Modulation of reactivities of dienophiles for diels-alder reactions via complexation of α,β-unsaturated chelating amides

Article abstract of DOI:10.1002/hlca.201400224

We describe the modulation of reactivities of dienophiles for Diels-Alder reactions via a new principle based on chelating amides positioned adjacent to their C-C bond. It is demonstrated for modified acrylic acid derivatives and related dienophiles with three different chelating entities. Complexation of the chelators leads to an intensified electron-withdrawing effect leading to an enhancement of reactivity in Diels-Alder reactions depending on the complexed metal ion. The application of this new approach might be extended to other reactions with reacting entities adjacent to chelating amides.

Full text of DOI:10.1002/hlca.201400224

Helvetica Chimica Acta – Vol. 98 (2015)
287
Modulation of Reactivities of Dienophiles for DielsꢀAlder Reactions via
Complexation of a,b-Unsaturated Chelating Amides
by Markus Sterk and Willi Bannwarth*
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg, Albertstraße 21, DE-79104
Freiburg (fax: þ 49-761-2038705; e-mail: willi.bannwarth@organik.chemie.uni-freiburg.de)
We describe the modulation of reactivities of dienophiles for DielsꢀAlder reactions via a new
principle based on chelating amides positioned adjacent to their C¼C bond. It is demonstrated for
modified acrylic acid derivatives and related dienophiles with three different chelating entities.
Complexation of the chelators leads to an intensified electron-withdrawing effect leading to an
enhancement of reactivity in DielsꢀAlder reactions depending on the complexed metal ion. The
application of this new approach might be extended to other reactions with reacting entities adjacent to
chelating amides.
Introduction. – In the last decade, the interest in applications of the chelating entity
bis(pyridin-2-ylmethyl)amine (bpa; 5) and related amides thereof has increased
significantly. It was recently demonstrated that the photochemical and photophysical
properties of chromophores equipped with bpa could be significantly influenced by
complexation of metal ions. In Scheme 1, we present an example where the complex-
ation of the boron-dipyrromethane (BODIPY; 4,4-difluoro-4-bora-3a,4a-diaza-s-
2þ
indacene) dye 1 with Cd led to an electron-withdrawing effect in 2, influencing the
p-conjugated backbone of the molecule and hence its fluorescence properties. Thus, the
2þ
complexation of the Cd resulted in a blue shift of the fluorescence emission from 656
to 597 nm [1].
Further examples of the electron-withdrawing effect caused by complexation of bpa
2þ
are shown in Fig. 1, and they range from modulation of the luminescence by Zn ions
Scheme 1. Example of the Complexation of bpa-Containing Chromophore 1 Used as a Selective
Fluorescent Sensor
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Fig. 1. bpa-Containing complex 3 and chelating ligand 4
2þ
in Ir complex 3 to detection of protein-coupled phosphates via coordination to Zn ,
complexed by bpa-containing chromophores [2][3]. Besides these photochemical
applications, alterations of affinities for intercomponent H-bonds of bpa-modified
2þ
amides due to complexation of Cd were described as well [4].
bpa Derivatives were also used to modulate catalyst reactivities, such as those of
metal-complexes with 4, which showed increasing catalytic activity in hydrolysis
reactions due to a metal ion-induced allosteric transition [5].
The influence of chelating systems on chemical reactivities was already demon-
strated in 1970. It was observed that bpa amides of carboxylic acids dissolved in MeOH
were prone to a conversion to the pertinent methyl esters after complexation to Cu2
þ
[
6]. The synthetic potential of this seminal observation had not been recognized, until
our group has used these intriguing features to develop two different linker units for
solid-phase chemistry and to establish a novel relay protection scheme for carboxylic
acids as outlined in Scheme 2 [7 – 9].
The protection can easily be performed by standard amide couplings by employing
the carboxylic acid, bpa (5), and an activation agent. The resulting amide is chemically
very robust, and hence it is highly inert towards different reaction conditions, allowing
for a wide array of chemical operations on the adjacent residue to be performed. Yet,
its deprotection can be achieved under very mild conditions and proceeds in an
orthogonal fashion compared to most commonly employed protecting groups for
carboxylic acids. Disadvantages due to use of Cu(OTf) could be solved by selecting
2
amine 6 (Fig. 2) as an alternative for bpa (5) [10]. It showed the same general features
as described for the protection with bpa, but the deprotection of the pertinent amide
was significantly faster by applying CuCl . In addition, we had synthesized the
2
structurally related ligand 7 (Fig. 2), which was similar to ligand 6 but carried an
additional coordinating N-atom.

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Scheme 2. Principle of the bpa-Based Relay Protection of Carboxylic Acids
Fig. 2. Structures of chelating ligands 6 and 7
In a simultaneous application of carboxylic acid amides, which were modified with
the three chelating entities 5 – 7, it was even possible to cleave one chelating unit after
the other in an orthogonal fashion by employing different metal salts [11].
At this point, we surmised that complexation of chelating entities and the resulting
electron-withdrawing effect might open up a general strategy for the modulation of
reactivities or the induction of a reaction. Along these lines, this was first probed for the
Hoveyda-type catalysts of type 8.
We were able to demonstrate that a complexation of the chelating unit in catalyst 8
(
Fig. 3) had a significant positive effect on its efficiency in metathesis reactions [12].
Herein, we report on an application of this new principle on DielsꢀAlder reactions
of acrylic acid amides and related derivatives as dienophiles. Such reactions of electron-
poor dienophiles with electron-rich dienes (normal electron demand) are governed by

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Fig. 3. Hoveyda-type catalyst 8
the energy gap between the highest occupied molecular orbital (HOMO) of the diene
and the lowest unoccupied molecular orbital (LUMO) of the dienophile [13][14]. This
gap can be lowered by factors increasing the electron density on the diene or decreasing
that on the dienophile. A common strategy to achieve the latter is the addition of Lewis
acids acting on the amideꢃs O-atom [15]. We assumed that an inhibition of the amide
resonance by complexation, as illustrated in Fig. 4, should result in the same effect. To
the best of our knowledge, this would represent a novel and innovative approach to
modulate reactivities of dienophiles in DielsꢀAlder reactions and might have
implications for other reactions as well.
The strategy would allow us to employ different but related dienophiles (R ¼ H,
COOEt, CONEt ) in combination with our three different chelating units (5, 6, and 7)
2
with and without complexation. It would also enable comparison of earlier results on
the influence of different metal ions on the methanolysis of the pertinent amides with
the reactivity in DielsꢀAlder reactions.
An additional interesting aspect would concern the influence of the complexation
on secondary orbital interactions governing the endo/exo ratio of the cycloadduct.
Fig. 4. Effect of the complexation on the frontier orbitals of the dienophile

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Results and Discussion. – As a first step we performed DielsꢀAlder reactions as
outlined in Scheme 3 with acrylic acid (prop-2-enoic acid) derivatives 9 – 11 as
dienophiles and cyclopentadiene without or after addition of stoichiometric amounts of
2þ
a Cu -ion source [16].
The results of these studies are outlined in Fig. 5. For each case, the curves indicate
the combined formation of the endo- and the exo-cycloadduct as a function of the
Scheme 3. DielsꢀAlder Reactions of Some Acrylic Acid Derivatives without or in the Presence of
Cu(OTf) Using 4.0 equiv. of Cyclopenta-1,3-diene (12)
2
Fig. 5. DielsꢀAlder reactions of 9 – 11 with cyclopenta-1,3-diene (12) without and after addition of
Cu(OTf)
2

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reaction time. The reaction of dienophile 9 served as a benchmark reaction due to its
2þ
inability to complex Cu , and hence its addition had no influence on the reactivity. The
ester dienophile 10 showed a significantly enhanced reaction rate, caused by the much
lower resonance energy of esters compared to amides, and its reactivity was not
influenced by the addition of an equimolar amount of Cu(OTf) . In contrast,
2
coordination of chelating unit of 11 to an equimolar amount of Cu(OTf) revealed, to
2
our delight, a significant enhancement of the reactivity, even surmounting that of the
ester dienophile 10.
Besides the use of Cu(OTf) , we evaluated the impact of various metal salts all
2
of which had shown an influence on the methanolysis rate of bpa-modified amides
in earlier studies [11]. Surprisingly, other Cu sources such as CuCl and CuCl2
had no influence on the reactivity. Hence, the effect can be regarded as Cu(OTf)2-
specific, indicating at the same time that the effect of the counter ion cannot be
neglected.
In addition to the acceleration of the DielsꢀAlder reaction by complexation we
observed also a significant effect on the endo/exo ratio of the cycloadducts. The ratio in
the uncomplexed state, 1.3 :1, increased to 6.8 :1 after complexation which can only be
explained by an influence on secondary orbital interactions.
The aforementioned investigations concerning the bpa-amide 11 were then
extended to the related chelating derivatives 16 and 17 (Scheme 4).
Scheme 4. DielsꢀAlder Reactions of Acrylic Acid Derivatives 16 and 17 Using 4.0 Equiv. of Cyclopenta-
1,3-diene (12)
Addition of Cu(OTf) to 16 led only to a slight enhancement of reactivity and an
2
alteration of the endo/exo rate from 1.5 :1 to 4.5 :1. In contrast, addition of CuCl
resulted in a pronounced acceleration of the cycloaddition (Fig. 6) but without change
of the endo/exo ratio. As opposed to these results, the addition of Cu salts to amide 17
carrying the tetradentate entity had only a moderate effect. The most significant effect
was observed with Zn(OTf) (Fig. 6), and the endo/exo ratio increased from 1.6 :1 to
2
9.5.1.

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Fig. 6. DielsꢀAlder reactions of 16 before and after addition of CuCl and 17 before and after addition of
Zn(OTf) with cyclopenta-1,3-diene (12)
2
After having established that the bpa-modified acrylamide 11 was most influenced
by the addition of Cu(OTf) , and that CuCl had the highest impact on the dmepa-
2
amide 16, and Zn(OTf) had led to the highest acceleration of the tetradentate-amide
2
17, we expanded our investigations to the corresponding fumaric amides ((2E)-but-2-
enediamides) 20 – 22 and 23 – 25, as outlined in Scheme 5.
Compared to the acrylamides 11, 16 and 17, we expected a higher benchmark
reactivity of these amides in the uncomplexed form due to the additional amide or ester
function, respectively. Hence, it was interesting to see whether an influence on the
activities by complexation was still observable.
According to the results obtained with the acrylamides, compounds 20 and 23 were
tested before and after the addition of Cu(OTf) , whereas amides 21 and 24 were
2
complexed with CuCl. Finally, amides 22 and 25 were investigated before and after
complexation with Zn(OTf) . The results are compiled in Figs. 7 and 8.
2
As can be deduced from Fig. 7, the complexation resulted again in a significant
enhancement of the reaction despite of the higher benchmark reaction rates of the
uncomplexed dienophiles. In contrast to the results with the acrylamides, no distinct
change in the endo/exo selectivity was observed.
Similar results were obtained for the even more reactive derivatives 23 – 25 before
and after complexation (Fig. 8), demonstrating at the same time a slight influence on
the endo/exo ratios (see Exper. Part).

