Synthesis of 3,3-Dichloropiperidines and Further Functionalization via Pd-Catalyzed Cross-Coupling Reactions of the Dichloromethylene Moiety

Article abstract of DOI:10.1002/ejoc.201801613

A new synthetic methodology for the functionalization of the dichloromethylene moiety in 3,3-dichloropiperidines via Pd-catalyzed cross-coupling reactions is reported. A range of 3,3-dichloropiperidines was synthesized via a hydride induced cyclization of α,α,δ-trichloroaldimines or an indium(III) triflate catalyzed alkynylation/cyclization procedure of α,α,δ-trichloroaldimines. Subsequently, a dehydrochlorination followed by a cross-coupling with the thus formed vinylic chloride was envisioned. The non-alkynylated 3,3-dichloropiperidines could be regioselectively eliminated and by careful choice of solvent and base both of the two regioisomeric vinyl chlorides could be exclusively formed. Palladium-catalyzed Suzuki cross-coupling of the thus formed 5-chloro-1,2,3,6-tetrahydropyridines led to C3-substituted 1,2,3,6-tetrahydropyridines, which could be easily reduced to 3-substituted piperidines, generating therapeutic agent (±)-Preclamol for example. The 2-alkynyl-3,3-dichloropiperidines were regioselectively eliminated giving the cyclic enamine, which was subsequently cross-coupled in one-pot. The presence of the alkynyl function, in this case, clearly directs elimination towards enamine structures. Hydrogenation of the resulting, unstable 2-alkynyl-3-substituted-1,2,3,4-tetrahydropyridines, yields stable 2,3-disubstituted piperidines.

Full text of DOI:10.1002/ejoc.201801613

A Journal of
Accepted Article
Title: Synthesis of 3,3-dichloropiperidines and the further
functionalization via Pd-catalyzed cross-coupling reactions of the
dichloromethylene moiety
Authors: Wim E. Van Beek, Robert Smets, Khushbu Kushwaha,
Wouter A Herrebout, and Kourosch Abbaspour Tehrani
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801613
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801613
Supported by

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 3,3-dichloropiperidines and the further
functionalization via Pd-catalyzed cross-coupling reactions of the
dichloromethylene moiety
Wim E. Van Beek,[a] Robert J. Smets,[a] Khushbu Kushwaha,[a] Wouter A. Herrebout,[b] and Kourosch
Abbaspour Tehrani*[a]
Dedication ((optional))
Abstract: A new synthetic methodology for the functionalization of
the dichloromethylene moiety in 3,3-dichloropiperidines via Pd-
catalyzed cross-coupling reactions is reported. A range of 3,3-
dichloropiperidines was synthesized via
cyclization of -trichloroaldimines or an indium(III) triflate
catalyzed alkynylation/cyclization procedure of -
a
hydride induced
trichloroaldimines. Subsequently, a dehydrochlorination followed by
a cross-coupling with the thus formed vinylic chloride was envisioned.
The
non-alkynylated
3,3-dichloropiperidines
could
be
regioselectively eliminated and by carefull choice of solvent and
base both of two regioisomeric vinyl chlorides could be exclusively
formed. Palladium catalyzed Suzuki cross-coupling of the thus
formed 5-chloro-1,2,3,6-tetrahydropyridines led to C3- substituted
1,2,3,6-tetrahydropyridines, which could be easily reduced to 3-
substituted piperidines, generating for example, the therapeutically
active agent (±)-Preclamol for example. The 2-alkynyl-3,3-
dichloropiperidines were regioselectively eliminated giving the cyclic
enamine which was subsequently cross-coupled in one-pot. The
presence of the alkynyl function, in this case, clearly directs
elimination towards enamine structures. Hydrogenation of the
Scheme 1. Examples of C3-substituted piperidines in natural products and
bioactive compounds.
Syntheses of C3-substituted piperidines have therefore been
studied extensively over the past decades.[2] Syntheses can be
divided in four major groups. In a first group the piperidine
skeleton is created via a Suzuki-Miyaura cross-coupling of 3-
halopyridines and arylboronic acids, followed by N-alkylation and
hydrogenation of the pyridine-ring to yield piperidines[3] (Scheme
2 – path a) or NaBH4 reduction of pyridines to yield 1,2,3,6-
tetrahydropyridines,[4] which can lead to enantiopure piperidines
via asymmetric hydrogenation.[5] A second approach towards
C3-substituted piperidines is the ring expansion/rearrangement
of pyrrolidines via an aziridinium intermediate (Scheme 2 – path
b).[2a, 6] This transformation can be achieved enantioselectively
when enantiopure prolinols are used as starting materials. A
third approach, more suitable for more substituted piperidines,
builds up the piperidine ring starting from a tertiary amine
containing one or two unsaturations via cycloaddition reactions,
radical cyclizations or metathesis reactions (Scheme 2 – path c).
In a fourth approach a secondary amine is ring closed via
intramolecular reductive amination or nucleophilic substitution
(Scheme 2 – path d and e).
resulting,
unstable
2-alkynyl-3-substituted-1,2,3,4-
tetrahydropyridines, yields stable 2,3-disubstituted piperidines.
Introduction
C3-Substituted piperidines are an important class of building
blocks and are present in many natural products, such as the
alkaloids isoanabasine (1) and stenusine (2) and bioactive
compounds such as antiparkinson drugs Pecazine (3) and
Metixene (4), and the anticholinergic agent Piperidolate (5)
(Scheme 1).[1]
[a]
[b]
Dr. W. E. Van Beek, R. J. Smets, Dr. K. Kushwaha and Prof. Dr. Ir.
K. Abbaspour Tehrani Organic Synthesis, Department of Chemistry,
University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp,
Belgium. Fax: (+32)32653233; phone: (+32)32653226; e-mail:
kourosch.abbaspourtehrani@uantwerpen.be
https://www.uantwerpen.be/en/rg/orsy/
Prof. Dr. W. A. Herrebout Molecular Spectroscopy, Department of
Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020
Antwerp, Belgium.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 2. Routes to C3-substituted piperidines.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
Polyhalogenated imines are a class of substrates that are
interesting due to the increased electrophilicity of the C=N bond
in comparison to non-halogenated imines. Apart from additions
of strong nucleophiles to the azomethine carbon (cyanation,[7]
Mannich-type reactions[8]), where the electrophilicity of the imine
is of little importance, there are also examples of catalyzed
nucleophilic additions to the azomethine carbon, in which
enhanced electrophilicity is required.[9] One-pot nucleophilic
addition to trichlorinated imines and sequential ring closing
reactions often leads to interesting substrates, still bearing an
electrophilic dichloromethylene group.[10]
Until present, the dichloromethylene group has been used in
amine, dihaloalkane, alkyne (AHA) coupling reactions and
elimination reactions.[10] Unfortunately, AHA coupling reactions
suffer from a small substrate scope, since only dihalomethanes
(dichloromethane, dibromomethane and diiodomethane)[11] and
benzal halides[12] can be used. In the AHA coupling the
dichloromethylene group acts as a masked carbonyl function.
