Synthesis of 1-Aza-6,7-dehydrotropanes via Copper(I)-Catalyzed Coupling of 5-Chloropentan-2-one with Hydrazines and Terminal Alkynes

Article abstract of DOI:10.1055/s-0037-1611041

A one-pot, three-component, Cu(I)-catalyzed coupling of primary hydrazines, 5-chloropentan-2-one, and terminal alkynes was developed. The resulting 1-aza-6,7-dehydrotropanes compose a new class of substances while related 1-azatropanes are scarcely described in literature and closely resemble tropane alkaloids. Hydrogenation of the double bond in 1-aza-6,7-dehydrotropanes triggered a rearrangement, involving a [1,3]-hydride shift, forming cyclic hydrazones.

Full text of DOI:10.1055/s-0037-1611041

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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W. E. Van Beek et al.
Letter
Synlett
Synthesis of 1-Aza-6,7-dehydrotropanes via Copper(I)-Catalyzed
Coupling of 5-Chloropentan-2-one with Hydrazines and Terminal
Alkynes
Wim E. Van Beeka
Karel Weemaesa
Wouter A. Herreboutb
Christophe M. L. Vande Veldec
Kourosch Abbaspour Tehrani*a
O
R1
R1
R2
N
Cl
OH
H
R2
+
N
N
R2
Cu2O (25 mol%)
N
R2
NH2
+
H2O
N
N
Cu
N
DCM, 24 h, 50 °C
H
H
R1
15 examples, 14–67% yield
R1 = Alk, Ar, R2 = Alk
R2
N
a Organic Synthesis, Department of Chemistry, University of
Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
Kourosch.AbbaspourTehrani@uantwerpen.be
b Research group Molecular Spectroscopy, Department of
Chemistry, University of Antwerp, Groenenborgerlaan 171,
2020 Antwerp, Belgium
c Faculty of Applied Engineering, Advanced Reactor Technology,
University of Antwerp, Groenenborgerlaan 171,
2020 Antwerp, Belgium
Three-component reaction,
starting from commercially
available materials, to give
1-azatropane scaffold in one pot
N
R2
N
N
R1
Pd/C, H2
resting state
Received: 23.08.2018
Accepted after revision: 25.09.2018
Published online: 24.10.2018
categories: C,N-cyclic,2d,e,3 N,N-cyclic,2a,4 and acyclic azome-
thine imines2b,c (Scheme 1, b–d).5 Other azomethine imines,
generated from hydrazines, are generally unstable and can
only be formed in situ.2b,c Recently, we reported a three-
component coupling of ω-halogenated ketones, primary
amines, and terminal alkynes, where a cyclic iminium spe-
cies was found to possess enhanced electrophilic proper-
ties.6 We were curious whether a cyclic hydrazonium or
azomethine imine species would likewise exhibit similar
enhanced electrophilic properties or special reactivity.
DOI: 10.1055/s-0037-1611041; Art ID: st-2018-k0544-l
Abstract A one-pot, three-component, Cu(I)-catalyzed coupling of
primary hydrazines, 5-chloropentan-2-one, and terminal alkynes was
developed. The resulting 1-aza-6,7-dehydrotropanes compose a new
class of substances while related 1-azatropanes are scarcely described in
literature and closely resemble tropane alkaloids. Hydrogenation of the
double bond in 1-aza-6,7-dehydrotropanes triggered a rearrangement,
involving a [1,3]-hydride shift, forming cyclic hydrazones.
Key words multicomponent reactions, alkynes, hydrazines, ketones,
copper catalysis, 1-azatropanes
O
O
H
R
BF3Li
N
N
a)
Ph
N
H
N
Ph
N
N
H
O
O
Alkynylation of hydrazones is, compared to alkynylation
of imines, an underexplored research topic due to the in-
trinsic low electrophilicity of hydrazones. To the best of our
knowledge, there has only been one example of direct alky-
nylation of hydrazones reported to date (Scheme 1, a).1
Alkynylation could in this case be accomplished by using
n-BuLi to form in situ the lithium alkynyl trifluoroborate.