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Scheme 5. DielsꢀAlder Reactions of the Fumaric Acid Derivatives 20 – 25
Conclusions. – In summary, we were able to verify as a new principle that
DielsꢀAlder reactions of chelating ligand-modified dienophiles could indeed be
accelerated by addition of metal salts, thereby indicating that the resulting complexes
are affecting frontier orbitals of these modified dienophiles and, in some cases, also the
secondary orbital interactions. Reactivity enhancements of bpa-modified dienophiles
1
1, 20, and 23 can be regarded as nearly selective for Cu(OTf) and an influence on the
2
endo/exo ratios could be observed as well. In contrast, mixed tridentate-modified
dienophiles, 16, 21, and 24, showed the most pronounced acceleration with CuCl,
without influencing the endo/exo selectivity. Addition of Zn(OTf) to the DielsꢀAlder
2
reaction of tetradentate-modified dienophiles 17, 22, and 25 resulted in a significant
enhancement of reactivity as well as a moderate effect on the endo/exo selectivities. The
described results offer an elegant possibility of modulating reactivities of DielsꢀAlder
reactions with a,b-unsaturated chelating amides. The principle might be more generally
applicable to activate reacting entities in the neighborhood of chelating amides. For
these reasons, we assume that the presented data could be of more general interest.

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Fig. 7. DielsꢀAlder reactions of 20 – 22 before and after complexation
Fig. 8. DielsꢀAlder reactions of 23 – 25 before and after complexation

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Experimental Part
General. All reactions with air- and moisture-sensitive compounds were carried out under Ar. All
solvents were of anal. grade or better.
The DielsꢀAlder reactions carried out in 1.5-ml Eppendorf tubes; evaporations in a Hettlab IR-
Dancer.
Column chromatography (CC): Merck silica gel 60 (40 – 63 mm) or MacheryꢀNagel basic aluminium
oxide (activity 1); solvents, i.e., CH Cl , cyclohexane, AcOEt, EtOH, freshly distilled or of p.a. quality
2
2
(
MeOH); the progress of the reactions checked by TLC (silica gel 60, F-254, Merck); and detection
under UV light (254 nm) or after staining with aq. KMnO -soln. HPLC: Agilent 1100 series HPLC system
4
or MERCK-HITACHI system, containing the following components: L-5025 column thermostat, L-4400
Diode array detector, L-6200Aintelligent pump, AS-2000A autosampler, and D-6000 interface; columns,
solvents, and the flow rates depending on the DielsꢀAlder reaction; all solvents filtered before being used
for the measurements. Used columns were: Daicel Chiralpak (0.4 cm ꢁ 25 cm with ADH couting and
ADH precolumn), Daicel Chiralpak (0.4 cm ꢁ 25 cm with ODH couting and ODH precolumn), Waters
1
X-Terra RP (5 mm 4.6 mm ꢁ 250 mm), and LiChrosphor LiChroCART 250-4 Si 60 (5 mm). H-NMR
18
Spectra (first order): Bruker AM 400 (400 MHz) or a Varian Mercury VX 300 (300 MHz) spectrometers;
in CDCl ; chemical shifts (d) in ppm with reference to TMS (d ¼ 0.00 ppm) and to CHCl (7.26 ppm) as
3
3
13
internal standards; coupling constants (J) as absolute values. C-NMR Spectra: Bruker AM 400
(
100 MHz) or a Bruker Avance DRX (125 MHz) spectrometer; in CDCl . chemical shifts (d) in ppm with
3
reference to TMS (d ¼ 0.00 ppm) and to CHCl (77.2 ppm, t) as internal standards. MS: Finnigan
3
MAT312 and TSQ 700 spectrometers by using electron impact (EI), chemical ionization (CI), and GC/
MS (EI or CI); additionally, electrospray ionization mass spectrometry (ESI) and atmospheric-pressure
chemical-ionization (APCI) mass spectra recorded with a LCQ Advantage or Exactive. HR-MS: Thermo
Exactive with orbitrap-analysator spectrometer; the molecular fragments quoted in m/z, the intensities as
a percentage value relative to the intensity of the base signal (100%). Elemental analyses: Elementar
Vario EL (Elementar Analysesysteme GmbH).
General Procedure for Acylation of Various Amines Using TBTU (GP 1). The carboxylic acid
(
1
1.5 equiv.) and TBTU (O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate;
i
.5 equiv.) were suspended in the chosen solvent (either DMF or CH Cl ) [17]. EtN( Pr) (6.0 equiv.)
2
2
2
was added, and the mixture was stirred for 20 min. After addition of amine 5, 6 or 7 (1.0 equiv.) and
stirring overnight at r.t., the mixture was washed with sat. aq. NaHCO3 soln. and H O, and dried
2
(
(
Na SO ). The org. solvent was evaporated, and the crude product was purified via flash chromatography
2 4
FC; SiO ; CH Cl /MeOH 99 :1 ! 85 :15).
2
2
2
General Procedure for DielsꢀAlder Reactions with Cyclopentadiene (12) without Metal Salts (GP 2).
The dienophile (1.0 equiv.) was dissolved in benzene and after addition of freshly cracked and distilled 12
4.0 equiv.), the mixture was stirred at r.t. After evaporation of the solvent, the residue was dissolved in
CH Cl and washed with sat. aq. NaHCO soln. and H O. After drying (Na SO ), the org. solvent was
(
2
2
3
2
2
4
evaporated, and the crude product was purified by FC (SiO ; CH Cl /MeOH 99 :1 ! 85 :15).
2
2
2
General Procedure for DielsꢀAlder Reactions with 12 and Cu(OTf) (GP 3). The dienophile
2
(
1.0 equiv.) was dissolved in benzene, mixed with Cu(OTf) (1.1 equiv.), and stirred for 30 min to obtain
2
2þ
the Cu complex. After addition of freshly cracked and dist. 12 (4.0 equiv.), the mixture was stirred at
r.t., and the solvent was evaporated under reduced pressure. The residue was dissolved in CH Cl and
2
2
washed with KCN soln. (0.5m) and H O (2ꢁ). After drying (Na SO ), the org. solvent was evaporated,
2
2
4
and the crude product purified by FC (SiO ).
2
General Procedure for the Kinetic Studies of DielsꢀAlder Reactions with 12 (GP 4). The dienophile
1.0 equiv.) was dissolved in benzene in a 1.5-ml Eppendorf tube and mixed with the appropriate salt
1.0 equiv.), in the case of metal addition. After shaking for 30 min at 258 with 850 rpm, freshly cracked
(
(
and dist. 12 (4.0 equiv.) was added, and the mixture was shaken at 258 (850 rpm). Samples for HPLC
were prepared by taking 10 ml of the soln. and addition of heptane (0.5 ml). The org. phase was washed
with KCN soln. (0.5m) and H O (2ꢁ). The org. phase was used for HPLC.
2
General Procedure for the Kinetic Studies of the DielsꢀAlder Reactions with 12 (GP 5): The
dienophile (1.0 equiv.) was dissolved in benzene in a 1.5-ml Eppendorf tube and mixed, in the case of