Dehydrochlorination of dichloromethylene containing molecules,
lead to vinylic chlorides, that can be further exploited.[13] In this
work, the applicability of a dichloromethylene moiety, present in
a piperidine system, was further extended by using the group in
Pd-catalyzed cross-coupling reactions.
An earlier report describes a two-step protocol for the synthesis
of 1-isopropyl-3-chloropiperidine by reaction of -
trichloropentanaldimine with lithium aluminiumhydride in diethyl
ether, followed by a treatment with potassium carbonate.[14] In
order to avoid the loss of one chloro atom in the initially formed
dichloropiperidine, in the present work, a milder reducing agent
was used. The reaction of -trichloroaldimines with sodium
cyanoborohydride in methanol in the presence of acetic acid
directly gave rise to N-substituted-3,3-dichloropiperidines 8 in
nearly quantitative yields (Scheme 3). However, for substrates
with sterically hindered amine groups (tert-butyl 7b), only after
two days the precipitation of the corresponding salt of piperidine
8b was observed from the reaction mixture and the ring closure
takes up to 9 days for completion, whereas for n-propyl- 8a and
PMB-piperidines 8c ring closure is complete after 18 hours.
Elimination of one chlorine atom from 3,3-dichloropiperidine 8a
can give either vinyl chloride 9a or chlorinated enamine 10a,
depending on the regioselectivity of the elimination. Therefore,
different bases and reaction conditions were screened (Table 1).
Table 1. Optimization of regioselective elimination of 3,3-dichloropiperidine 8a.
Results and Discussion
The synthesis of N-substituted 3,3-dichloropiperidines 8 starts
with the condensation of 2,2,5-trichloropentanal (6) with a
primary amine (Scheme 3). For non-bulky primary amines (e.g.
n-propylamine) this condensation can be easily performed by
using 4 Å molecular sieves as drying agent in toluene (Method
A). For more sterically hindered primary amines (e.g. tert-butyl
and p-methoxybenzylamine) a more difficult procedure[8a] that
makes use of TiCl4 is needed (Method B). Imines 7 synthesized
via these methods were generally pure enough to use as such in
the next steps.
Entry[a]
Base (equiv.)
Solvent (mL)
T/t
(°C/h)
Yield 9a/10a/8a
(%)[b]
1
2
3
KOtBu (3)
NaOtBu (3)
KOtAm (3)
THF (1)
THF (1)
70/17
70/17
70/17
19/4/11
4/0.1/52
41/16/-
THF
(1)
+
PhCH3 (1)
THF (1)
THF (1)
THF (1)
4
5
6
DBU (3)
70/17
70/17
70/17
-/-/62
-/-/62
-/-/46
Cs2CO3 (3)
Proton sponge
(3)
7
KOtAm (3)
KOtBu (3)
NaOtBu (3)
n-BuLi (3)
PhCH3 (3)
PhCH3 (2)
PhCH3 (2)
70/17
80/6
80/6
r.t./4
32/2/17
-/-/50
-/-/31
-/5/-
8
9
PhCH3 (1)
C6H14 (1)
+
10
11
12
13
14
15
NaH (2)
PhCH3 (2)
THF (2)
70/24
100/17
60/20
r.t./70
60/20
-/-/27
LDA (1.2)
-/-/72
BTPP (1.1)
LiHMDS (1.1)
LiHMDS (1.1)
PhCH3 (2)
PhCH3 (2.5)
PhCH3 (2.5)
-/-/90
-/18/78
-/25/51
Scheme 3. Synthesis of 3,3-dichloropiperidines 8 from 2,2,5-trichloropentanal
(6).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
interaction with the lithium cation is important. In the case of
toluene, LiHMDS is not solvated and the presence of Li+ is
important. Interaction of Li+ with nitrogen probably anchors the
base so that the proton next to nitrogen is removed in the
elimination reaction and product 10a is obtained (Scheme 4 –
top). In the case of DMSO, Li+ is solvated and thus the base is
stronger and will react faster. Meanwhile, the carbocation
generated via E1 elimination is more stabilized in a more polar
solvent. Kinetic deprotonation occurs on the most accessible
position leading to vinyl chloride 9a (Scheme 4 – bottom).
16
17
18
19
LiHMDS (2)
LiHMDS (6)
KHMDS (2)
LiHMDS (2)
PhCH3 (2)
PhCH3 (4)
PhCH3 (2)
DMSO (2)
100/4
100/2
100/4
100/2.5
-/35/-
-/41/-
7/12/-
37/-/-
[a] All reactions were performed at 0.5 mmol scale in a sealed vial under
argon. [b] Yields were calculated from the 1H NMR of the reaction mixture
using 1,4-diacetylbenzene as an internal standard.
With vinyl chloride 9a in hands, attempts were made to use
this vinyl chloride in Suzuki-Miyaura cross coupling reactions
with phenylboronic acid (Table 2). At first, common reaction
conditions such as a Pd or Ni source in combination with the
popular PPh3 ligand (Entries 1-3) were tried, but no coupling
product was observed. Since a low reactive vinyl chloride
substrate is used, we switched our attention directly to more
reactive Pd(NHC) catalyst systems. When using 2.5 mol-% of
IPrPd(Allyl)Cl in combination with 2 equivalents of NaOtBu and
1.3 equivalents of phenylboronic acid in dioxane for 5 hours at
100 °C, 50% product was formed, and around 50% starting
material was still present (Entry 4). The filtration of this black
mixture over Celite produced an orange/yellow mixture, which
made believe that palladium black was formed during the
reaction. Therefore, the same reaction was repeated at lower
temperature (80 °C – Entry 5) which gave a better result and
higher NMR yield (68%) of intended product but no full
conversion yet. By doubling the amount of catalyst, in the hope
of speeding up the reaction no improvement was observed
(Entry 6), probably due to a more rapid formation of palladium
black. In an attempt to avoid the formation of Pd black, only 1
mol-% of IPrPd(Allyl)Cl was used, but even if the reaction was
carried out for a longer time (16 instead of 5 hours) only 12% of
intended product was obtained (Entry 7). In another attempt to
speed up the reaction, 2 equivalents of phenylboronic acid were
used (Entry 8), but this led to homocoupling of the boronic acid.
Other coupling partners such as pinacol ester (Entry 9) or
trifluoroborate (Entry 10) did not work as well as the boronic acid.
The application of other Pd precatalysts such as IPrPEPPSI and
IPrPd(Cinnamyl)Cl (Entries 11 and 12) did not give higher yields.