Often, products of alkynylation of hydrazones are subject to
intramolecular hydrohydrazination reactions, generating
(annulated) pyrazoline derivatives.2 However, these prod-
ucts could also arise from [3+2] cycloaddition of azome-
thine imines, generated from hydrazones and alkynes.
Many examples of [3+2] cycloadditions of azomethine
imines and alkynes exist, and generally azomethine imines
need to be formed in a separate step. Stable azomethine
imines are easily made from hydrazides, i.e., hydrazines
possessing an electron-withdrawing carbonyl moiety, and
aldehydes or ketones, and can be divided into different
O
R
O
O
R2
H
R2
N
N
N
b)
N
N,N-cyclic azomethine imines
or
N
N
R2
R1
R1
R1
C,N-cyclic azomethine imines
H
R2
c)
d)
e)
N
N
EWG
EWG
N
N
R2
R4
N
O
R3
H
R2
H
N
acyclic azomethine
imines, generated in
situ from hydrazides
EWG
R1
R3
R4
N
R1
N
+
H
R2
EWG
this work
O
H
N
H
R2
acyclic azomethine
imines, generated in situ
from primary hydrazines
Cl
?
H2N
EDG
+
Scheme 1 a) Alkynylation on hydrazone; b) to d) previously reported
[3+2] cycloadditions of different azomethine imines and alkynes; e) our
approach.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
W. E. Van Beek et al.
Letter
Synlett
An initial trial experiment using methylhydrazine (1a),
5-chloropentan-2-one (2a), and phenylacetylene (3a) un-
der Cu2O catalysis (25 mol%) in acetonitrile at 50 °C for 24
hours yielded a single product 4a in a moderate 35% yield
(Scheme 2).
were observed. The absence of reaction products 4 could in
these cases also be explained by additional complexation of
the Cu(I) ion with the heteroatom rendering the alkyne less
nucleophilic. An aliphatic acetylene, such as cyclohexyl-
acetylene, generates the product 4i in a low yield of 28%,
but illustrates that the reaction is still possible. Conducting
the reaction with an internal alkyne such as dimethyl acet-
ylenedicarboxylate (DMAD), a popular dipolarophile in
[3+2] cycloadditions, did not lead to any [3+2]-cycloaddi-
tion product 4. Although DMAD is a very good dipolaro-
phile for [3+2] cycloadditions, it is not capable of forming a
copper acetylide species, since it does not possess a termi-
nal C(sp)–H proton. In a similar way, the use of 1-propynyl-
benzene, closely resembling phenylacetylene but lacking a
terminal C(sp)–H proton, did not lead to any coupling prod-
uct 4. Furthermore, other dipolarophiles, such as alkenes,
did not lead to coupling products 4 either.
In situ formation of unstable azomethine imine
H
Ph
N
3a (1.2 equiv)
O
H
catalyst (25 mol%)
N
N
Ph
N
Cl
N
+
H2N
solvent, 50 °C, 24 h
1a (2.5 equiv)
2a
4a
Cu
Ph
Scheme 2 Metal-catalyzed three-component coupling of methyl-
hydrazine, 5-chloropentan-2-one, and phenylacetylene leads to the
formation of 1-aza-6,7-dehydrotropane 4a
A number of different transition-metal catalysts was
evaluated and this revealed the superior catalytic activity of
Cu(I) salts over, among others, Fe(III), Ag(I), Au(I), Zn(II),
and Cu(II) salts (see Supporting Information – Table S1),
with copper(I) oxide as the best catalyst. Interestingly, the
choice of metal catalyst counterion was previously found to
be important, due to the possibility of protonation of the
counterion leading to formation of an acid that could cata-
lyze the dimerization of azomethine imines.2c Other Cu(I)
salts such as the acetate, chloride, or triflate all gave similar
results as the oxide. With regard to the pKa an improvement
could be expected from triflic acid to hydrochloric acid,
acetic acid, and water, but in fact CuOTf, surprisingly, gave a
slightly better yield of 41% in comparison to Cu2O (35%).