Helvetica Chimica Acta – Vol. 98 (2015)
297
metal addition, with the appropriate salt (1.0 equiv.). After shaking for 30 min at 258 (850 rpm), freshly
cracked and dist. 12 (4.0 equiv.) was added, and the mixture was stirred at 258 (850 rpm). Samples for
HPLC were prepared by taking 10 ml of the soln. After evaporation under reduced pressure IR Dancer,
the residue was dissolved in Et O and washed with KCN soln. (0.5m) and H O (2ꢁ). The org. solvent was
2
2
evaporated using an IR Dancer, and the crude mixture was dissolved in an adequate HPLC solvent.
N,N-Bis(pyridin-2-ylmethyl)prop-2-enamide (11). Compound 11 was synthesized according to GP 1
by using acrylic acid (0.25 g, 3.75 mmol, 1.5 equiv.) and 1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)methan-
amine (5; 0.50 g, 2.50 mol, 1.0 equiv.) in DMF. The resulting dark oil was purified by CC (SiO ; CH Cl /
2
2
2
1
MeOH 99 :1 ! 90 :10) to yield 11 (0.49 g, 1.94 mmol, 78%). Brown oil. H-NMR (CDCl , 400 MHz):
3
4
.80 (s, CH N); 4.85 (s, CH N); 5.71 (dd, J ¼ 10.5, 2.0, 1 H, CH¼CH ); 6.45 (dd, J ¼ 16.8, 2.0, 1 H,
2
2
2
CH¼CH ); 6.65 (dd, J ¼ 16.8, 10.4, CH¼CH ); 7.15 – 7.21 (m, 3 arom. H); 7.36 – 7.40 (m, 1 arom. H);
2
2
13
7
.62 – 7.68 (m, 2 arom. H); 8.49 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 51.9; 53.2; 120.9;
3
1
22.5; 122.6; 122.8; 127.7; 129.2; 136.9; 137.0; 149.3; 150.0; 156.9; 157.3; 167.3. ESI-MS (pos.): 254.1 (100,
þ
þ
þ
[
M þ H] ). HR-APCI-MS (pos.): 254.1290 ([M þ H] , C H N O ; calc. 254.1293).
15
16
3
N,N-Diethylbicyclo[2.2.1]hept-5-ene-2-carboxamide (13). A mixture of 13a and 13b was synthesized
according to GP 2, by using N,N-diethylprop-2-enamide (9; 0.50 g, 3.90 mmol, 1.0 equiv.), and freshly
cracked and dist. 12 (1.30 ml, 15.7 mmol, 4.0 equiv.). After 5 d, and removal of solvent and remaining 12
under reduced pressure, the crude product was purified by CC (SiO ; cyclohexane/AcOEt 98 :2) to yield
2
1
3a (0.30 g, 1.55 mmol, 40%) and 13b (0.18 g, 0.93 mmol, 24%). Colorless oils.
1
Data of 13a. H-NMR (CDCl , 400 MHz): 1.11 (t, J ¼ 7.1, MeCH ); 1.20 (t, J ¼ 7.1, MeCH ); 1.34 –
3
2
2
1
2
1
.40 (m, 1 H of CH (7)); 1.75 – 1.79 (m, 1 H, CH (7)); 1.80 – 1.86 (m, 1 H, CH (3)); 2.25 – 2.30 (m, CH);
2
2
2
13
.89 – 2.92 (m, CH, CH(2)); 3.31 – 3.42 (m, 2 MeCH ); 6.12 – 6.17 (m, CH¼CH). C-NMR (CDCl3,
2
00 MHz): 13.1; 14.5; 31.5; 40.1; 40.7; 41.6; 41.7; 46.6; 46.9; 136.4; 138.3; 174.9.
1
Data of 13b. H-NMR (CDCl , 400 MHz): 1.07 (t, J ¼ 7.1, MeCH ); 1.16 (t, J ¼ 7.14, MeCH ); 1.28 –
3
2
2
1.31 (m, 1 H, CH (7)); 1.39 – 1.46 (m, 1 H of CH (7), 1 H of CH (3)); 1.88 – 1.95 (m, 1 H, CH (3)); 2.87 –
2 2 2 2
2
.91 (m, CH); 2.99 – 3.03 (m, CH(2)); 3.06 – 3.09 (m, CH); 3.17 – 3.53 (m, 2 MeCH ); 6.02 (dd, J ¼ 5.6, 3.0,
2
13
CH¼CH); 6.17 (dd, J ¼ 5.6, 3.0, CH¼CH). C-NMR (CDCl , 100 MHz): 13.0; 14.5; 31.2; 39.8; 41.1; 41.8;
3
þ
4
1
2.8; 46.1; 49.7; 132.8; 136.4; 173.2. APCI-MS (pos.): 194.2 (100, [M þ H] ). HR-APCI-MS (pos.):
þ
þ
94.1546 ([M þ H] , C H NO ; calc. 194.1545).
12
20
Conversion from dienophile 9 to the mixture 13a/13b was monitored via GP 4. HPLC was performed
i
with an achiral Si60 column (LiChroCHART 250-4) with heptane/ PrOH 4 :1, a flow rate of 0.5 ml/min
and detection at 210 nm, resulting in the following retention times (t : 8.3 (13a), 9.3 (13b), and 13.7 (9)
R
min.
Ethyl Bicyclo[2.2.1]hept-5-ene-2-carboxylate (14). A mixture 14a/14b was synthesized according to
GP 2, by using ethyl prop-2-enoate (10; 0.25 g, 2.50 mmol, 1.0 equiv.) and freshly cracked and dist. 12
(
0.83 ml, 10.0 mmol, 4.0 equiv.). After 30 h, and removal of solvent and remaining 12 under reduced
pressure, the crude product was purified by CC (SiO ; cyclohexane/AcOEt 9 :1 ! 1.5 :1) to yield 14a/14b
2
(
0.38 g, 2.30 mmol, 94%; endo/exo 3 :1). Colorless oil.
1
Data of 14a. H-NMR (CDCl , 400 MHz): 1.24 (t, J ¼ 7.3, MeCH ); 1.25 – 1.29 (1 H, CH (7)); 1.40 –
3
2
2
1
4
(
2 2
.45 (m, 1 H of CH (7), 1 H of CH (3)); 1.86 – 1.95 (m); 2.88 – 2.96 (m, CH, CH(2)); 3.19 – 3.22 (m, CH);
13
.03 – 4.12 (m, MeCH ); 5.93 (dd, J ¼ 5.6, 2.8, CH¼CH); 6.19 (dd, J ¼ 5.7, 3.0, CH¼CH). C-NMR
2
CDCl , 100 MHz): 14.4; 29.3; 42.7; 43.5; 45.8; 49.7; 60.2; 132.5; 137.8; 174.8.
3
1
Data of 14b. H-NMR (CDCl , 400 MHz): 1.26 (t, J ¼ 7.2, MeCH ); 1.26 – 1.39 (m, 1 H of CH (7),
3
2
2
1
H of CH (3)); 1.51 – 1.56 (m, 1 H, CH (7)); 1.86 – 1.95 (m, 1 H, CH (3)); 2.18 – 2.24 (m, CH(2)); 2.88 –
2 2 2
2
.96 (m, CH); 3.02 – 3.05 (m, CH); 4.10 – 4.18 (m, MeCH ); 5.93 (dd, J ¼ 5.6, 2.9, CH¼CH); 6.14 (dd, J ¼
2
13
5
1
.6, 2.8, CH¼CH). C-NMR (CDCl , 100 MHz): 14.4; 30.4; 41.7; 43.3; 46.4; 46.7; 60.4; 135.9; 138.1;
3
þ
þ
þ
76.3. APCI-MS (pos.): 167.1 (100, [M þ H] ). HR-APCI-MS (pos.): 167.1072 ([M þ H] , C H O ;
10
15
2
calc. 167.1072).
Conversion of dienophile 10 to the mixture 14a/14b was monitored via GP 4. HPLC was performed
i
with a achiral Si60-column (LiChroCHART 250-4) with heptane/ PrOH 95 :5; a flow rate of 0.5 ml/min
and detection at 210 nm resulting in the following tR values: 7.7 (14b), 9.2 (14a), and 10.4 (10) min.
N,N-Bis(pyridin-2-ylmethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide (15). A mixture 15a/15b was
synthesized according to GP 3 by using N,N-bis(pyridin-2-ylmethyl)prop-2-enamide (11; 39.5 mg,

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Helvetica Chimica Acta – Vol. 98 (2015)
0
.16 mmol, 1.0 equiv.), Cu(OTf)2 (57.8 mg, 0.16 mmol, 1.0 equiv.), and freshly cracked and dist. 12
(
51.5 ml, 0.62 mmol, 4.0 equiv.). After 16 h, the solvent and remaining 12 were removed under reduced
pressure. The crude product was dissolved in CH Cl (25 ml), washed with sat. aq. NaHCO soln. (25 ml),
and H O (25 ml) and the org. phase was dried (Na SO ). The solvent was removed under reduced
2
2
3
2
2
4
pressure. Purification by CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) afforded 15a/15b (48.2 mg, 0.15 mmol,
2
2
2
9
7%; endo/exo 1.3 :1). Slightly brown gum.
1
Data of 15a. H-NMR (CDCl , 400 MHz): 1.22 – 1.27 (m, 1 H, CH (7)); 1.40 (ddd, J ¼ 8.3, 4.5, 1.9,
3
2
1
2
H, CH (7)); 1.52 (ddd, J ¼ 11.3, 4.6, 2.6, 1 H, CH (3)); 1.90 (ddd, J ¼ 11.3, 9.3, 3.8, 1 H, CH (3)); 2.87 –
2
2
2
.91 (m, CH); 3.09 – 3.12 (m, CH); 3.19 (ddd, J ¼ 9.2, 4.6, 3.2, CH(2)); 4.56 – 4.96 (m, 2 CH N); 6.03 (dd,
2
J ¼ 5.6, 2.9, CH¼CH); 6.22 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.12 – 7.25 (m, 4 arom. H); 7.60 – 7.71 (m, 2 arom.
13
H); 8.47 – 8.59 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 31.0; 41.7; 42.9; 46.3; 49.8; 51.4; 52.8; 120.7;
3
1
22.2; 122.3; 122.5; 132.5; 136.8; 137.0 (2ꢁ); 149.2; 150.0; 157.4; 157.8; 175.2.
1
Data of 15b. H-NMR (CDCl , 400 MHz): 1.31 – 1.35 (m, 1 H, CH (7)); 1.36 – 1.42 (m, 1 H, CH (3);
3
2
2
1
.77 – 1.81 (m, 1 H, CH (7)); 1.86 – 1.95 (m, 1 H, CH (3)); 2.41 – 2.45 (m, CH(2)); 2.87 – 2.93 (m, CH);
2
2
2
.97 – 3.00 (m, CH); 4.56 – 4.96 (m, 2 CH N); 6.05 (dd, J ¼ 5.6, 3.2, CH¼CH); 6.11 (dd, J ¼ 5.6, 3.0,
2
13
CH¼CH); 7.11 – 7.30 (m, 4 arom. H); 7.60 – 7.71 (m, 2 arom. H); 8.47 – 8.59 (m, 2 arom. H). C-NMR
(
CDCl , 100 MHz): 31.5; 40.9; 41.8; 46.6; 46.9; 51.5; 53.0; 120.7; 122.2; 122.3; 122.5; 132.5; 136.1; 136.7;
3
þ
1
3
38.3; 149.2; 149.9; 157.2; 157.8; 176.8. APCI-MS (pos.): 320.2 (100, [M þ H] ). HR-APCI-MS (pos.):
þ
þ
20.1763 ([M þ H] , C H N O ; calc. 320.1763).
20
22
3
Conversion of dienophile 11 to 15a/15b was monitored via GP 5. HPLC was performed with a chiral
i
ODH-column (25 cm) with heptane/ PrOH/EtOH 380 :19 :1, a flow rate of 1.0 ml/min, and detection at
2
1
10 nm, resulting in the following t
5a was possible, using chiral ODH column. For reaction times for full conversion with and without
R
values: 27.3 (15b), 30.9 þ 34.9 (15a), and 42.7 (11) min. Separation of
1.0 equiv. of chosen metal-salts and endo/exo ratios, see Table 1.
Table 1
1
1 ! 15
endo/exo
Time [min]
without
Cu(OTf)2
CuCl2
1.3 : 1
6.8 : 1
1.9 : 1
1.6 : 1
3.5 : 1
4.6 : 1
3000
250
> 3000
> 3000
> 3000
800
CuCl
FeCl
Zn(OTf)2
3
N-[2-(Dimethylamino)ethyl]-N-(pyridin-2-ylmethyl)prop-2-enamide (16). A soln. of N,N-dimethyl-
N’-(pyridin-2-ylmethyl)ethane-1,2-diamine (6; 0.40 g, 2.20 mmol, 1.0 equiv.) in CH Cl (20 ml) was
2
2
cooled to 08 and freshly distilled acryloyl chloride (¼ prop-2-enoyl chloride; 0.62 g, 6.60 mmol, 3.0 equiv.)
was added in one portion. After stirring at 08 for 1 h, the soln. was warmed up to r.t., and the solvent was
removed under reduced pressure. The residue was dissolved in CH Cl (20 ml), and the org. soln. was
2
2
washed with a sat. aq. soln. of NaHCO (20 ml), and H O (2 ꢁ 20 ml) and dried (Na SO ). The solvent
3
2
2
4
was removed under reduced pressure, and the resulting oil was purified by CC (basic aluminium oxide,
1
CH Cl /MeOH 99.5 :0.5 ! 95 :5) to yield 16 (362 mg, 1.55 mmol, 71%). Brown gum. H-NMR (CDCl ,
2
2
3
4
00 MHz): 2.23 (s, Me); 2.25 (s, Me); 2.43 – 2.55 (m, CH NMe ); 3.51 – 3.64 (m, NCH CH ); 4.76 – 4.80
2 2 2 2
(
m, CH N); 5.62 – 5.77 (m, 1 H, CH¼CH ); 6.36 – 6.46 (m, CH¼CHH); 6.49 – 6.71 (m, HC¼CH ); 7.15 –
2
2
2
13
7.34 (m, 2 arom. H); 7.61 – 7.71 (m, 1 arom. H); 8.51 – 8.60 (m, 1 arom. H). C-NMR (CDCl , 100 MHz):
3
4
5.0; 45.7; 45.8; 52.1; 57.3; 122.4; 127.4; 128.6; 136.8; 149.2; 157.5 (2ꢁ); 166.6. APCI-MS (pos.): 234.2
þ
þ
þ
(
100, [M þ H] ). HR-APCI-MS (pos.): 234.1603 ([M þ H] , C H N O ; calc. 234.1606).
13
20
3
N-{2-[Propyl(pyridin-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)prop-2-enamide (17). Com-
pound 17 was synthesized according to GP 1, by using acrylic acid (0.14 g, 2.00 mmol, 1.5 equiv.) and N-
ethyl-N,N’-bis(pyridin-2-ylmethyl)ethane-1,7-diamine (7; 0.37 g, 1.30 mmol, 1.0 equiv.) in DMF. The