Microwave experiments at higher temperatures faced the same
problem and gave no full conversion (Entries 13 and 14).
Changing from Pd(NHC) catalysts to Pd sources in combination
with well-known electron-rich phosphine ligands,[15] allowed the
reaction to be run at 50 °C, albeit in low yield (Entry 15 and 16).
By lowering the temperature we hoped to avoid the formation of
Pd black, and have a more efficient catalytic system. Eventually,
the combination of 5 mol-% of Pd(OAc)2 and 10 mol-% of XPhos
and 2 equivalents of sodium tert-butoxide in dioxane produces
68% of product 12a, along with some starting material (Entry 17).
I was decided that this was a good starting point for further
optimization of the base and the solvent. Different bases other
than sodium tert-butoxide were evaluated (see SI), but sodium
tert-butoxide remained the best. Also, other solvents were
evaluated (see SI), and the best result was obtained for
methanol, giving an NMR-yield of 95% (Entry 18).
Typical sterically hindered bases such as KOtBu, NaOtBu and
even KOtAm (Entries 1-3) yielded mostly vinyl chloride 9a but
also non-negligible amounts of enamine 10a, next to
degradation products and some starting material 8a. Weaker
bases such as DBU, Cs2CO3 and proton sponge (N, N, N', N'-
tetramethyl-1,8-naphthalenediamine)
did not give any
elimination at all (Entries 4-6). Changing the solvent from THF to
toluene gave a better vinyl chloride/enamine ratio 9a/10a for
KOtAm (Entry 7), but did not yield any product when KOtBu or
NaOtBu was used (Entries 8, 9). Stronger bases such as n-BuLi,
NaH, LDA or BTPP (phosphazene base P1-tert-butyl-
tris(tetramethylene)) did not give satisfactory results either
(Entries 10-13). However, when LiHMDS was used, only vinyl
chloride 9a is formed, even at room temperature (Entry 14). Full
conversion is obtained by modifying the amount of LiHMDS,
reaction time and temperature (Entries 15, 16) until an optimum
is realized (Entry 17). KHMDS on the other hand, yields a
mixture of both regioisomers again (Entry 18).
Scheme 4. Solvent-dependent elimination.
In order to obtain higher yields, we reasoned that for an E1
elimination a more polar solvent would stabilize the transition-
state, leading to an enhanced reaction. Changing the solvent
from toluene to DMSO, to our surprise, changes the
regioselectivity completely and only regioisomer 10a was
observed (Entry 19). Because KHMDS did not give solely
product 9a and changing the solvent changes the
regioselectivity, we reasoned that the elimination probably does
not follow a straightforward E1-type elimination and that the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
withdrawing groups such as 3-BnO, 3-OH 3-CF3, 4-CF3 and 4-
CN were difficult to couple and could only be obtained in
moderate yields (Entries 5-9), while in the case of 4-NO2 only
traces of the coupling product 12j were seen (Entry 10). In
addition, also styrylboronic acid could be used as a coupling
partner although only 25% of the coupling product 12k was
obtained after column chromatography (Entry 11). The coupling
of 12a with isobutylboronic acid, which can serve as an alkyl
boronic acid representative, was not possible under the given
reaction conditions (Entry 12). In order to widen the scope of the
reaction, also other nitrogen substituents were examined. To our
surprise a sterically hindered group, such as tert-butyl on the
substrate 12b worked even better, and gave 98% isolated yield
of 12m after column chromatography (Entry 13). Another
interesting example is the vinyl chloride 12c bearing a PMB
(para-methoxybenzyl) group, as this can serve as a protective
group, and product 12n was obtained in 85% yield (Entry 14).
In a next step, the synthetic value of the double bond remaining
in 3-aryl-1,2,3,6-tetrahydropyridines 12 was examined. As the
reaction mixture contains palladium and the solvent is methanol,
we realized that these are suitable conditions for catalytic
hydrogenation. Hence, for some entries in Table 3, a one-pot
cross-coupling and hydrogenation procedure was evaluated.
The cross-coupling was finished after 16 hours at 50 °C and
then the reaction mixtures were cooled to room temperature and
brought under H2 atmosphere with a balloon. The reaction
mixtures were further stirred at room temperature for 24 hours.
In the particular case of 12f, the pharmaceutically important drug
(±)-Preclamol[16] (3-(3- hydroxyphenyl)-N-propylpiperidine (13f)
or 3-PPP) could be synthesized in a one-pot fashion. The S-(-)-
enantiomer acts as a selective dopamine autoreceptor agonist
and has been synthesized via an asymmetric hydrogenation of
12f as described by Verendel et al.[17]
Table 2. Optimization of Suzuki cross-coupling of 9a with phenylboronic acid.
Entry[a]
1[b]
Catalyst (mol-%)
PdCl2 (2.5), PPh3 (5)
Pd(ClPPh3)2 (2.5)
Ni(ClPPh3)2 (2.5)
IPrPd(Allyl)Cl (2.5)
IPrPd(Allyl)Cl (2.5)
IPrPd(Allyl)Cl (5)
IPrPd(Allyl)Cl (1)
IPrPd(Allyl)Cl (2.5)
IPrPd(Allyl)Cl (2.5)
IPrPd(Allyl)Cl (2.5)
IPrPEPPSI (2.5)
T/t (°C/h)
80/5
9a/12a (%)
90/0
2[b]
80/5
85/0
3[b]
80/5
92/0
4[c]
100/5
80/5
51/48
34/65
44/55
63/12
87/6
5[c]
6[c]
80/5
7[c]
80/16
80/5
8[d]
9[e]
80/5
47/44
45/22
51/37
10[f]
11[c]
80/5
80/5
12[c]
13[c]
14[c,g]
15[h]
IPrPd(Cinnamyl)Cl (2.5)
IPrPd(Allyl)Cl (2.5)
IPrPd(Allyl)Cl (2.5)
80/5
54/30
33/41
29/41
72/27
100/30’ MW
110/10’ MW
50/16
Pd(OAc)2 (5), DavePhos
(10)
Table 3. Scope of Suzuki-Miyaura cross-coupling of vinyl chloride 12 with
16[c,i]
17[j]
Pd(OAc)2 (5), SPhos (10)
Pd(OAc)2 (5), XPhos (10)
Pd(OAc)2 (5), XPhos (10)
80/5
38/51
15/68
0/95
50/16
50/16
18[k]
[a] All reactions were carried out on 0.3 mmol scale using 9a (1.0 equiv.),
phenylboronic acid (1.1 equiv.), NaOtBu (2 equiv.) in 1,4-dioxane (2 mL). [b] 3
equiv. NaOtBu. [c] 1.3 equiv. of phenylboronic acid. [d]
2 equiv. of
phenylboronic acid. [e] 1.3 equiv. of phenylboronic acid pinacol ester. [f] 1.3
equiv. of potassium phenyltrifluoroborate. [g] neat. [h] 2 mL THF/H2O 1/1, 2
equiv. Cs2CO3 instead of NaOtBu. [i] 2 equiv. CsF instead of NaOtBu. [j] 1
equiv. of phenylboronic acid. [k] Reaction in MeOH (2 mL) instead of 1,4-
dioxane.