Since one equivalent of HCl is already formed by the ring
closure of the starting material, most likely the role of the
counterion is not of much importance here, and therefore
Cu2O was selected as the catalyst of choice. A number of sol-
vents was evaluated (see Supporting Information – Table
S2). Generally, polar and apolar solvents gave low yields,
while intermediately polar solvents such as chlorinated sol-
vents dichloromethane (DCM), 1,2-dichloroethane, and
chloroform gave the best yields. Dichloromethane as sol-
vent gave the best result, with an associated 58% NMR yield.
Prolongation of reaction times and higher reaction tem-
peratures did not lead to higher yields. The low screening
yield can be explained by the formation of cyclic hydrazone
side product (cf. Scheme 6).
R
O
N
Cu2O (25 mol%)
H
N
Cl
H
+
R
+
H2N
N
1a
DCM, 24 h,
50 °C
2a
R1 = H 4a 56%
3
R1 = 4-MeO 4b 46%
R1 = 3-MeO 4c 47%
R1 = 2-MeO 4d 41%
R1 = 4-NO2 4e 19%
R1 = 4-CF3 4f 21%
R1 = 4-Cl 4g 43%
4a–p
R1
N
N
N
N
R1 = 4-Br 4h 51%a
4i 28%
Scheme 3 Scope of the reaction regarding the alkyne.a 4 mmol
reaction scale.
A few of the molecules 4 were solids, and example 4g
gave, after recrystallization from DCM, suitable crystals for
X-ray diffraction, so that the structure of 1-azatropane 4
could be confirmed (see Figure 1 and Supporting Informa-
tion – Figure S1).8
Next, we investigated the scope of the reaction with re-
gard to the alkyne component (Scheme 3).7 A number of
substituted terminal aryl alkynes were evaluated. Electron-
donating groups were tolerated well (4b–d), but strong
electron-withdrawing groups such as 4-nitro or 4-trifluoro-
methyl gave only low yields of products 4e–f, while weak
electron-withdrawing 4-chloro or 4-bromo gave similar
yields of 4g and 4h as nonsubstituted phenylacetylene 4a.
The presence of heteroatoms such as nitrogen in 2-pyridi-
nylacetylene and oxygen in methyl propiolate or 1-phenyl-
prop-2-yn-1-ol rendered the alkyne less nucleophilic and
completely blocked the reaction as no reaction products 4
Figure 1 Crystal structure of the major disorder component of the
asymmetric unit in 4g, containing four molecules (two times two enan-
tiomers). Displacement ellipsoids are drawn at the 50% probability
level, and hydrogen atoms are drawn as spheres of arbitrary radius.
Next, the scope of hydrazines was investigated (Scheme
4). Other primary aliphatic hydrazines were evaluated;
more sterically hindered isopropylhydrazine gave an im-
proved yield of 67% of 4j. Although the steric hindrance
around the reaction center increases, the nucleophilicity of
the hydrazine decreases,9 thus resulting in more difficult
formation of hydrazone side product, which is beneficial for
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
W. E. Van Beek et al.
Letter
Synlett
the synthesis of wanted product 4j. When the steric hin-
drance is increased to tert-butylhydrazine, the overall yield
decreased to 40%, including a degradation product 4k′. This
product was not present after workup, but probably formed
during column chromatography on silica. We reasoned that
the slightly acidic nature of silica would prompt molecule
4k to de-tert-butylate and rearrange to 4k′.10 To test this
hypothesis, product 4k was treated with dry trifluoroacetic
acid (TFA) in DCM. After basic workup, the product was
completely transformed into product 4k′ in 85% yield.