Helvetica Chimica Acta – Vol. 98 (2015)
299
resulting black gum was purified by CC (SiO ; CH Cl /MeOH 99 :1 ! 90 :10) to afford 17 (0.38 g.
2
2
2
1
1
.12 mmol, 86%). Dark green oil. H-NMR (CDCl , 400 MHz): 0.87 (t, J ¼ 8.2, MeCH ); 1.46 – 1.55 (m,
3
2
MeCH ); 2.48 (t, J ¼ 7.4, NCH CH N); 2.65 (t, J ¼ 7.4, NCH CH N); 3.48 – 3.62 (m, NCH CH Me); 3.73
2
2
2
2
2
2
2
(
6
s, pyCH N); 4.70 (s, CH N); 5.63 (dd, J ¼ 10.3, 2.3, 1 H, CH¼CH ); 6.35 (dd, J ¼ 16.7, 2.2, CH¼CH );
2
2
2
2
.51 (dd, J ¼ 16.7, 10.3, CH¼CH ); 7.10 – 7.30 (m, 3 arom. H); 7.39 – 7.41 (m, 1 arom. H); 7.59 – 7.69 (m, 2
2
13
arom. H); 8.47 ꢀ 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.8; 20.5; 46.6; 52.0; 54.1; 57.2;
3
6
3
3.8; 122.1; 122.4; 123.1; 127.8; 128.6; 136.6; 136.8; 137.1; 149.0; 149.8; 157.7 (2ꢁ); 166.5. APCI-MS (pos.):
þ þ þ
39.2 (100, [M þ H] ). HR-APCI-MS (pos.): 339.2184 ([M þ H] , C H N O ; calc. 339.2185).
20
27
4
N-[2-(Dimethylamino)ethyl]-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide (18).
A mixture 18a/18b was synthesized according to GP 3 by using 16 (30.0 mg, 0.13 mmol, 1.0 equiv.),
Cu(OTf)2 (45.1 mg, 0.13 mmol, 1.0 equiv.), and freshly cracked and dist. 12 (42.0 ml, 0.52 mmol,
4
.0 equiv.). After of 16 h, the solvent and remaining 12 were removed under reduced pressure. The crude
product was dissolved in CH Cl (25 ml), washed with sat. aq. NaHCO soln. (25 ml) and H O (25 ml),
2
2
3
2
the org. phase was dried (Na SO ), and the solvent was removed under reduced pressure. Purification by
2
4
CC (basic aluminium oxide, CH Cl /MeOH 98 :1 ! 95 :5) yielded 18a/18b (27.5 mg, 0.09 mmol, 71%;
2
2
endo/exo 1.7:1). Slightly brown gum.
1
Data of 18a. H-NMR (CDCl , 400 MHz): 1.13 – 1.17 (m, 1 H, CH (7)); 1.18 – 1.44 (m, 1 H of
3
2
CH (7), 1 H of CH (3)); 1.75 – 1.82 (m, 1 H, CH (3)); 2.17 (s, Me); 2.18 (s, Me); 2.36 – 2.46 (m,
2
2
2
CH
2
2 2 2
NMe ); 2.95 – 3.01 (m, CH); 3.07 – 3.10 (m, CH); 3.40 – 3.52 (m, NCH CH ); 3.53 – 3.61 (m, CH(2));
4
2
4
.63 – 4.83 (m, CH N); 5.94 (dd, J ¼ 5.6, 2.6, CH¼CH); 6.14 (dd, J ¼ 5.6, 3.3, CH¼CH); 7.13 – 7.23 (m,
2
13
arom. H); 7.59 – 7.70 (m, 1 arom. H); 8.49 – 8.56 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 30.9;
3
1.7; 42.7; 45.4; 45.8; 49.8; 53.2; 56.6; 58.0; 120.4; 122.4; 132.4; 136.6; 136.9; 149.8; 158.2; 174.8.
1
Data of 18b. H-NMR (CDCl , 400 MHz): 1.05 – 1.11 (m, 1 H, CH (7)); 1.31 – 1.45 (m, 1 H of
3
2
CH (7), 1 H of CH (3)); 1.87 – 2.00 (m, 1 H, CH (3)); 2.17 (s, Me); 2.18 (s, Me); 2.77 – 2.82 (m, CH);
2
2
2
2
.84 – 2.88 (m, CH); 2.89 – 2.92 (m, CH NMe ); 3.40 – 3.61 (m, NCH CH , CH(2)); 4.63 – 4.83 (m,
2 2 2 2
CH N); 6.02 (dd, J ¼ 5.7, 2.7, CH¼CH); 6.09 (dd, J ¼ 5.7, 2.5, CH¼CH); 7.13 – 7.23 (m, 2 arom. H); 7.59 –
2
13
7
.70 (m, 1 arom. H); 8.49 – 8.56 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 31.2; 41.5; 44.4; 46.2; 46.3;
3
4
9.9; 51.4; 56.6; 58.0; 122.0; 122.1; 132.5; 136.7; 136.9; 149.0; 157.7; 174.8. APCI-MS (pos.): 300.2 (100,
þ
þ
þ
[
M þ H] ). HR-APCI-MS (pos.): 300.2077 ([M þ H] , C18
26 3
H N O ; calc. 300.2076).
Conversion of 16 to 18a/18b was monitored via GP 5. HPLC was performed with two Chiralpak
i
AGP columns (25 cm), NH OAC (0.01m)/ PrOH 1:1, a flow rate of 0.75 ml/min, and detection at 260 nm,
4
resulting in the following tR values: 6.9 (16), 9.3 (18a), and 10.5 (18b) min. For reaction times for full
conversion with and without 1.0 equiv. of chosen metal salts and endo/exo ratios, see Table 2.
Table 2
1
6 ! 18
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
CuCl
FeCl3
1.5 : 1
4.5 : 1
1.5 : 1
1.3 : 1
1.6 : 1
1.5 : 1
3600
2200
> 2200
2000
> 3600
> 3600
Zn(OTf)2
N-{2-[Propyl(pyridin-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]hept-5-ene-2-
carboxamide (19). A mixture 19a/19b was synthesized according to GP 3 by using 17 (0.05 g, 0.15 mmol,
1
.0 equiv.), Cu(OTf) (54.2 mg, 0.15 mmol, 1.0 equiv.), and freshly cracked and dist. 12 (48 ml, 0.60 mmol,
2
4
.0 equiv.). After 16 h, the solvent and remaining 12 were removed under reduced pressure. The crude
product was dissolved in CH Cl (25 ml), and washed with sat. NaHCO soln. (25 ml) and H O (25 ml).
2
2
3
2
The org. phase was dried (Na SO ), and the solvent was removed under reduced pressure. Purification by
2
4
CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) furnished 19a/19b (38.8 mg, 96.0 mmol, 64%; endo/exo 1.5 :1).
2
2
2
Slightly brown gum.

3
00
Helvetica Chimica Acta – Vol. 98 (2015)
Data of 19a: H-NMR (CDCl , 400 MHz): 0.88 (t, J ¼ 7.3, MeCH ); 1.18 – 1.27 (m, 1 H, CH (7));
1
3
2
2
1.34 – 1.45 (m, 1 H of CH (7), 1 H of CH (7)); 1.46 – 1.55 (m, MeCH ); 1.79 – 1.87 (m, 1 H, CH (3));
2 2 2 2
2
.43 – 2.52 (m, NCH CH N); 2.68 (t, J ¼ 7.2, NCH CH N); 2.82 – 2.90 (m, CH); 2.96 – 3.07 (m, CH(2),
2
2
2
2
CH); 3.43 – 3.65 (m, NCH CH Me); 4.48 (s, CH N); 4.65 – 4.83 (m, CH N); 5.98 (dd, J ¼ 5.6, 2.8,
2
2
2
2
CH¼CH); 6.20 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.10 – 7.23 (m, 3 arom. H); 7.38 – 7.46 (m, 1 arom. H); 7.56 – 7.70
13
(
m, 2 arom. H); 8.47 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.8; 20.5; 31.0; 41.7; 42.8; 46.2;
3
4
1
9.8; 51.4; 52.9; 53.5; 57.4; 63.8; 121.9; 122.1; 132.5; 132.6; 136.5; 136.7; 136.9; 137.0; 149.1; 149.9; 158.3;
74.5.
1
Data of 19b. H-NMR (CDCl , 400 MHz): 0.83 (t, J ¼ 7.1, MeCH ); 1.19 – 1.32 (m, 1 H, CH (7));
3
2
2
1.31 – 1.52 (m, 1 H, CH (7)); 1.46 – 1.55 (m, MeCH ); 1.70 – 1.77 (m, 1 H, CH (3)); 2.20 – 2.35 (m, 1 H,
2
2
2
CH (3)); 2.41 – 2.52 (m, NCH CH N); 2.60 – 2.73 (m, NCH CH N); 2.83 – 2.91 (m, CH); 2.96 – 3.07 (m,
2
2
2
2
2
CH(2), CH); 3.43 – 3.65 (m, NCH CH Me); 4.48 (s, CH N); 4.65 – 4.83 (m, CH N); 6.06 (dd, J ¼ 5.6, 2.9,
2
2
2
2
CH¼CH); 6.08 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.10 – 7.23 (m, 3 arom. H); 7.38 – 7.46 (m, 1 arom. H); 7.56 – 7.70
13
(
m, 2 arom. H); 8.47 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.8; 20.5; 31.2; 41.3; 41.4; 46.0;
3
4
1
9.8; 52.0; 52.9; 53.5; 57.4; 60.9; 121.9; 122.1; 132.5; 132.6; 136.5; 136.7; 136.9; 137.0; 149.1; 149.9; 158.3;
þ
þ
þ
74.5. APCI-MS (pos.): 405.3 (100, [M þ H] ). HR-APCI-MS (pos.): 405.2654 ([M þ H] , C H N O ;
25
33
4
calc. 405.2654).
Conversion of 17 to 19a/19b was monitored via GP 5. HPLC was performed with a chiral ADH
i
column (25 cm), heptane/ PrOH/EtOH 45 :4 :1, a flow rate of 1.0 ml/min, and detection at 230 nm
resulting in the following t values: 15.9 (19b), 17.2 þ 20.1 (19a), and 22.0 (17) min. Cycloadduct 19a was
R
separated by using the chiral ADH column. For reaction times for full conversion with and without
1.0 equiv. of chosen metal salts, and endo/exo ratios, see Table 3.
Table 3
1
7 ! 19
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
1.7: 1
6.2 : 1
1.9 : 1
1.7: 1
2.0 : 1
9.5 : 1
> 10000
1800
8600
> 10000
8600
CuCl
FeCl
Zn(OTf)2
3
450
(
2E)-N,N-Diethyl-Nꢀ,Nꢀ-bis(pyridin-2-ylmethyl)but-2-enediamide (20). (2Z)-4-(Diethylamino)-4-
oxobut-2-enoic acid was prepared by addition of Et NH (3.14 ml, 30.6 mmol, 1.0 equiv.) to a stirred
2
soln. of furan-2,5-dione (3.00 g, 30.6 mmol, 1.0 equiv.) in Et O (100 ml) at 08. After 1 h, the resulting solid
2
was filtered and washed with cold Et O. Recrystallization in Et O provided the product (2.18 g,
2
2
1
2.7 mmol, 42%). Colorless solid.
Diamide 20 was synthesized according to GP 1, by using the acid (0.50 g, 2.92 mmol, 1.5 equiv.)
mentioned above and bis(pyridin-2-ylmethyl)amine (5; 0.39 g, 1.95 mmol, 1.0 equiv.) in DMF. The
resulting black gum was purified via CC (SiO ; CH Cl /MeOH 99 :1 ! 9 :1) to yield a dark-green oil
2
2
2
(
0.67 g, 1.90 mmol, 97%; (E)/(Z) mixture).
The mixture (0.53 g, 1.50 mmol, 1.0 equiv.) was dissolved in MeCN (1.50 ml) in a microwave tube.
After addition of piperidine (12.0 ml, 0.12 mmol, 8 mol-%), the mixture was heated under microwave at
208 with 150 W for 45 min [18]. The mixture was dissolved in CH Cl (50 ml) and washed with sat.
1
2
2
NH Cl soln. (20 ml), sat. aq. NaHCO soln. (20 ml), and H O (20 ml). After drying (Na SO ), the
4
3
2
2
4
1
solvent was removed under reduced pressure to give 20 (0.52 g, 1.47 mmol, 98%). H-NMR (CDCl ,
3
4
00 MHz): 1.14 (t, J ¼ 7.1, MeCH ); 1.20 (t, J ¼ 7.2, MeCH ); 3.43 (q, J ¼ 7.1, MeCH ); 3.44 (q, J ¼ 7.2,
2
2
2
MeCH ); 4.84 (s, CH N); 4.85 (s, CH N); 7.15 – 7.20 (m, 3 arom. H); 7.31 – 7.34 (m, 1 arom. H); 7.46 (br. s,
2
2
2
13
CH¼CH); 7.61 – 7.67 (m, 2 arom. H); 8.50 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 13.1; 15.1;
3
4
1.0; 42.5; 50.9; 53.1; 121.1; 122.5; 122.6; 122.7; 131.0; 132.8; 136.8; 136.9; 149.4; 150.0; 156.2; 157.0; 164.4;