With these optimized reaction conditions in hand, the
coupling of different boronic acids was examined (Table 3). The
coupling product 12a of vinyl chloride 9a with phenylboronic acid
was obtained in an excellent isolated yield of 94% (Entry 1).
Other weak electron-donating groups such as 4-Me (Entry 2)
and even the very sterically hindered 2-i-Pr (Entry 3) on the
phenylboronic acid were well tolerated, and products were
obtained in excellent yields. Stronger electron-donating groups
such as 4-OMe (Entry 4) substituted phenylboronic acid, were
also well tolerated. Phenylboronic acids with weakly electron-
boronic acids.
Entry[a]
R1
R2
Yield 12 Yield 13
(%)
(%)[b]
1
nPr
H, 12a
94
89
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
which could not be purified via column chromatography. Heck
reactions on the other hands require higher temperatures, and
indeed an even faster formation of Pd black was observed
without a trace of cross-coupled product.
2
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
tBu
PMB
4-Me, 12b
2-iPr, 12c
82
90
57
71
75
50
37
31
trace
25
0
-
3
-
4
4-MeO, 12d
3-BnO, 12e
3-OH, 12f
-
5
-
6
69
-
7
3-CF3, 12g
4-CF3, 12h
4-CN, 12i
8
-
9
-
Scheme 6. Sonogashira cross-coupling of vinyl chloride 9b.
10
11
12
13
14
4-NO2, 12j
styryl, 12k
isobutylboronic acid, 12l
H, 12m
-
-
The double bond in tetrahydropyridines 12 can be used in a BF3-
catalyzed
[2+2]-cycloaddition
reaction
with
dimethyl
-
acetylenedicarboxylate (DMAD), giving rise to azabicyclic
molecules 17 in a diastereoselective fashion (Scheme 7).
98
85
72
91
H, 12n
[a] All reactions were carried out on 0.3 mmol scale. Yields are isolated yields
after column chromatography. [b] Yield calculated from 9.
When using heteroarylboronic acids such as 2-pyridinylboronic
acid, no coupling product was observed (Scheme 5). Oxidative
addition into the C-Cl bond does occur, however. This is proven
by the isolation of hydrodechlorinated product 1-(4-
methoxybenzyl)-1,2,3,6-tetrahydropyridine (14) in 31%. It is well
known that heteroarylboronic acids easily protodeboronate[15] in
the presence of base and polar protic solvents such as methanol.
Usually this problem is solved by using superstoichiometric
amounts of heteroarylboronic acid or by changing to potassium
heteroaryltrifluoroborates or N- methyliminodiacetic (MIDA)
boronates, as they slowly hydrolyze and expose the
heteroarylboronic acid in situ.[18] However, since not even a trace
of coupling product was observed, no further attempts were
made to couple heteroarylboronic acids.
Scheme 7. [2+2]-Cycloaddition of 1,2,3,6-tetrahydropyridine 12a with DMAD.
To overcome regioselectivity problems and low yields
associated with the elimination of 3,3-dichloropiperidines 8, we
reasoned that using an soft, in situ formed, metal acetylide
instead of a hydride for the nucleophile induced cyclization of
trichloroimine 7 may lead to molecules which are less prone to
give regioselectivity issues. After all, when an alkyne moiety is
placed on position C2 of a piperidine ring, the hydrogen at the
C2 position becomes more acidic, leading to an easier
elimination and forming a more conjugated double bond.
Therefore, the reaction of -trichloroaldimine 7a with
phenylacetylene in the presence of a metal catalyst was
examined (Table 4). Entry 1 uses the same reaction conditions
as obtained for the synthesis
of 3,3-dichloropyrrolidines.[10] Although product 19a was
obtained in a decent 59% yield, another 18% of propargylamine
18a was still present in the reaction mixture. Using two
equivalents of phenylacetylene (Entry 2) or a higher loading of
In(OTf)3 (Entry 3) did not result in a higher yield of product 19a.
Since intramolecular ring closing reactions are relatively easier
for five-membered rings than for six-membered rings, it was
expected that a higher reaction temperature could lead to
increased yields of 19a. Indeed, by applying a reaction
temperature of 80 °C and toluene instead of CH2Cl2, a 71% yield
of 19a was obtained (Entry 4). The use of other solvents
resulted in lower yields (Entries 5 and 9), while different other
metal catalysts resulted in trace amounts or no product 19a at all
Scheme 5. The use of 2-pyridinylboronic acid results in dehalogenation.
Aside from Suzuki-Miyaura cross couplings, we examined the
possibility whether these reaction conditions are viable for other
cross coupling reactions (Scheme 6). The Sonogashira cross-
coupling of phenylacetylene and vinyl chloride 9b gives 51%
isolated yield of 15 after column chromatography. Also,
alkylacetylenes, such as 1-hexyne, can be coupled, albeit in a
moderate 34% yield of 16. Other popular cross-coupling
reactions are less viable for different reasons. Buchwald-Hartwig
cross-coupling reactions lead to unstable enamine products,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
(Entries 17-29). Apart from indium(III) triflate, only indium(III)
chloride and silver triflate were able to catalyze the coupling,
albeit in lower yields than indium(III) triflate (Entries 17, 22, 23
and 24). The reaction time could be diminished to 3 hours
without loss of yield (Entry 10). Using less (10 mol-% - Entry 12)
or more (50 mol-% - Entry 13) catalyst also resulted in lower
yields, and thus the optimized reaction conditions were set on 25
mol-% indium(III) triflate, with toluene as solvent at 80 °C for 3
hours (Entry 10). For the optimized screening yield of 71%, no
starting material was observed. The one-pot three-component A³
coupling of 2,2,5-trichloropentanal, n-propylamine and
phenylacetylene, did not result in the formation of product 19a
under the optimized reaction conditions (toluene, 80 °C, 3 h).
After workup, imine 7a was the main product.