Mechanistically, this rearrangement probably starts with
protonation of the hydrazine moiety (by either acidic silica
or TFA), followed by de-tert-butylation with the loss of gas-
eous isobutene. The presence of an N–H can now provide a
loss of ring strain by rearrangement of the molecule. To our
delight, the use of benzylhydrazine resulted in the forma-
tion of product 4l in a decent 67% yield. Product 4m was
formed in a low 14% yield, indicating difficulties when
hydroxyl moieties were used. When trifluoroethylhydra-
zine was used, product 4n was isolated, next to a very simi-
lar isomer. High-temperature NMR spectroscopy excluded
the possibility of rotamers, and a second purification
attempt provided 4n in 36% yield. The other isomer is
thought to be 4n′, since the trifluoroethyl group probably
lowers the nucleophilicity of the substituted hydrazine
nitrogen atom, resulting in formation of hydrazone via the
unsubstituted hydrazine nitrogen atom. This assumption
should be confirmed by X-ray analysis of product 4n′, but
unfortunately no suitable crystals could be grown. When
phenylhydrazine was used, no reaction product 4o was ob-
served, but instead cyclic hydrazone 4o′ was isolated in 14%
yield. The use of phenylhydrazide resulted in a sluggish 15%
yield of 4p, while the use of acethydrazide did not lead to
product 4q. Instead, 2-alkynylpyrrolidine 4q′ was isolated,
Ph
N
O
Cu2O (25 mol%)
DCM, 24 h, 50 °C
N
R
H
N
Cl
H
+
Ph
+
R
H2N
1
2a
3a
4j–q
Ph
Ph
Ph Ph
Ph
N
N
N
N
N
N
N
N
N
N
Ph
4a 56%
4j 67%
Ph
4k 20%
4k' 20%
4l 67%
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
N
Ph
Ph
F3C
HO
CF3
4m 14%
4n 36%
4n' 4%
4o 0%
4o' 14%
O
Ph
N
N
Ph
N
N
N
N
O
O
H
Ph
Ph
4p 15%
4q 0%
4q' 39% rotameric mixture
Scheme 4 Scope of hydrazines
Tropane scaffold
Tropane alkaloid
1-Azatropane scaffold
CO2Me
O
9
9
8
N
8
N
2
2
1
N
1
N
4
4
5
3
3
5
7
7
O
6
6
1,8-diazabicyclo[3.2.1]octane
8-azabicyclo[3.2.1]octane
cocaine (5)
Figure 2 Tropane- and 1-azatropane scaffold, cocaine (5) as example
gas (Scheme 5). Product 4a was dissolved in methanol and
stirred for 24 hours at room temperature under an atmo-
sphere of hydrogen with Pd/C. To our surprise, the hydroge-
nated product 6 was never observed, but hydrazone 7 was
formed as the reaction product in 92% yield. Although this
structure seems far-fetched at first sight, a logical explana-
tion can be given for the formation of this reaction product.
Two pathways are presented. The first pathway involves N-
inversion, followed by syn-addition of hydrogen. The addi-
tion of hydrogen can only occur at one side of the double
bond, since the other side is blocked by the largest ring.
Molecule 6 therefore encounters strong steric hindrance,
pushing the molecule into a twisted-boat conformer from
where a concerted [1,3]-hydride shift might occur, forming
hydrazone 7. A second, stepwise pathway starts again with
the syn-addition of hydrogen to molecule 4a to create
hydrogenated product 6. The steric hindrance can, in this
case, be lowered by breaking the N–C(Ph) bond, generating
a secondary benzylic carbocation. Ring flip to a boat con-
former allows for a [1,6]-hydride shift, eventually leading to
molecule 7. The overall process is an internal redox neutral
process and is closely related to reactions were the tert-
amino effect is invoked.15 Similar [1,6]-hydride shifts are
rare but examples exist and are generally explained by the
geometry of the carbocation.16 In order to differentiate be-
tween the two hydride shifts density functional theory
1
which exhibited two sets of signals in the 13C and H NMR
spectra. The coalescence of the signals was observed at
120 °C. These double signals are therefore believed to origi-
nate from the restricted rotation of the acetyl group around
the O=C-N bond, like in DMF.11 The use of tosylhydrazide
did not lead to any intended product 4. Disubstituted
hydrazines and other ω-chloroketones did not lead to cou-
pling products (see Supporting Information – Schemes S1
and S2).