Helvetica Chimica Acta – Vol. 98 (2015)
301
þ
þ
þ
1
66.5. APCI-MS (pos.): 353.2 (100, [M þ H] ). HR-APCI-MS (pos.): 353.1973 ([M þ H] , C H N O ;
20
25
4
2
calc. 353.1978).
(
2E)-N-[2-(Dimethylamino)ethyl]-Nꢀ,Nꢀ-diethyl-N-(pyridin-2-ylmethyl)but-2-enediamide (21). A
soln. of (2Z)-4-(diethylamino)-4-oxobut-2-enoic acid (0.53 g, 3.07 mmol, 1.1 equiv.) in CH Cl
2
2
(
10.0 ml) was stirred at r.t. After the addition of DCC (N,N’-dicyclohexylcarbodiimide; 0.63 g,
3
.07 mmol, 1.1 equiv.), a soln. of 6 (0.50 g, 2.79 mmol, 1.0 equiv.) was added, and the mixture was
stirred for 8 h. The mixture was added to CH Cl (50 ml), washed with sat. aq. NH Cl soln. (20 ml), sat.
2
2
4
NaHCO soln. (20 ml), and H O (20 ml) and dried (Na SO ). The solvent was removed under reduced
3
2
2
4
pressure, and the resulting oil was purified by CC (basic aluminium oxide, CH Cl /MeOH 99.5 :0.5 !
2
2
9
4 :6) to yield a brown gum (0.73 g, 2.20 mmol, 82%; (E)/(Z) mixture).
The mixture (0.73, 2.20 mmol, 1.0 equiv.) was dissolved in MeCN (10 ml) in a microwave tube. After
addition of piperidine (17.4 ml, 0.18 mmol, 8 mol-%), the mixture was heated under microwave at 1208
with 150 W for 60 min [18]. The mixture was dissolved in CH Cl (50 ml), and washed with sat. NH Cl
2
2
4
soln. (20 ml), sat. aq. NaHCO soln. (20 ml) and H O (20 ml). After drying (Na SO ), the solvent was
3
2
2
4
1
removed under reduced pressure to afford 21 (0.69 g, 2.09 mmol, 95%). H-NMR (CDCl , 400 MHz):
3
1
3
1
1
.12 – 1.25 (m, 2 MeCH ); 2.25 (s, NMe ); 2.48 – 2.59 (m, NCH CH N); 3.39 – 3.50 (m, 2 MeCH ); 3.58 –
2
2
2
2
2
.66 (m, NCH CH N); 4.82 (s, CH N); 7.15 – 7.37 (m, 2 arom. H); 7.38 (d, J ¼ 14.8, CH¼CH); 7.45 (d, J ¼
2
2
2
1
3
4.7, CH¼CH); 7.61 – 7.71 (m, 1 arom. H); 8.51 – 8.60 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 13.0;
3
3.1; 41.0; 41.1; 44.8; 45.4; 45.8; 52.2; 56.7; 121.0; 122.6; 132.3; 132.4; 137.0; 149.9; 156.6; 164.3; 165.6.
þ
þ
þ
2
APCI-MS (pos.): 333.2 (100, [M þ H] ). HR-APCI-MS (pos.): 333.2289 ([M þ H] , C H N O ; calc.
18
29
4
3
33.2291).
2E)-N,N-Diethyl-Nꢀ-{2-[propyl(pyridin-2-ylmethyl)amino]ethyl}-Nꢀ-(pyridin-2-ylmethyl)but-2-
(
enediamide (22). Diamide 22 was synthesized according to GP 1, by using (2Z)-4-(diethylamino)-4-
oxobut-2-enoic acid (0.54 g, 3.17 mmol, 1.5 equiv.) and 7 (0.60 g, 2.11 mmol, 1.0 equiv.) in DMF. The
resulting black gum was purified by CC (SiO ; CH Cl /MeOH 99 :1 ! 9 :1) to yield a dark-green oil
2
2
2
(
0.92, 2.10 mmol, 99%, (E)/(Z) mixture).
The mixture (0.69 g, 1.57 mmol, 1.0 equiv.) was dissolved in MeCN (2.0 ml) in a microwave tube.
After addition of piperidine (16.7 ml, 8 mol-%), the mixture was heated under microwave at 1208 with
50 W for 60 min [18]. The mixture was dissolved in CH Cl (80 ml) and washed with sat. NH Cl soln.
1
2
2
4
(
80 ml), sat. NaHCO soln. (80 ml) and H O (80 ml). After drying (Na SO ), the solvent was removed
3 2 2 4
1
under reduced pressure to afford 22 (0.67 g, 1.52 mmol, 97%). H-NMR (CDCl , 400 MHz): 0.93 (t, J ¼
3
7
.4, MeCH ); 1.16 (t, J ¼ 7.0, MeNCH ); 1.21 (t, J ¼ 7.4, MeNCH ); 1.46 – 1.53 (m, CH CH Me); 2.46 – 2.51
2
2
2
2
2
(
t, J ¼ 7.5, NCH CH Me); 2.70 (t, J ¼ 6.7, NCH CH N); 3.43 (q, J ¼ 6.7, MeCH N); 3.47 (q, J ¼ 7.2,
2
2
2
2
2
MeCH N); 3.60 (t, J ¼ 6.8, NCH CH N); 3.75 (s, CH N); 4.72 (s, CH N); 7.10 – 7.24 (m, CH¼CH, 3 arom.
2
2
2
2
2
H); 7.33 – 7.36 (m, 1 arom. H); 7.47 – 7.52 (d, J ¼ 14.5, CH¼CH); 7.59 – 7.76 (m, 2 arom. H); 8.49 – 8.56 (m,
1
3
2
1
4
arom. H). C-NMR (CDCl , 100 MHz): 11.8; 13.1 (2ꢁ); 20.5; 41.1; 42.5; 46.8; 52.1; 53.4; 57.0; 60.8;
3
22.0; 122.2; 122.7; 123.1; 130.8; 132.1; 136.4; 136.8; 149.0; 149.4; 157.4 (2ꢁ); 164.4; 165.6. ESI-MS (pos.):
þ
þ
þ
38.3 (100, [M þ H] ). HR-ESI-MS (pos.): 438.2864 ([M þ H] , C H N O
2
; calc. 438.2869).
25
36
5
Ethyl (2E)-4-[Bis(pyridin-2-ylmethyl)amino]-4-oxobut-2-enoate (23). Ester 23 was synthesized
according to GP 1, by using ethyl fumarate (3.05 g, 21.0 mmol, 1.5 equiv.), and 5 (2.80 g, 14.0 mmol,
1
.0 equiv.) in CH Cl . The resulting brown oil was purified by CC (SiO ; CH Cl /MeOH 99 :1 ! 9 :1) to
2
2
2
2
2
1
yield 23 (3.73 g. 11.5 mmol, 82%). Slightly brown oil. H-NMR (CDCl , 400 MHz): 1.27 – 1.31 (t, J ¼ 7.2,
3
MeOCH O); 4.18 – 4.24 (q, J ¼ 7.2, MeOCH O); 4.84 (s, CH N); 4.86 (s, CH N); 6.88 – 6.92 (d, J ¼ 15.3,
2
2
2
2
CH(2)); 7.18 – 7.23 (m, 3 arom. H); 7.38 – 7.42 (m, 1 arom. H); 7.47 – 7.52 (d, J ¼ 15.3, CH(3)); 7.63 – 7.72
13
(
m, 2 arom. H); 8.48 – 8.57 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 14.1; 51.4; 53.2; 61.1; 121.3;
3
1
22.7 (2ꢁ); 128.3; 132.1; 133.9; 136.9; 137.4; 148.6; 150.0; 155.9; 156.4; 165.6; 165.9. ESI-MS (pos.): 326.0
þ
(
100, [M þ H] ). Anal. calc. for C H N O (325.36): C 66.45, H 5.89, N 12.91; found: C 66.27, H 6.00, N
18
19
3
3
1
2.73.
Ethyl (2E)-4-{[2-(Dimethylamino)ethyl](pyridin-2-ylmethyl)amino}-4-oxobut-2-enoate (24). Oxalyl
chloride (3.44 ml, 39.5 mmol, 2.5 equiv.) was added to a stirred suspension of ethyl fumarate (2.28 g,
5.8 mmol, 1.0 equiv.) in CH Cl (20.0 ml) at r.t. After addition of DMAP ((4-dimethylamino)pyridine; 1
1
2
2
drop), the resulting soln. was stirred for 1.5 h, and the solvent was removed under reduced pressure. The