22
23
24
25
26
27
28
29
AgOTf (25)
AgOTf (25)
AgOTf (25)
LiOTf (25)
PhCH3
PhCH3
Hexane
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
80/3
80/18
80/4
80/3
80/3
80/3
80/3
70/18
0/24[d]
0/55[d]
0/15[b]
0/0
Mg(OTf)2 (25)
ZnCl2 (25)
0/0
0/0
Zn(OTf)2 (25)
Al(OTf)3 (25)
0/ trace
0/0
[a] All reactions are carried out on 0.5 mmol scale with 7a (1.0 equiv.),
phenylacetylene (1.0 equiv.) in a sealed microwave vial (under air). [b]
Calculated from the 1H NMR spectrum with 1,3,5-trimethoxybenzene as
internal standard. [c] 2 equiv. phenylacetylene used. [d] Yield after acid-base
extraction. [e] Yield after column chromatography on SiO2. [f] Reaction under
microwave heating with maximal input of 300 W.
The scope of this reaction was evaluated by varying the
amine and alkyne substituent (Table 5). Electron rich and
electron poor aromatic acetylenes are well tolerated in this
reaction (Entries 1-5). Also, aliphatic acetylenes could be used
and were coupled efficiently (Entries 6, 7). In the case that TMS-
Table 4. Optimization of reaction conditions for the alkynylation of -
trichloroaldimine 7a.
acetylene was used, to generate
a
protected terminal
propargylamine 19j (Entry 10), the aqueous workup was omitted,
and the reaction mixture was directly purified via column
chromatography. The amine substituent can be varied and other
substituents like allyl and i-Pr groups can be used (Entries 8 and
9). When the protecting group PMB is used as a substituent
(Entry 11), the reaction works well, which is important for the
generation of N-unsubstituted 2-alkynyl-3,3-dichloropiperidines.
Entry[a]
Catalyst (mol-%)
T/t (°C/h)
Solvent
Yield
18a/19a (%)
Table 5. Variation of the alkyne and amine substituent.
1
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (30)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (10)
In(OTf)3 (50)
In(OTf)3 (25)
In(OTf)3 (25)
In(OTf)3 (25)
InCl3 (25)
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
THF
50/18
50/18
50/18
80/18
50/18
100/18
100/6
80/6
18/59[b]
28/49[b]
12/50[b]
0/71[d]
2[c]
3
4
5
0/trace(SM)
6
PhCH3
PhCH3
PhCH3
CH3CN
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
0/71
7
0/70[d]
Entry[a]
R1
R2
19
Yield 19 (%)[b]
70 (41)
72 (42)
68 (37)
73 (42)
74 (42)
60 (36)
61 (30)
70 (47)
88 (41)
92 (46)
81 (30)
8
0/70[d]
1
nPr
nPr
nPr
nPr
nPr
nPr
nPr
Allyl
iPr
Ph
19a
19b
19c
19d
19e
19f
19g
19h
19i
9
80/6
0/45[b]
2
4-EtPh
4-ClPh
2-MePh
3-MeOPh
Cy
10
11[c]
12
13
14[f]
15[f]
16[f]
17
18
19
20
21
80/3
0/71[d](41) [e]
0/74[d] (41) [e]
0/47[d]
80/3
3
80/3
4
80/3
0/68[d]
5
80/0.5
100/0.5
100/1
80/3
0/46[b]
0/52[b]
6
0/45[b]
7
nBu
0/47[b]
8
Ph
Cu(OTf)2 (25)
CuBr (25)
80/3
0/ trace
0/0
9
Ph
80/3
10
11
nPr
PMB
TMS
Ph
19j
CuOAc (25)
Sc(OTf)3 (25)
80/3
0/ trace
0/0
80/3
19k
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
Clearly the introduction of an alkynyl group on the 3,3-
dichloropiperidine avoided regioselectivity problems during the
dehydrochlorination and allowed to perform the elimination and
cross coupling in a one pot fashion. Although full conversion was
obtained, the isolated yields after column chromatography were
rather low (Scheme 9). This is due to the instability of the
enamine structure in products 21 during purification. When 2.5
mol-% Pd catalyst was used instead of 10% the crude reaction
mixture was very pure, and no further purification was required.
When the nitrogen substituent was changed from n-propyl to
isopropyl and the same reaction conditions were applied,
complete conversion was only reached after 55 hours, and a
57% crude yield was determined. The more sterically hindered
amine substituent clearly causes a slower elimination and cross
coupling. The combination of the In(III) catalyzed alkynylation
reaction and the Pd catalyzed cross coupling in one pot, was not
possible since only piperidine 19a was formed.
[a] All reactions were carried out on 0.5 mmol scale. [b] Crude yield (isolated
yield).
With the optimal catalyst and reaction conditions in hand, the
elimination of 19 was investigated (Scheme 8). When KOtBu
was used as base, to our delight, only one regioisomer was
obtained in 79% yield. The β-chloro enamines 20, however,
could not be purified due to their unstable nature. After 24 hours
storage at room temperature the samples completely degraded.
Next, the Heck reaction of 19a with styrene was evaluated,
but due to the higher reaction temperatures, an increased
degradation of the intermediate elimination product 20 was
observed. Fortunately, Heck-type products could be obtained via
Suzuki-type cross coupling of 19a with a vinylboronic acid in the
presence of 10 mol-% IPrPd(allyl)Cl and 3 equivalents of
NaOtBu in 1,4-dioxane. The crude yield 21f was nearly
quantitative, but again the product was not stable enough to
purify via column chromatography, problably due to its enamine
character. Therefore only the crude yield can be reported
(Scheme 10).
Scheme 8. Regioselective elimination yielding unstable β-chloro enamines 20.
To overcome the stability problems associated with cyclic
enamines 20, we envisioned a strategy in which the elimination
and cross coupling would take place consecutively, without
intermediate isolation of products. Earlier work by Nolan et al.
uses NaOtBu in combination with Pd(NHC) complexes in
ethereal solvents to couple aryl chlorides and various coupling
partners.[19] Considering that the dehydrochlorination of the 3,3-
dichloropiperidines work well with tert-butoxides, it was expected
that these cross coupling conditions should match with a prior
elimination of HCl in 19. To our delight, this reaction worked well,
and full conversion to the cross-coupled product 21 was
obtained within 5 h at 80 °C with 10 mol-% IPrPd(allyl)Cl, 3
equivalents of NaOtBu and 1 equivalent of the corresponding
boronic acid in 1,4-dioxane.
Scheme 10. Suzuki cross-coupling on 19a gives Heck-type product 21f.
Next, Buchwald-Hartwig amination was tried using aniline
and substrate 19a under the previously developed reactions
conditions. Although the reaction took place, we were never able
to identify the product, since the product is not stable enough to
purify via column chromatography. Due to the reactive nature of
these type of molecules, no further attempts were made to
synthesize Buchwald-Hartwig adducts of 19a.
To avoid losses on column chromatography due to the
instable nature of the intermediate tetrahydropyridines, an extra
hydrogenation step was introduced, and purification was only
done after this last step (Scheme 11). Generally, the yields
improved when this strategy was used, and evidently only the
cis-diastereomer 22 was obtained in this way.