The structure of molecules 4 is interesting as they are
aza-analogues of tropane alkaloids, that are known as anti-
cholinergic drugs, with cocaine (5) as one of the most fa-
mous examples (Figure 2).12 Previous literature methods for
the preparation of similar compounds describe the cycload-
dition of alkenes/alkynes with diazinium betaines13 or nu-
cleophilic addition of in situ formed N-acylhydrazonium in-
termediates.14
In view of the limited examples of 1-azatropanes in the
literature, an attempt was made to reduce the olefinic bond
in the bicyclic compounds 4 by using Pd/C and hydrogen
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
W. E. Van Beek et al.
Letter
Synlett
(DFT) calculations were performed (see Supporting Infor-
mation – Figure S3). These calculations support the [1,3]-
hydride shift, since for the [1,6]-hydride shift no feasible
carbocationic intermediate could be obtained.
S3).4a,17 Unfortunately, this intermediate could not be
trapped, probably because of the unavoidable formation of
HCl as proton source in the reaction mixture.
O
OH
Cl
H2N
HN
N
N
+
N
N
H
[1,3]-hydride shift,
concerted pathway
Cl
N
Cl
N
N
ring-flip
H
N
H
N
H
8
8'
– HCl
H
H
H
H2N
N
Me
- HCl
OH
DFT calculations:
: + 43,6 kJ/mol
H
Ph
H
twist-boat
conformer
H
6
N
N
N
N
N
1,3-DC
N
N
NH
N
N-inversion
H2O
H2O
Product 7 : - 204,5 kJ/mol
11
9
10
11'
9'
resting state
resting state
Ph
Ph
N
N
N
N
Pd/C, H2
Ph
N
+
N
[3+2] cycloaddtion
pathway
N
Ph
Cu
Ph
Cu2O
Ph
Ph
Cu
12
H
MeOH, 24 h,
r.t.
N
N
N
NH
alkynylation/
hydrohydrazination
pathway
H2O
N
7, 92%
4a
6, 0%
4a
13
Ph
H2O
H2O
never observed
[1,6]-hydride shift,
stepwise pathway
– MeOH
N-inversion
OMe
N
H
N
Ph
N
N
N
NH
4a
H
N
H
N
ringflip
H
+
MeOH
H
H
H
- MeO-
H
N
NH
Scheme 6 Proposed reaction mechanism
6
boat conformer
Scheme 5 Hydrogenation of 1-azatropane 4a yields a rearranged
cyclic hydrazone 7
In conclusion, we developed a one-pot, three-compo-
nent coupling using primary hydrazines, 5-chloropentan-2-
one, and terminal alkynes that form in situ azomethine
imines, that would otherwise be unstable. The formation of
a nonhydrolyzable cyclic hydrazone side product hampers
the reaction, and generally leads to moderate yields. Differ-
ent substituted hydrazines could be used, but when elec-
tron-withdrawing substituents are used, the reactivity
changes, as the nonsubstituted nitrogen atom preferably
reacts in that case. Furthermore, different aryl- and alkyl-
substituted alkynes can be coupled to generate a rare class
of 1-azatropane scaffolds, which can potentially be import-
ant as aza-analogues of naturally occurring aza-tropanes.
