C 70.12; H 12.36; N 8.18. Found: C
70.17; H 12.27; N 8.28.
1-(Piperidin-4-yl)cycloheptan-1-ol (25e). Yield 0.84 g (96% from 23e
(1.20 g, 4.44 mmol)); white solid; mp 82–84 °C. 1H NMR (500 MHz,
CDCl3) δ 3.14 (d, J = 12.2 Hz, 2H), 2.55 (td, J = 12.2, 2.4 Hz, 2H), 2.18 (s,
2H), 1.74 – 1.70 (m, 3H), 1.68 (s, 1H), 1.64 – 1.53 (m, 6H), 1.51 – 1.46
(m, 2H), 1.43 – 1.36 (m, 3H), 1.28 (qd, J = 12.2, 3.6 Hz, 2H). 13C NMR
(126 MHz, CDCl3) δ 76.4, 48.0, 47.0, 38.4, 29.8, 27.3, 22.6. LC/MS (CI):
m/z = 198 [M+H]+. Anal. Calcd. for C12H23NO: C 73.04; H 11.75; N 7.1.
Found: C 73.34; H 12.06; N 6.86.
Phenyl(piperidin-4-yl)methanol (25o). Yield 1.36 (94% from 23o (2.00
g, 7.57 mmol)); white solid; mp 169–171 °C. 1H NMR (500 MHz, CDCl3) δ
7.35 (t, J = 7.5 Hz, 2H), 7.31 – 7.26 (m, 3H), 4.35 (d, J = 7.5 Hz, 1H),
3.10 (dt, J = 12.5, 3.4 Hz, 1H), 2.99 (dt, J = 12.5, 3.4 Hz, 1H), 2.56 (td, J
= 12.3, 2.7 Hz, 1H), 2.48 (td, J = 12.3, 2.7 Hz, 1H), 2.10 – 1.91 (m, 3H),
1.72 (tdt, J = 11.6, 7.5, 3.7 Hz, 1H), 1.30 – 1.21 (m, 2H), 1.12 (qd, J =
12.3, 4.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 143.3, 128.3, 127.6,
126.6, 78.9, 46.4, 46.4, 43.7, 29.6, 29.6. LC/MS (CI): m/z = 192 [M+H]+.
Anal. Calcd. for C12H17NO: C 75.35; H 8.96; N 7.32. Found: C 75.16; H
9.09; N 7.00.
tert-Butyl 3-hydroxy-3-(piperidin-4-yl)azetidine-1-car-boxylate (25g).
Yield 1.73 g (89% from 23g (2.50 g, 7.59 mmol)); white solid; mp 166–
168 °C. 1H NMR (400 MHz, DMSO-d6) δ 5.42 (s, 1H), 3.74 (d, J = 8.6 Hz,
2H), 3.55 (s, 2H), 2.94 (d, J = 12.0 Hz, 2H), 2.37 (t, J = 12.0 Hz, 2H),
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
FULL PAPER
General procedure for the preparation of 17a, 17b, 32a, and 32b
under the flow reaction conditions. The corresponding halopyridine 14
or 31 (42.0 g/L, 0.370 M in THF, 25.5 mL/min flow rate) and LDA (1 M in
THF, 9.5 mL/min flow rate) were set off into the first mixer (600 mL) at –
50 °C with 17 min residence time in the tube. Then, the reaction mixture
and the corresponding ketone (2 M in THF, 4.7 mL/min flow rate) were
set off into the second mixer at –50 °C with 7.5 min residence time in the
tube. The reaction mixture was collected into the receiving tank in a –
40 °C bath under argon atmosphere. When all the reaction mixture
passed through the tube, the receiving container was removed from the
bath and stirred at rt for 8 h. Then saturated aq NH4Cl (500 mL) was
added, and the reaction mixture was evaporated in vacuo. The residue
was extracted with CH2Cl2 (3350 mL), the organic phase was dried over
Na2SO4 and evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel using hexanes – t-BuOMe (1:1) as
eluent (Rf = 0.6 for 32a, Rf = 0.5 for 32b).
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Hydrogenation of the products obtained was performed according to a
slightly modified representative procedure described above. Thus, 32a
(198 g, 1.16 mol) was hydrogenated in a 5 L autoclave in MeOH (4 L) in
the presence of 10% Pd-C (160 g) under 50 atm of H2 at 50 °C. The
crude product after work-up and extraction was not transformed into
hydrochloride, but purified by distillation in vacuo instead; bp 21–23 °C /
2 mmHg. Yield of 18a – 116 g (78%). For 18b: bp 51–53 °C / 2 mmHg,
yield 71%. For spectral and physical data, see ref.[42]
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Acknowledgements
The work was funded by Enamine Ltd. O.O.G. was also funded
by Ministry of Education and Science of Ukraine (project No.
19БФ037-03). The authors thank Prof. Andrey A. Tolmachev for
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[24]
his
encouragement
and
support,
and
UOSLab
(www.en.uoslab.com) for providing high pressure reactors.
P. W. Ondachi, C. M. Kormos, S. P. Runyon, J. B. Thomas, S. W.
Mascarella, A. M. Decker, H. A. Navarro, T. R. Fennell, R. W.
Snyder, F. I. Carroll, J. Med. Chem. 2018, 61, 7525–7545.
M. Keller, C. Tränkle, X. She, A. Pegoli, G. Bernhardt, A. Buschauer,
R. W. Read, Bioorg. Med. Chem. 2015, 23, 3970–3990.
S. Yamashita, N. Kurono, H. Senboku, M. Tokuda, K. Orito, Eur. J.
Org. Chem. 2009, 1173–1180.
Keywords: heteroaliphatic compounds, piperidine,
regioselective reaction, directed ortho metalation, catalytic
hydrogenation
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10.1002/ejoc.201900450
European Journal of Organic Chemistry
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(Cyclo)alkyl Piperidines
Andrii I. Subota, Anton O. Lutsenko,
Bohdan V. Vashchenko,
Dmitriy M. Volochnyuk,
Vitalina Levchenko, Yurii V. Dmytriv,
Eduard B. Rusanov, Alina O. Gorlova,
Sergey V. Ryabukhin,
An efficient approach towards introducing (cyclo)alkyl substituents at C-2, C-3 or C-
4 positions of the piperidine ring based on the formal sp3–sp3 retrosynthetic
disconnection is described. The procedure commenced with selective directed
ortho metalation of halopyridines, followed by reaction with aldehydes or ketones.
Catalytic hydrogenation of these adducts could be performed selectively for the
synthesis of (cyclo)alkylpiperidines or the corresponding saturated amino alcohols
on up to 0.5 kg scale.
Oleksandr O. Grygorenko*
Page No. – Page No.
Scalable and Straightforward
Synthesis of All Isomeric
(Cyclo)alkylpiperidines
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