3
02
Helvetica Chimica Acta – Vol. 98 (2015)
crude product was purified by bulb-to-bulb distillation and yielded a colorless oil (2.40 g, 14.7 mmol,
9
3%; [19]: 96%).
A soln. of 6 (0.40 g, 2.01 mmol, 1.0 equiv.) in CH Cl (10.0 ml) was cooled to 08 and freshly distilled
2
2
fumaric acid ethyl ester chloride (0.89 g, 5.48 mmol, 2.5 equiv.) was added in one portion. After stirring at
8, for 1 h, the soln. was warmed up to r.t., and the solvent was removed under reduced pressure. The
residue was dissolved in CH Cl (20 ml), and the org. soln. was washed with a sat. aq. soln. of NaHCO
0
2
2
3
(
20 ml) and H O (2 ꢁ 20 ml), and dried (Na SO ). The solvent was removed under reduced pressure, and
2
2
4
the resulting oil was purified by CC (basic aluminium oxide, CH Cl /MeOH 99.5 :0.5 ! 9 :1) to yield 24
2
2
1
(
0.55 g. 1.70 mmol, 85%). Brown gum. H-NMR (CDCl , 400 MHz): 1.25 – 1.35 (m, MeCH ); 2.23 (s,
3 2
MeN); 2.25 (s, MeN); 2.44 – 2.54 (m, NCH CH N); 3.53 – 3.63 (m, NCH CH N); 4.17 – 4.29 (m, MeCH );
2
2
2
2
2
4
.79 (s, CHHN); 4.80 (s, CHHN); 6.85 (d, J ¼ 15.3, CH¼CH); 7.16 – 7.32 (m, 2 arom. H); 7.45 (d, J ¼ 15.4,
13
CH¼CH); 7.60 – 7.71 (m, 1 arom. H); 8.50 – 8.60 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 14.2; 45.6;
3
4
3
5.8; 53.9; 56.9; 58.4; 61.1; 121.0; 122.5; 122.8; 131.7; 134.0; 136.9; 150.0; 157.5; 165.9. APCI-MS (pos.):
06.2 (100, [M þ H] ). HR-APCI-MS (pos.): 306.1814 ([M þ H] , C H N O ; calc. 306.1818).
þ
þ
þ
3
16
24
3
Ethyl (2E)-4-Oxo-4-[{2-[propyl(pyridin-2-ylmethyl)amino]ethyl}(pyridin-2-ylmethyl)amino]but-2-
enoate (25). Ester 25 was synthesized according to GP 1 by using ethyl fumarate (0.38 g, 2.60 mmol,
.5 equiv.) and 7 (0.49 g, 1.70 mmol, 1.0 equiv.) in CH Cl . The residue was dissolved in CH Cl (20 ml),
1
2
2
2
2
and the org. soln. was washed with a sat. aq. NaHCO soln. (20 ml) and H O (20 ml), and dried (Na SO ).
3
2
2
4
The solvent was removed under reduced pressure, and the resulting brown oil was purified by CC (SiO ;
2
1
CH Cl /MeOH 99 :1 ! 9 :1) to yield 25 (0.49 g, 1.30 mmol, 72%). Slightly brown oil. H-NMR (CDCl ,
2
2
3
4
00 MHz): 0.80 – 0.83 (t, J ¼ 7.5, MeCH ); 1.27 ꢀ 1.31 (t, J ¼ 7.2, MeOCH O); 1.50 – 1.53 (m,
2
2
MeCH CH ); 2.48 – 2.51 (m , NCH CH Me); 2.68 (m, NCH CH N); 3.55 (m, NCH CH N); 4.18 – 4.24
2
2
c
2
2
2
2
2
2
(
q, J ¼ 7.2, MeCH O); 4.65 (s, CH N); 4.75 (s, CH N); 6.88 – 6.92 (d, J ¼ 15.3, CH¼CHester); 7.10 – 7.22 (m,
2
2
2
3
8
1
4
arom. H); 7.25 – 7.28 (m, 1 arom. H); 7.47 – 7.52 (d, J ¼ 15.3, CH¼CH
); 7.56 – 7.62 (m, 2 arom. H);
amide
13
.45 – 8.51 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.8; 14.2; 20.2; 46.8; 51.9; 53.0; 54.0; 57.0; 61.1;
3
22.8; 123.0; 123.2; 123.3; 128.5; 131.9; 136.9; 137.0; 149.2; 150.1; 156.7 (2ꢁ); 159.1; 166.0. CI-MS (NH ):
3
þ
þ
þ
3
11.2 (100, [M þ H] ). HR-CI-MS (NH ): 411.2392 ([M þ H] , C H N O ; calc. 411.2396).
3
23 31
4
N,N-Diethyl-Nꢀ,Nꢀ-bis(pyridin-2-ylmethyl)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxamide (26). A mix-
ture 26a/26b was synthesized according to GP 2, by using 20 (0.15 g, 0.44 mmol, 1.0 equiv.), Cu(OTf)2
0.16 g, 0.44 mmol, 1.0 equiv.), and freshly cracked and dist. 12 (0.15 ml, 1.76 mmol, 4.0 equiv.). After
6 h, removal of solvent and remaining 12 under reduced pressure, the crude product was dissolved in
CH Cl (25 ml), washed with a sat. aq. soln. of NaHCO (20 ml) and H O (20 ml), and dried (Na SO ).
(
1
2
2
3
2
2
4
After evaporation of the solvent, purification by CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) yielded 246a/26b
2
2
2
(
0.11 g, 0.26 mmol, 60%; endo/exo 2.8 :1). Slightly brown gum.
1
Data of 26a. H-NMR (CDCl , 400 MHz): 1.16 (t, J ¼ 7.1, MeCH ); 1.20 (t, J ¼ 6.8, MeCH ); 1.37
3
2
2
(
(
(
ddd, J ¼ 8.5, 3.2, 1.6, 1 H, CH ); 1.98 (ddd, J ¼ 8.5, 1.6, 1.6, 1 H, CH ); 2.85 – 2.87 (m, H ); 3.06 – 3.20
2
2
syn
m, 2 CH); 3.28 – 3.48 (m, 2 MeCH ); 3.79 (dd, J ¼ 4.6, 3.4, H ); 4.51 – 5.02 (m, 2 CH N); 6.10 – 6.05
2
anti
2
dd, J ¼ 5.6, 2.9, CH¼CH); 6.36 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.11 – 7.26 (m, 4 arom. H); 7.58 – 7.68 (m, 2
13
arom. H); 8.50 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 31.0 (2ꢁ); 41.7; 42.9; 46.3; 49.8; 51.4;
3
5
3.0 (2ꢁ); 120.7 (2ꢁ); 122.2; 122.3; 132.5 (2ꢁ); 136.9; 137.0; 149.9; 150.0; 157.4; 157.8; 175.2 (2ꢁ).
1
Data of 26b. H-NMR (CDCl , 400 MHz): 0.99 (t, J ¼ 7.1, MeCH ); 1.06 (t, J ¼ 7.1, MeCH ); 1.43
3
2
2
(
(
ddd, J ¼ 8.3, 3.3, 1.7, 1 H, CH ); 2.01 (ddd, J ¼ 8.4, 1.9, 1.6, 1 H, CH ); 2.92 – 3.02 (m, H ); 3.06 – 3.20
2
2
syn
m, 2 CH); 3.28 – 3.48 (m, 2 MeCH ); 3.64 (dd, J ¼ 4.9, 3.5, H ); 4.51 – 5.02 (m, 2 CH N); 6.00 (dd, J ¼
2
anti
2
5
8
(
(
.6, 3.0, CH¼CH); 6.22 (dd, J ¼ 5.6, 3.2, CH¼CH); 7.11 – 7.26 (m, 4 arom. H); 7.58 – 7.68 (m, 2 arom. H);
1
3
.50 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 31.5 (2ꢁ); 40.9; 41.8; 46.6; 46.9; 51.5; 52.8
3
2ꢁ); 120.7 (2ꢁ); 122.2; 122.4; 136.1; 136.7; 136.8; 138.3; 149.2 (2ꢁ); 157.2; 157.8; 176.8 (2ꢁ). CI-MS
þ
þ
þ
NH ): 419.3 (100, [M þ H] ). HR-CI-MS (NH ): 419.2444 ([M þ H] , C H N O ; calc. 419.2447).
3
3
25 31
4
2
Conversion of 20 to 26a/26b was monitored via GP 5. HPLC was performed with a chiral ODH
i
column (25 cm) using heptane/ PrOH (5 :1) as solvent. HPLC-runs were performed with a flow rate of
0
3
.5 ml/min, and detection at 210 nm resulting in the following t values: 20.0 þ 21.8 (26b), 26.6 (26a), and
R
5.7 (20) min. Separation of 26b was possible, using the chiral ODH column. For reaction times for full
conversion with and without 1.0 equiv. of chosen metal salts, and endo/exo ratios, see Table 4.