Scheme 9. One-pot elimination and Suzuki cross-coupling of N-alkyl-2-
alkynyl-3,3-dichloropiperidines 19. Reactions on 0.7 mmol scale. Yields are
crude yields. a) Isolated yield after column chromatography.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
1
device Biotage IsoleraTM using Grace ResolvTM (12 g) columns. H (13C)
NMR spectra were recorded at 400 (100) MHz on a Bruker Avance III HD
spectrometer using CDCl3 as solvent and TMS as the internal standard.
Chemical shifts are given in parts per million (ppm), J-values are given in
hertz (Hz), and number of protons for each signal are also indicated. For
high resolution mass spectrometric analysis (HRMS), samples were
dissolved in methanol or acetonitrile and diluted to a concentration of
approximately 10-5 M and measured on a microTOF spectrometer
equipped with orthogonal electrospray interface (ESI). The parent ions
[M+H]+ are quoted.
General procedures for the synthesis of -trichloroaldimines 7
-Trichloroaldimines 7 were synthesized via two methods. A first
approach (A), makes use of molecular sieves (4 Å) as desiccant, and can
be applied for non-sterically hindered amines (n-propylamine). A second
method (B) makes use of TiCl4 and is used for more sterically hindered
amines (p-methoxybenzylamine, tert-butylamine). Imines were not further
purified and are generally pure enough to be used as such. 2,2,5-
Trichloropentanal (6) was synthesized according to
a
known
procedure.[14]
Scheme 11. Hydrogenation of structures 21 gives stable N-alkyl-2,2-
disubstituted piperidines 22.
Method A:
In a three-necked round bottomed flask were introduced 4 Å molecular
sieves (2 g - 66.6 g/mol, activated overnight at 180 °C under vacuum),
2,2,5-trichloropentanal (6) (5.68 g, 30 mmol) and toluene (30 mL). Then,
a non-sterically hindered amine (36.0 mmol) was added at 0 °C via a
dropping funnel. The reaction mixture was heated during 2 h at 60 °C.
Afterwards the reaction mixture was filtered over a glass filter and the
filter was rinsed with EtOAc. The resulting solution was washed with 0.5
N NaOH solution (50 mL), extracted with CH2Cl2 (3 × 50 mL) and dried
over anhydrous MgSO4. The reaction mixture was filtered and
concentrated in vacuo to yield the -trichloroaldimines 7 as orange
oils.
Conclusions
In conclusion, a new synthetic strategy to functionalize a
geminal dichloride in piperidines was developed. 3,3-
Dichloropiperidines or 2-alkynyl-3,3-dichloropiperidines were
synthesized via hydride or acetylide induced ring closing
reactions of -trichloroaldimines. The elimination step
towards vinyl chlorides for the first-mentioned gave
regioselectivity problems. However by a careful choice of solvent
and base one regioisomer was formed exclusively; the use of
LiHMDS in toluene gave β-chloro enamine structures, while the
use of LiHMDS in DMSO gave rise to vinylic chlorides. A Pd-
catalyzed Suzuki cross coupling protocol was established, which
was applied to synthesize, between others, the pharmaceutical
interesting molecule (±)-Preclamol. Furthermore the feasibility of
a Sonogashira reaction was illustrated, and the synthetic utility
of the vinylic double bond was shown.
Next, the indium(III) catalyzed alkynylation of -
trichloroaldimines was investigated. Functionalization of the
dichloromethylene group in 2-alkynyl-3,3-dichloropiperidines
was easier since no regioselectivity problems arose and a one-
pot elimination, cross coupling protocol could be applied. Yields,
however, were low for cross-couplings products due to the
unstable nature of these molecules, and an extra hydrogenation
step led to improved yields of hydrogenated piperidines.
Method B:
In
a three-necked round bottomed flask were introduced 2,2,5-
trichloropentanal (6) (5.68 g, 30 mmol) and Et2O (30 mL). The flask was
cooled with an ice bath and TiCl4 (1.89 mL, 17.14 mmol) in dry pentane
(6 mL) was added dropwise via a dropping funnel. Then, sterically
hindered amine (30 mmol) and triethylamine (6.07 g, 60 mmol) in Et2O
(30 mL) was added dropwise via a dropping funnel. The ice bath was
removed and the reaction mixture was stirred for 3 hours at room
temperature. Afterwards, the reaction mixture was filtered over a layer of
K2CO3 on Celite and washed with Et2O (100 mL). The organic phase was
washed with 0.5 N NaOH (50 mL) and extracted with Et2O (2 × 50 mL),
the organic phases were dried over MgSO4, filtered and concentrated in
vacuo to obtain a yellow oil of sterically hindered -trichloroaldimine 7.
General procedure for the reduction of -trichloroaldimines 7 to
3,3-dichloropiperidines 8
In a round bottomed flask filled with -trichloroaldimine 7 (30 mmol),
MeOH (100 mL) was added, quickly followed by sodium
cyanoborohydride (3.77 g, 60 mmol) and acetic acid (1.802 g, 30 mmol).
The mixture was stirred at room temperature for y hours. Afterwards the
reaction mixture was poured in 0.5 N NaOH solution (100 mL) and the
reaction mixture was extracted with CH2Cl2 (2 × 100 mL). The organic
phases were dried over MgSO4 and concentrated in vacuo to obtain 3,3-
dichloropiperidine 8 as a crude yellow oil.
Experimental Section
General Information
Solvents used for purification (heptanes, acetone and EtOAc) were
distilled prior to use. All reagents were purchased from commercial
suppliers (Sigma-Aldrich, Acros Organics, Alfa-Aesar, Fluorochem and
J&K). Products were purified on an automated column chromatography
General procedure for the regioselective elimination of 3,3-
dichloropiperidines 8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
In an oven dried 10 mL microwave vessel 3,3-dichloropiperidine 8 (0.5
mmol) was dissolved in dry DMSO (1 mL) or toluene (1 mL) and the
vessel was capped while an argon balloon was pierced through the
General
dichloropiperidines 19
procedure for the synthesis of
2-alkynyl-3,3-
septum. Then, lithium bis(trimethylsilyl)amide (167 mg,
1 mmol),
In an oven dried 10 mL microwave vial, -trichloroaldimine 7 (0.5
mmol), aryl or alkylacetylene (1.0 mmol) and In(OTf)3 (0.125 mmol) were
added successively and the vial was quickly sealed under air.
Subsequently, toluene (2 mL) was added and the reaction mixture was
placed in a preheated oil bath at 80 °C and allowed to reflux for 18 h.