For the synthesis of 1-aza-6,7-dihydrotropanes 4, a re-
action mechanism consisting of two possible pathways can
be envisaged (Scheme 6). Both pathways start with the for-
mation of hydrazonium salt 8 from attack of the substituted
hydrazine nitrogen atom. Loss of HCl via an intramolecular
substitution reaction generates cyclic hydrazonium 9. From
there azomethine imine 10 could be formed together with
the tautomeric enehydrazine 11, which can be considered
as a resting state for the reaction. On the other hand, the
nonsubstituted hydrazine nitrogen can react to form hydra-
zone 8′ which upon intramolecular substitution generates a
cyclic hydrazone 9′ or enehydrazine 11′, which are consid-
ered resting states for the reaction as they cannot undergo a
1,3-dipolar cycloaddition (1,3-DC). Independently, copper
phenylacetylide is formed from copper(I) oxide with the aid
of any weak base present (e.g. methylhydrazine). Copper
phenylacetylide then reacts via a [3+2] cycloaddition with
azomethine imine 10 to form vinyl copper species 12,
which is protonated to form target compound 4a. Alterna-
tively, copper phenylacetylide may react with cyclic hydra-
zonium 9 to form propargyl hydrazine 13, which quickly
undergoes intramolecular hydrohydrazination to form
target compound 4a. Compound 13 was, however, never ob-
served. Propargyl hydrazine 13 could also form a π-com-
plex with Cu+, so that vinyl copper species 12 is formed, and
after hydrolysis target compound 4a can be formed. Trap-
ping of vinyl copper species 12 was attempted with other
Funding Information
This work was financed by the Agency for Innovation by Science and
Technology (IWT-Flanders), the University of Antwerp (BOF), and the
Hercules Foundation (project AUGE/11/029 ‘3D-SPACE: 3D Structural
Platform Aiming for Chemical Excellence’).()
Acknowledgment
We thank Prof. dr. F. Lemière for HRMS measurements and Philippe
Franck (Organic Synthesis, University of Antwerp) for technical assis-
tance.
Supporting Information
Supporting information for this article is available online at
electrophiles (see Supporting Information
– Scheme
https://doi.org/10.1055/s-0037-1611041.
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p
p
orti
n
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n
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p
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n
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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W. E. Van Beek et al.
Letter
Synlett
References and Notes
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(7) General Experimental Procedure for the Synthesis of Prod-
ucts 4
(10) Mechanism for the de-tert-butylation and rearrangement of 4k
into 4k′ (Scheme 7)
Ph
TFA
DCM
H
Ph
Ph
H+
Ph
N
N
–
N
N+
H
N
HN
N
N
4k
4k' 85%
Scheme 7
(11) Geffe, M.; Andernach, L.; Trapp, O.; Opatz, T. Beilstein J. Org.
Chem. 2014, 10, 701.
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In an oven-dried microwave vessel (10 mL) were introduced
Cu2O (36 mg, 0.25 mmol), hydrazine 1 (2.5 mmol), ketone 2a (1
mmol), alkyne 3 (1.2 mmol), and DCM (4 mL). The vessel was
flushed with argon for 30 s, sealed, and introduced in a pre-
heated oil bath of 50 °C and stirred during 24 h. Afterwards, the
reaction mixture was poured into 0.5 N NaOH solution (20 mL)
and extracted with DCM (2 × 20 mL). The organic phases were
combined and dried over MgSO4·3H2O, filtered, and evaporated
in vacuo. The crude product was then purified by automated
column chromatography on a 12 g Grace column with hep-
tanes/EtOAc as eluting solvents.
(15) Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem. 1972, 14,
211.
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Decroix, B. Tetrahedron 2001, 57, 4939. (b) Mori, K.; Sueoka, S.;
Akiyama, T. J. Am. Chem. Soc. 2011, 133, 2424. (c) Verboom, W.;
Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49,
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5,8-Dimethyl-7-phenyl-1,8-diazabicyclo[3.2.1]oct-6-ene (4a)
(17) Yu, X.; Xu, J.; Zhoua, Y.; Song, Q. Org. Chem. Front. 2018, 5, 2463.
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 2 H), 7.34–7.26 (m,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E