Helvetica Chimica Acta – Vol. 98 (2015)
303
Table 4
2
0 ! 26
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
2.8 : 1
3.5 : 1
3.2 : 1
3.0 : 1
3.2 : 1
3.5 : 1
800
450
700
900
900
700
CuCl
FeCl
Zn(OTf)2
3
N-[2-(Dimethylamino)ethyl]-Nꢀ,Nꢀ-diethyl-N-(pyridin-2-ylmethyl)bicyclo[2.2.1]hept-5-ene-2,3-di-
carboxamide (27). A mixture of 27a/27b was synthesized according to GP 2 by using 21 (50.0 mg,
0
(
.15 mmol, 1.0 equiv.), Cu(OTf)2 (54.2 mg, 0.15 mmol, 1.0 equiv.), and freshly cracked and dist. 12
49.7 ml, 0.60 mmol, 4.0 equiv.). After 16 h, removal of solvent and remaining 12 under reduced pressure,
the crude product was dissolved in CH Cl (25 ml), and washed with a sat. aq. soln. of NaHCO (20 ml)
2
2
3
and H O (20 ml). After drying the org. phase (Na SO ), the solvent was removed under reduced
2
2
4
pressure. Purification by CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) yielded 27a/27b (41.0 mg, 0.10 mmol,
2
2
2
6
9%; endo/exo ratio of 2.5 :1). Slightly brown gum.
1
Data of 27a: H-NMR (CDCl , 400 MHz): 1.04 – 1.22 (m, 2 MeCH ); 1.32 – 1.38 (m, 1 H, CH (7));
3
2
2
1
2
4
.99 – 2.03 (m, 1 H, CH (7)); 2.30 (s, Me); 2.41 (s, Me); 2.51 – 2.65 (m, CH NMe ); 2.83 – 2.89 (m, CH);
2
2
2
.96 – 3.01 (m, CH); 3.25 – 3.49 (m, NCH CH N, 2 NCH Me); 3.51 – 3.59 (m, CH); 3.63 – 3.68 (m, CH);
2
2
2
.42 – 4.94 (m, CH N); 6.09 (dd, J ¼ 5.3, 2.9, CH¼CH); 6.17 (dd, J ¼ 5.4, 3.2, CH¼CH); 7.13 – 7.23 (m, 2
2
13
arom. H); 7.59 – 7.70 (m, 1 arom. H); 8.49 – 8.56 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 14.5; 14.8;
3
4
1
0.2; 41.7; 44.8; 45.2; 45.9; 46.7; 48.6; 49.0; 51.8; 53.7; 56.1; 57.8; 122.0; 122.7; 134.2; 134.5; 136.6; 136.7;
49.2; 171.6; 171.8.
1
Data of 27b: H-NMR (CDCl , 400 MHz): 1.04 – 1.22 (m, 2 MeCH ); 1.40 – 1.46 (m, CHH); 1.91 –
3
2
1
.98 (m, CHH); 2.30 (s, Me); 2.37 (s, Me); 2.51 – 2.65 (m, CH NMe ); 3.06 – 3.29 (m, 2 CH); 3.25 –
2 2
3
6
8
.49 (m, NCH CH , 2 NCH Me); 3.51 – 3.59 (m, CH); 3.70 – 3.76 (m, CH); 4.42 – 4.94 (m, pyCH N);
2
2
2
2
.00 – 6.05 (m, CH¼CH); 6.33 – 6.37 (m, CH¼CH); 7.13 – 7.23 (m, 2 arom. H); 7.59 – 7.70 (m, 1 arom. H);
13
.49 – 8.56 (m, 1 arom. H). C-NMR (CDCl , 100 MHz): 13.0; 13.1; 40.5; 42.0; 44.7; 45.2; 45.8; 46.6; 48.9
3
(
3
2ꢁ); 51.7; 53.5; 56.0; 58.0; 122.2; 122.6; 134.4; 134.7; 136.9; 137.0; 149.8; 173.2; 173.5. APCI-MS (pos.):
þ
þ
þ
2
99.3 (100, [M þ H] ). HR-APCI-MS (pos.): 399.2758 ([M þ H] , C H N O ; calc. 399.2760).
23
35
4
Conversion of 21 to 27a/27b was monitored via GP 5. HPLC was performed with a Luna C8 column
25 cm), MeCN/aq. NH OAc (0.01m) 1:1, a flow rate of 1.0 ml/min and detection at 270 nm, resulting in
(
4
the following t values: 4.20 (21) and 5.45 (27a þ 27b) min. For reaction times for full conversion with and
R
without 1.0 equiv. of chosen metal-salts and endo/exo ratios, see Table 5.
Table 5
2
1 ! 27
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
CuCl
FeCl3
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
2.5 : 1
1400
1100
1250
900
1400
1500
Zn(OTf)2
N,N-Diethyl-Nꢀ-{2-[propyl(pyridin-2-ylmethyl)amino]ethyl}-Nꢀ-(pyridin-2-ylmethyl)bicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxamide (28). A mixture 28a/28b was synthesized according to GP 2 by using 22
(
45.0 mg, 0.10 mmol, 1.0 equiv.), Zn(OTf) (37.4 mg, 0.10 mmol, 1.0 equiv.), and freshly cracked and dist.
2

3
04
Helvetica Chimica Acta – Vol. 98 (2015)
1
2 (34.0 ml, 0.41 mmol, 4.0 equiv.). After 16 h, removal of solvent and remaining 12 under reduced
pressure, the crude product was dissolved in CH Cl (25 ml), washed with a sat. aq. soln. of NaHCO
3
2
2
(
20 ml) and H O (20 ml), dried (Na SO ), and the solvent was removed under reduced pressure.
2 2 4
Purification by CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) yielded 28a/28b (29.8 mg, 0.06 mmol, 58%; endo/
2
2
2
exo of 1.7:1). Slightly brown gum.
1
Data of 28a. H-NMR (CDCl , 400 MHz): 0.80 – 0.82 (t, J ¼ 8.3, MeCH ); 1.03 – 1.21 (m, 2 MeCH );
3
2
2
1
.32 – 1.41 (m, CHH); 1.42 – 1.55 (m, MeCH ); 1.91 – 2.03 (m, 1 H, CH (7); 2.41 – 2.54 (m, NCH CH N);
2 2 2 2
2
.70 – 2.76 (m, CH); 2.82 – 2.89 (m, CH); 2.95 – 3.04 (m, CH); 3.11 – 3.22 (m, NCH CH N); 3.25 – 3.51 (m,
2
2
NCH CH Me, 2 NCH Me); 3.65 – 3.68 (m, CH); 3.73 (s, CH N); 4.41 – 4.87 (m, CH N); 5.94 – 6.06 (m,
2
2
2
2
2
CH¼CH); 6.16 – 6.27 (m, CH¼CH); 7.10 – 7.30 (m, 3 arom. H); 7.39 – 7.41 (m, 1 arom. H); 7.59 – 7.69 (m, 2
1
3
arom. H); 8.47 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.9; 14.7 (2ꢁ); 20.7; 40.1; 40.5; 41.6;
3
4
2.0; 44.9; 45.0; 46.7; 47.7; 48.9; 51.8; 53.6; 57.2; 122.1 (2ꢁ); 134.4; 134.6; 136.5; 136.6; 137.1; 137.2; 158.2
(
2ꢁ); 173.4; 174.9.
1
Data of 28b. H-NMR (CDCl , 400 MHz): 0.80 – 0.82 (t, J ¼ 8.3, MeCH ); 1.03 – 1.21 (m, 2 MeCH );
3
2
2
1
.32 – 1.41 (m, 1 H, CH (7)); 1.42 – 1.55 (m, MeCH ); 1.91 – 2.03 (m, 1 H, CH (7)); 2.41 – 2.54 (m,
2
2
2
NCH CH N); 2.70 – 2.76 (m, CH); 2.82 – 2.89 (m, CH); 2.95 – 3.04 (m, CH); 3.11 – 3.22 (m, NCH CH N);
2
2
2
2
3
6
.25 – 3.51 (m, NCH CH Me, 2 NCH ); 3.65 – 3.68 (m, CH); 3.73 (s, CH N); 4.41 – 4.87 (m, CH N); 5.94 –
2 2 2 2 2
.06 (m, CH¼CH); 6.30 – 6.36 (m, CH¼CH); 7.10 – 7.30 (m, 3 arom. H); 7.39 – 7.41 (m, 1 arom. H); 7.59 –
þ
7.69 (m, 2 arom. H); 8.47 – 8.58 (m, 2 arom. H). APCI-MS (pos.): 504.3 (100, [M þ H] ). HR-APCI-MS
þ
þ
2
(
pos.): 504.3336 ([M þ H] , C H N O ; calc. 504.3339).
30
42
5
Conversion of 22 to 28a/28b was monitored via GP 5. HPLC was performed with a Luna C8 column
(
25 cm), aq. NH OAc (0.01m)/MeCN 4 :6 ! 6 :4, a flow rate of 0.5 ml/min, and detection at 270 nm,
4
resulting in the following tR values: 8.7 (22), 12.3 (28a), and 12.8 (28b) min. For reaction times for full
conversion with and without 1.0 equiv. of chosen metal salts and endo/exo ratios, see Table 6.
Table 6
2
2 ! 28
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
1.7: 1
1.7: 1
1.7 : 1
1.7: 1
1.7 : 1
1.7: 1
4800
3000
> 4800
> 4800
> 4800
2000
CuCl
FeCl
Zn(OTf)2
3
Ethyl 3-[Bis(pyridin-2-ylmethyl)carbamoyl]bicyclo[2.2.1]hept-5-ene-2-carboxylate (29). A mixture
9a/29b was synthesized according to GP 2 by using 23 (0.12 g, 0.37 mmol, 1.0 equiv.) and freshly cracked
2
and dist. 12 (0.13 ml, 1.48 mmol, 4.0 equiv.). After 16 h, removal of solvent and remaining 12 under
reduced pressure, the crude product was dissolved in CH Cl (25 ml), and washed with a sat. aq. soln. of
2
2
NaHCO3 (25 ml) and H O (25 ml), and dried (Na SO ). Purification by CC (SiO ; CH Cl /MeOH
2
2
4
2
2
2
9
8 :2 ! 9 :1) yielded 29a/29b (0.12 g, 0.16 mmol, 83%; endo/exo of 0.4 :1). Slightly brown gum.
1
Data of 29a. H-NMR (CDCl , 400 MHz): 1.20 (t, J ¼ 7.1, MeCH ); 1.41 – 1.46 (m, 1 H, CH (7));
3
2
2
1.97 – 2.02 (m, 1 H, CH (7)); 2.78 – 2.83 (m, CH); 2.91 – 2.93 (m, CH); 3.25 – 3.29 (m, CH); 3.58 – 3.61 (m,
2
CH); 3.93 – 4.03 (m, MeCH ); 4.60 – 5.02 (m, 2 CH N); 6.03 – 6.05 (dd, J ¼ 5.6, 2.9, CH¼CH); 6.17 – 6.22
2
2
(
dd, J ¼ 5.6, 3.0, CH¼CH); 7.16 – 7.35 (m, 4 arom. H); 7.63 – 7.72 (m, 2 arom. H); 8.47 – 8.57 (m, 2 arom.
13
H). C-NMR (CDCl , 100 MHz): 45.4 (2ꢁ); 46.7; 48.0; 48.1; 48.2; 51.3; 53.1; 60.7; 121.0; 121.2; 134.1;
3
1
35.8; 137.0; 137.2; 149.8 (2ꢁ); 157.2; 157.3; 174.8; 175.0.
1
Data of 29b. H-NMR (CDCl , 400 MHz): 1.16 (t, J ¼ 7.1, MeCH ); 1.41 – 1.46 (m, 1 H, CH (7));
3
2
2
1
.55 – 1.59 (m, 1 H, CH (7)); 2.91 – 2.93 (m, CH); 3.13 – 3.16 (m, 2 CH); 3.63 – 3.66 (m, CH); 4.01 – 4.11
2
(
m, MeCH ); 4.60 – 5.02 (m, 2 CH N); 6.02 – 6.04 (dd, J ¼ 5.3, 3.2, CH¼CH); 6.33 – 6.37 (dd, J ¼ 5.2, 3.0,
2
2
13
CH¼CH); 7.16 – 7.35 (m, 4 arom. H); 7.63 – 7.72 (m, 2 arom. H); 8.47 – 8.57 (m, 2 arom. H). C-NMR