Afterwards, the reaction mixture was cooled down, diluted with CH2Cl2
(10 mL), washed with 0.5 N NaOH solution (15 mL) and extracted with
CH2Cl2 (10 mL). The organic phases were dried over MgSO4, filtered,
and the solvent was evaporated in vacuo to obtain the corresponding
products 19a-k as yellow oils. Usually, products were clean, but short,
manual column chromatography with heptanes/EtOAc was always
performed.
dissolved in the DMSO or toluene, was added at 0 °C. The argon balloon
was removed and the mixture was stirred for 2.5 h at 100 °C. Afterwards,
the reaction mixture was poured in 10 mL of 0.5 N NaOH and extracted
with Et2O (2 × 15 mL). The ethereal fractions were washed with brine (15
mL), dried over anhydrous MgSO4, filtered, and the solvent was
evaporated in vacuo to yield either vinyl chlorides 9 or enamine chlorides
10.
General procedure for Suzuki-Miyaura cross-coupling on N-alkyl-5-
chloro-1,2,3,6-tetrahydropyridines 9
In an oven dried 10 mL microwave vessel were introduced Pd(OAc)2
(3.37 mg, 0.015 mmol), XPhos (0.030 mg, 0.03 mmol), NaOtBu (57.7 mg,
0.6 mmol) and arylboronic acid (x mg, 0.3 mmol). Then, under argon, a
solution of vinyl chloride 9 (0.3 mmol) in MeOH (2 mL) was added. The
reaction mixture was then heated at 50 °C for 16 hours. Afterwards, the
reaction mixture was filtrated over a layer of Celite and rinsed with EtOAc.
Then, the product was concentrated in vacuo and purified via column
chromatography on an automated system using a Grace 12g silica
column and heptanes/EtOAc.
General procedure for the elimination of 19 leading to 20
In a 10 mL microwave vessel were placed 3,3-dichloro-2-(arylethynyl)-N-
alkylpiperidine 19 (0.338 mmol) and THF (2.5 mL), the mixture was
stirred and cooled to 0 °C. Then, KOtBu (114 mg, 1.013 mmol) was
added portion wise, and the vial was quickly sealed. The reaction mixture
was heated and stirred for 3 h at 80 °C. After cooling to room
temperature, the resulting mixture was quenched with water (4 mL). The
reaction mixture was extracted with Et2O (4, 4, 3 mL), dried over
anhydrous MgSO4, filtered and concentrated in vacuo. No purification
can be done due to the unstable nature of the compound.
General procedure for Suzuki-Miyaura cross-coupling of 9 followed
by in situ hydrogenation
General procedure for the Suzuki-Miyaura cross-coupling of 19
In an oven dried 10 mL microwave vessel were introduced Pd(OAc)2
(3.37 mg, 0.015 mmol), XPhos (0.030 mg, 0.03 mmol), NaOtBu (57.7 mg,
0.6 mmol) and arylboronic acid (0.3 mmol). Then, under argon, a solution
of vinyl chloride 9 (0.3 mmol) in MeOH (2 mL) was added After 16 hours
at 50 °C, a balloon filled with H2 was pierced through the septum and the
reaction mixture was stirred for another 48 hours at room temperature.
Afterwards, the reaction mixture was filtrated over a layer of Celite and
rinsed with EtOAc. Then, the product was concentrated in vacuo and
purified via column chromatography on an automated system using a
Grace 12g silica column and heptanes/EtOAc.
In an oven dried 10 mL microwave vial were introduced inside the glove
box
allylchloro[1,3-bis(2,6-di-iso-propylphenyl)-4,5-dihydroimidazol-2-
ylidene]palladium(II) (10.0 mg, 0.018 mmol), arylboronic acid (0.700
mmol) and sodium tert-butoxide (0.202 g, 2.1 mmol). Subsequently,
outside the glove box, 3,3-dichloro-2-(arylethynyl)-N-alkylpiperidine 19
(0.7 mmol), dissolved in 1,4-dioxane (3 mL) was added and the reaction
mixture was placed in a preheated oil bath at 80 °C and stirred for 5 h.
Afterwards, the reaction mixture was cooled, and filtered over a layer of
Celite and the filter was rinsed with EtOAc (50 mL). The solvent was
concentrated in vacuo to obtain the corresponding products 21a-e as
dark brown oils, crude NMR spectra of compounds 21a-e have decent
purity. Upon purification via column chromatography, the product
appeared as yellow oils and the yield drops dramatically.
General procedure for Sonogashira cross-coupling of 9
In a 10 mL microwave vessel were introduced Pd(OAc)2 (3.37 mg, 0.015
mmol), XPhos (14.30 mg, 0.030 mmol), CuI (2.86 mg, 0.015 mmol) and
sodium tert-butoxide (57.7 mg, 0.600 mmol). The vessel was capped and
then under argon, a solution of vinyl chloride 9 (0.3 mmol) and aryl or
alkylacetylene (0.300 mmol) in MeOH (2 mL) was added. The reaction
mixture was then heated and stirred for overnight/16 hours at 70 °C.
Afterwards, the reaction mixture was filtered over a layer of Celite and
rinsed with EtOAc, the solvent was evaporated in vacuo and the crude
reaction mixture was purified via column chromatography.
General procedure for the Suzuki-Miyaura cross-coupling of 19
followed by in situ hydrogenation
In an oven dried 10 mL microwave vial were introduced inside the glove
box
allylchloro[1,3-bis(2,6-di-iso-propylphenyl)-4,5-dihydroimidazol-2-
ylidene]palladium(II) (10.0 mg, 0.018 mmol), arylboronic aicd (0.700
mmol) and sodium tert-butoxide (0.202 g, 2.100 mmol). Subsequently
outside the glove box, 3,3-dichloro-2-(arylethynyl)-N-alkylpiperidine 19
(0.7 mmol), dissolved in 1,4-dioxane (3 mL) was added and the reaction
mixture was placed in a preheated oil bath at 80 °C and stirred for 5 h.
Afterwards, the reaction mixture was cooled down, and filtered over a
layer of Celite and the filter was rinsed with EtOAc (50 mL). The solvent
was evaporated in vacuo and the product was redissolved in MeOH (4
mL), Pd/C (74.5 mg, 0.7 mmol) was added and the reaction mixture was
stirred under H2 atmosphere for 24 hours at room temperature.
Afterwards, the reaction mixture was filtered over a layer of Celite and
the filter was rinsed with EtOAc (50 mL). The solvent was evaporated in
vacuo and the crude product was purified via column chromatography on
Dimethyl
1-phenyl-3-propyl-3-azabicyclo[4.2.0]oct-7-ene-7,8-
dicarboxylate (17): In a 10 mL microwave vial were introduced N-alkyl-
5-phenyl-1,2,3,6-tetrahydropyridine (12a, 0.25 mmol), dimethyl
acetylenedicarboxylate (35.5 mg, 0.25 mmol), toluene (2 mL), and
BF3.OEt2 (8.9 mg, 0.063 mmol). The vial was capped under air and the
reaction was heated and stirred at 70 °C for 5 h. Afterwards the reaction
mixture was poured into 0.5 N NaOH (10 mL) and extracted with EtOAc
(2 × 10 mL). The organic phases were dried over MgSO4, filtered and the
solvent was evaporated in vacuo and the crude product was purified via
column chromatography.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
[10] K. Kushwaha, C. C. Malakar, S. Stas, F. Lemière, K. Abbaspour
Tehrani, RSC Adv. 2015, 5, 10139-10151.
an automated system using
heptanes/EtOAc.
a Grace 12g silica column and
[11] a) D. Yu, Y. Zhang, Adv. Synth. Catal. 2011, 353, 163-169; b) S. R.