Helvetica Chimica Acta – Vol. 98 (2015)
305
(
1
(
CDCl , 100 MHz): 44.7 (2 x); 45.7; 46.9; 48.4; 48.8; 51.5; 53.2; 60.4; 122.5 (2ꢁ); 155.7 (2ꢁ); 137.7 (2ꢁ);
3
þ
49.6 (2ꢁ); 156.7 (2ꢁ); 173.7 (2ꢁ). APCI-MS (pos.): 392.2 (100, [M þ H] ). Anal. calc. for C H N O
23
25
3
3
391.46): C 70.57, H 6.44, N 10.73; found: C 69.97, H 6.51, N 10.43.
Conversion of 23 to 29a/29b was monitored via GP 5. HPLC was performed with a chiral ADH
i
column (25 cm), heptane/ PrOH 2 :1, a flow rate of 0.5 ml/min, and detection at 210 nm resulting in the
following tR values: 18.3 þ 24.9 (29a), 28.3 (29b), and 31.2 (23) min. Separation of 29b was using the
chiral ADH column. For reaction times for full conversion with and without 1.0 equiv. of chosen metal-
salts, and endo/exo ratios, see Table 7.
Table 7
2
3 ! 29
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
0.4 : 1
1.0 : 1
0.5 : 1
0.5 : 1
0.5 : 1
0.4 : 1
160
25
160
160
250
160
CuCl
FeCl
Zn(OTf)2
3
Ethyl 3-{[2-(Dimethylamino)ethyl](pyridin-2-ylmethyl)carbamoyl}bicyclo[2.2.1]hept-5-ene-2-car-
boxylate (30). A mixture 30a/30b was synthesized according to GP 2 by using 24 (37.0 mg, 0.11 mmol,
1.0 equiv.) and freshly cracked and dist. 12 (38.0 ml, 0.44 mmol, 4.0 equiv.). After 16 h, removal of solvent
and remaining 12 under reduced pressure, the crude product was dissolved in CH Cl2 (20 ml), and
2
washed with a sat. aq. soln. of NaHCO (20 ml) and H O (20 ml). After drying (Na SO ) and evaporation
3
2
2
4
of the solvent, the residue was purified by CC (SiO ; CH Cl /MeOH 98 :2 ! 9 :1) to yield 30a/30b
2
2
2
(
29.7 mg, 0.08 mmol, 69%; endo/exo of 0.2 :1). Slightly brown gum.
1
Data of 30a. H-NMR (CDCl , 400 MHz): 1.16 (t, J ¼ 7.1, MeCH ); 1.39 – 1.46 (m, 1 H, CH (7));
3
2
2
1
.95 – 2.04 (m, 1 H, CH (7)); 2.24 (s, Me); 2.25 (s, Me); 2.42 – 2.54 (m, CH NMe ); 2.78 – 2.84 (m, CH);
2 2 2
2
.87 – 2.96 (m, CH); 3.52 – 3.64 (m, NCH CH ); 3.03 – 3.14 (m, CH); 3.68 – 3.77 (m, CH); 3.93 – 4.16 (m,
2
2
MeCH ); 4.58 – 5.02 (m, CH N); 6.05 (dd, J ¼ 5.8, 2.7, CH¼CH); 6.32 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.14 –
2
2
13
7
.24 (m, 2 arom. H); 7.59 – 7.71 (m, 1 arom. H); 8.49 – 8.59 (m, 1 arom. H). C-NMR (CDCl , 100 MHz):
3
1
1
4.3; 44.4; 45.0; 45.6; 45.8 (2ꢁ); 46.4; 46.7; 48.5; 48.8; 56.9; 58.2; 60.4; 120.9; 122.5; 135.7; 136.9; 137.7;
49.8; 158.1; 174.4 (2ꢁ).
1
Data of 30b. H-NMR (CDCl , 400 MHz): 1.24 (t, J ¼ 7.1, MeCH ); 1.39 – 1.46 (m, 1 H, CH (7));
3
2
2
1.95 – 2.04 (m, 1 H, CH (7)); 2.24 (s, Me); 2.25 (s, Me); 2.42 – 2.54 (m, CH NMe ); 2.78 – 2.84 (m, CH);
2 2 2
2
.87 – 2.96 (m, CH); 3.52 – 3.64 (m, NCH CH ); 3.22 – 3.32 (m, CH); 3.33 – 3.47 (m, CH); 3.93 – 4.16 (m,
2
2
MeCH ); 4.58 – 5.02 (m, CH N); 6.14 (dd, J ¼ 5.6, 2.8, CH¼CH); 6.17 (dd, J ¼ 5.6, 3.0, CH¼CH); 7.14 –
2
2
13
7
.24 (m, 2 arom. H); 7.59 – 7.71 (m, 1 arom. H); 8.49 – 8.59 (m, 1 arom. H). C-NMR (CDCl , 100 MHz):
3
1
1
4.4; 44.4; 44.8; 45.6; 45.8 (2ꢁ); 46.8; 46.9; 48.5; 48.8; 56.9; 58.2; 60.4; 121.8; 122.2; 136.0; 136.8; 137.7;
þ
49.2; 158.1; 174.4; 174.5. APCI-MS (pos.): 372.2 (100, [M þ H] ). HR-APCI-MS (pos.): 372.22840
þ
þ
3
(
[M þ H] , C H N O ; calc. 372.22872).
21
30
3
Conversion of 24 to 30a/30b was monitored via GP 5. HPLC was performed with a chiral ODH
i
column (25 cm), heptane/ PrOH/EtOH 361:38 :1, a flow rate of 0.5 ml/min, and detection at 210 nm,
resulting in the following tR values: 16.4 þ 18.3 (30b), 21.5 (30a), and 29.7 (24) min. Separation of 30b
was possible using of the chiral ODH column. For reaction times for full conversion with and without
1.0 equiv. of chosen metal salts, and endo/exo ratios, see Table 8.
Ethyl 3-[{2-[Propyl(pyridin-2-ylmethyl)amino]ethyl}(pyridin-2-ylmethyl)carbamoyl]bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (31). A mixture 31a/31b was synthesized according to GP 2 by using 25
(
1
0.10 mg, 0.26 mmol, 1.0 equiv.) and freshly cracked and dist. 12 (85.0 ml, 1.0 mmol, 4.0 equiv.). After
6 h, removal of solvent and remaining 12 under reduced pressure, the crude product was dissolved in
CH Cl (25 ml), and washed with a sat. aq. soln. of NaHCO (20 ml) and H O (20 ml). The org. phase was
2
2
3
2

3
06
Helvetica Chimica Acta – Vol. 98 (2015)
Table 8
2
4 ! 30
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
0.2 : 1
0.2 : 1
0.2 : 1
0.2 : 1
0.2 : 1
0.2 : 1
80
30
80
10
80
80
CuCl
FeCl
Zn(OTf)2
3
dried (Na SO ), and the solvent was removed under reduced pressure. Purification by CC (SiO ; CH Cl /
2
4
2
2
2
MeOH 98 :2 ! 9 :1) yielded 31a/31b (75.0 mg, 0.16 mmol, 60%; endo/exo of 0.4 :1). Slightly brown gum.
1
Data of 31a. H-NMR (CDCl , 400 MHz): 0.89 (t, J ¼ 7.3, MeCH CH ); 1.15 (t, J ¼ 7.1, MeOCH );
3
2
2
2
1
.36 – 1.43 (m, CHH); 1.45 – 1.60 (m, MeCH CH ); 1.91 – 2.01 (m, 1 H, CH (7)); 2.44 – 2.56 (m,
2
2
2
NCH CH Me); 2.67 – 2.79 (m, NCH CH N); 2.79 – 2.92 (m, 2 CH); 3.10 – 3.18 (m, CH); 3.22 – 3.30 (m,
2
2
2
2
CH); 3.58 – 3.64 (m, NCH CH N); 3.73 (s, CH N); 3.93 – 4.13(m, MeOCH O); 4.47 – 4.95 (m, CH N);
2
2
2
2
2
5
.88 – 6.05 (m, CH¼CH); 6.12 – 6.34 (m, CH¼CH); 7.10 – 7.23 (m, 3 arom. H); 7.40 – 7.47 (m, 1 arom. H);
13
7.58 – 7.70 (m, 2 arom. H); 8.47 – 8.58 (m, 2 arom. H). C-NMR (CDCl , 100 MHz): 11.8; 14.2; 20.3; 44.4;
3
4
1
5.5; 45.7; 46.7; 46.9; 48.3; 48.6 (2ꢁ); 52.0; 60.4; 60.6; 122.1 (2ꢁ); 135.7; 135.9; 136.7; 136.8; 136.9; 137.6;
49.2; 149.7; 157.9; 158.0; 173.7; 173.9.
1
Data of 31b. H-NMR (CDCl , 400 MHz): 0.89 (t, J ¼ 7.3, MeCH CH ); 1.21 (t, J ¼ 7.1, MeOCH );
3
2
2
2
1.36 – 1.43 (m, 1 H, CH (7)); 1.45 – 1.60 (m, MeCH CH ); 1.91 – 2.01 (m, 1 H, CH (7)); 2.44 – 2.56 (m,
2
2
2
2
NCH CH Me); 2.67 – 2.79 (m, NCH CH N); 2.79 – 2.92 (m, 2 CH); 2.98 – 3.07 (m, CH); 3.22 – 3.30 (m,
2
2
2
2
CH); 3.58 – 3.64 (m, NCH CH N); 3.73 (s, CH N); 3.93 – 4.13(m, MeOCH O); 4.47 – 4.95 (m, CH N);
2
2
2
2
2
6
.02 – 6.05 (m, CH¼CH); 6.12 – 6.17 (m, CH¼CH); 7.10 – 7.23 (m, 3 arom. H); 7.40 – 7.47 (m, 1 arom. H);
þ
7.58 – 7.70 (m, 2 arom. H); 8.47 – 8.58 (m, 2 arom. H). CI-MS (NH ): 477.2 (100, [M þ H] ). HR-CI-MS
3
þ
þ
3
(
NH ): 476.2784 ([M þ H] , C H N O ; calc. 476.2787).
3
28 36
4
Conversion of 25 to 31a/31b was monitored via GP 5. HPLC was performed with a RP 18XTerra
column (25 cm), MeOH/aq. NH OAc (0.01m) 6 :4, a flow rate of 1.0 ml/min, and detection at 260 nm
4
resulting in the following tR values: 10.0 (25), 15.7 (31a), and 17.5 (31b) min. For reaction times for full
conversion with and without 1.0 equiv. of chosen metal salts, and endo/exo ratios, see Table 9.
Table 9
2
5 ! 31
endo/exo
Time [min]
Without
Cu(OTf)2
CuCl2
0.4 : 1
0.9 : 1
0.9 : 1
0.8 : 1
0.8 : 1
1.0 : 1
400
240
400
400
450
70
CuCl
FeCl
Zn(OTf)2
3
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Received July 03, 2014