Lanke, B. M. Bhanage, Appl. Organomet. Chem. 2013, 27, 729-733; c)
J. Gao, Q. W. Song, L. N. He, Z. Z. Yang, X. Y. Dou, Chem. Commun.
2012, 48, 2024-2026; d) D. Aguilar, M. Contel, E. P. Urriolabeitia, Chem.
Eur. J. 2010, 16, 9287-9296; e) Z. Lin, D. Yu, Y. N. Sum, Y. Zhang,
ChemSusChem 2012, 5, 625-628; f) X. Chen, T. Chen, Y. Zhou, C. T.
Au, L. B. Han, S. F. Yin, Org. Biomol. Chem. 2014, 12, 247-250; g) V. S.
Rawat, T. Bathini, S. Govardan, B. Sreedhar, Org. Biomol. Chem. 2014,
12, 6725-6729; h) R. K. Sharma, S. Sharma, G. Gaba, RSC Adv. 2014,
4, 49198-41211; i) A. Berrichi, R. Bachir, M. Benabdallah, N.
Choukchou-Braham, Tetrahedron Lett. 2015, 56, 1302-1306; j) M.
Rahman, A. K. Bagdi, A. Majee, A. Hajra, Tetrahedron Lett. 2011, 52,
4437-4439; k) Y. Tang, T. Xiao, L. Zhou, Tetrahedron Lett. 2012, 53,
6199-6201.
Acknowledgments ((optional))
This work was supported by the Agency for Innovation by
Science and Technology (IWT-Flanders), the University of
Antwerp (BOF) and the Hercules Foundation. We are thankful to
Ing. Heidi Seykens and Ing. Norbert Hancke for recording HRMS
spectra and to Philippe Franck for technical assistance.
[12] Z. Lin, D. Yu, Y. Zhang, Tetrahedron Lett. 2011, 52, 4967-4970.
[13] a) N. De Kimpe, M. Keppens, G. Fonck, Chem. Commun. 1996, 635-
636; b) S. Mangelinckx, S. Rooryck, J. Jacobs, N. De Kimpe,
Tetrahedron Lett. 2007, 48, 6535-6538; c) K. Abbaspour Tehrani, S.
Stas, B. Lucas, N. De Kimpe, Tetrahedron 2009, 65, 1957-1966.
[14] M. D'Hooghe, B. De Meulenaer, N. De Kimpe, Synlett 2008, 2437-2442.
[15] A. Thakur, K. Zhang, J. Louie, Chem. Commun. 2012, 48, 203-205.
[16] S.-O. Thorberg, L. Gawell, I. Csöregh, J. L. G. Nilsson, Tetrahedron
1985, 41, 129-139.
[17] a) G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J. Am. Chem. Soc. 2009,
131, 1366-1367; b) J. J. Verendel, T. Zhou, J.-Q. Li, A. Paptchikhine, O.
Lebedev, P. G. Andersson, J. Am. Chem. Soc. 2010, 132, 8880-8881.
[18] T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132,
14073-14075.
[19] a) O. Navarro, H. Kaur, P. Mahjoor, S. P. Nolan, J. Org. Chem. 2004,
69, 3173-3180; b) S. P. Nolan, N. Marion, O. Navarro, R. A. Kelly III,
Synthesis 2003, 2590-2592; c) G. Bastug, S. P. Nolan, Organometallics
2014, 33, 1253-1258; d) G. C. Fortman, S. P. Nolan, Chem. Soc. Rev.
2011, 40, 5151-5169; e) O. Navarro, N. Marion, Y. Oonishi, R. A. Kelly
III, S. P. Nolan, J. Org. Chem. 2006, 71, 685-692.
Keywords: alkynes • amines • cross-coupling •
dichloromethylene • transitions metals
[1]
a) C.-Q. Kang, Y.-Q. Cheng, H.-Q. Guo, X.-P. Qiu, L.-X. Gao,
Tetrahedron: Asymmetry 2005, 16, 2141-2147; b) T. Gedig, K. Dettner,
K. Seifert, Tetrahedron 2007, 63, 2670-2674; c) A. King, P. H. Mitchell,
P. Sykes, Br. Med. J. 1957, 1, 204-207; d) J. Schmutz, Wander Co.,
US2905590, 1959; e) J. J. Guy, T. A. Hamor, J. Chem. Soc. Perkin
Trans. 2 1974, 101-105.
[2]
a) D. Gomez Pardo, J. Cossy, Chem. Eur. J. 2014, 20, 4516-4525; b) M.
G. P. Buffat, Tetrahedron 2004, 60, 1701-1729.
[3]
[4]
[5]
[6]
[7]
J. L. Nallasivam, R. A. Fernandes, Eur. J. Org. Chem. 2015, 3558-3567.
W. Gessner, A. Brossi, Synth. Commun. 2006, 15, 911-916.
C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2006, 127, 8966-8967.
S. B. D. Jarvis, A. B. Charette, Org. Lett. 2011, 13, 3830-3833.
R. Verhé, N. De Kimpe, L. De Buyck, M. Tilley, N. Schamp,
Tetrahedron 1980, 36, 131-142.
[8]
[9]
a) S. Stas, K. Abbaspour Tehrani, Tetrahedron 2007, 63, 8921-8931; b)
S. Stas, K. Abbaspour Tehrani, Synthesis 2007, 433-441.
C. C. Malakar, B. U. W. Maes, K. Abbaspour Tehrani, Adv. Synth. Catal.
2012, 354, 3461-3467.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801613
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Metal Catalysis*
Reduction or alkynylation of
trichloroaldimines forms in situ
piperidines via ring closure. The
presence of the dichloromethylene
group allows for Pd-catalyzed cross-
coupling reactions via vinyl chloride
intermediates.
Wim E. Van Beek, Robert J. Smets,
Khushbu Kushwaha, Wouter A.
Herrebout, and Kourosch Abbaspour
Tehrani*
Page No. – Page No.
Synthesis of 3,3-dichloropiperidines
and the further functionalization via
Pd-catalyzed cross-coupling
reactions of the dichloromethylene
moiety
This article is protected by copyright. All rights reserved.