Tuning of the properties of transition-metal bispidine complexes by variation of the basicity of the aromatic donor groups

Article

pubs.acs.org/IC

Tuning of the Properties of Transition-Metal Bispidine Complexes by

Variation of the Basicity of the Aromatic Donor Groups

Peter Comba,* Michael Morgen, and Hubert Wadepohl

Anorganisch-Chemisches Institut, Universitat Heidelberg, INF 270, D-69120 Heidelberg, Germany

̈

S

* Supporting Information

ABSTRACT: Bispidines (3,7-diazabicyclo[3.3.1]nonanes) as

very rigid and highly preorganized ligands ﬁnd broad

application in the ﬁeld of coordination chemistry, and the

redox potentials of their transition-metal complexes are of

importance in oxidation reactions by high-valent iron

complexes, aziridination catalyzed by copper complexes, and

imaging by ⁶⁴Cu positron emission tomography tracers. Here,

we show that the redox potentials and stability constants of the

copper(II) complexes of 15 tetradentate bispidines can be

varied by substitution of the pyridine rings (variation of the

redox potential over ca. 450 mV and of the complex stability

over approximately 10 log units). It is also shown that these

variations are predictable by the pK_avalues of the pyridine groups as well as by the Hammett parameters of the substituents, and

the density functional theory based energy decomposition analysis also allows one to accurately predict the redox potentials and

concomitant complex stability. It is shown that the main contribution emerges from the electrostatic interaction energy, and the

partial charges of the pyridine donor groups therefore also correlate with the redox potentials.

A speciﬁc and important application for copper(II)

complexes of high stability is positron emission tomography

(PET), which has developed into one of the most important

diagnostic tools in oncology,^19,20and ⁶⁴Cu, in particular,

because of advantages in the decay scheme, half-life, and

⁶⁴Cu/⁶⁷Cu matched pair, is being studied with increasing

interest.²¹⁻²⁵Bispidine ligands have been used successfully in

this area,²⁶and the main advantages are the eﬃcient and often

high-yielding modular ligand synthesis, variability of the donor

set, high copper(II) complex stability and fast complexation

kinetics, and various possibilities for coupling of the ligands to

biomolecules. We have been interested in further improving the

copper(II) complex stability (i.e., reduce the redox potential)

without changing the structural properties of the ligand cavity.

Here, we therefore describe a series of new tetradentate

bispidine ligands with various para-substituted pyridine groups

and the thorough analysis of their copper(II) complexes.

Analogous penta- and hexadentate ligands with even higher

stabilities may be prepared, and their application as chelators in

PET will be reported elsewhere.

INTRODUCTION

■

A large variety of tetra-, penta-, and hexadentate bispidine

ligands (3,7-diazabicyclo[3.3.1]nonanes) and their transition-

metal coordination chemistry have been reported.¹⁻³Important

features of the adamantane-derived bispidine backbone are their

rigidity and the well-deﬁned cavity size and shape, which

establish, together with subtle diﬀerences of the electronic

properties of the donor groups, the thermodynamic and

electronic properties and reactivities of the transition-metal

complexes.⁴⁻⁷An important observation was therefore that

small modiﬁcations at the backbone may enforce well-deﬁned

structural changes [e.g., the stabilization of various and speciﬁc

“Jahn−Teller isomers” of tetragonal copper(II) complexes]⁸

with predictable variations of the thermodynamic properties

(complex stabilities and redox potentials, e.g., with two isomeric

forms of a pentadentate bispidine)^9,10and reactivities (e.g., the

stability and reactivity of the ferryl complexes of the two

isomers of the pentadentate bispidine ligand).¹¹The tuning of

redox potentials of these complexes has been shown to be of

importance in various applications of bispidine coordination

chemistry, i.e., iron-based oxidation catalysis,^12,13copper-based

aziridination catalysis,¹⁴⁻¹⁶and selective stabilization of

copper(II) complexes.^2,10,17The somewhat unexpected linear

correlation between the redox potentials and complex stabilities

of copper(II) complexes in general¹⁸has been shown to lead to

acceptable results (but separate correlations) for the two series

of bispidine complexes of the type discussed here and “second

generation” bispidines with aliphatic substituents at the

bispidine scaﬀold.^2,10

Because of the well-deﬁned correlation of the redox

potentials and copper(II) complex stabilities, it is of interest

that there is a range of relatively simple and partially well-

developed and promising methods to predict the redox

potentials. Apart from various rather expensive quantum-

chemical methods, schemes based on purely structural

Received: February 18, 2013

Published: May 10, 2013

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aspects,²⁷⁻²⁹ligand (and metal-ion)-based electrochemical

parameters have been reported,³⁰and other highly para-

metrized schemes, considering most of the decisive factors

(steric strain, solvation, entropy, and electronics), have been

proposed.³¹Because of the rigid structure of the bispidine

ligands and a fairly constant backbone that does not inﬂuence

solvation much, the redox potentials of the copper(II)

complexes described here are expected to be well-correlated

with the basicity of the substituted pyridine groups. Therefore,

the redox potentials of the newly synthesized 4′-substituted

tetradentate bispidine ligand copper(II) complexes as well as

some previously reported copper(II) compounds of substituted

tetradetate bispidine ligands are compared with the pK_avalues

of the corresponding pyridine groups. Because electronic

changes at the ligand atoms lead to predictable changes of

the ligand-ﬁeld and electron paramagnetic resonance (EPR)

spectra, these have also been studied and analyzed by ligand-

ﬁeld models. Moreover, energy decomposition analyses

(EDA)³²were performed on the various 4′-substituted

bispidine copper(II) complexes, and the electrostatic part of

the total energy and Mulliken charges are compared to the

redox potentials. We conclude that we are now able to predict

and tune the thermodynamic properties within the interesting

series of bispidine coordination compounds, and this enables a

true rational design of new compounds in this area based on

simple and eﬃcient methods.

manganese dioxide instead of selenium dioxide, see also refs 33

and 44). The latter product was also converted by acetyl

bromide in one step to 5, as reported previously.³³

The 4-chloro compound 9 was obtained in three steps

(Scheme 2). At ﬁrst, picolinic acid 6 was chlorinated in position

4 with thionyl chloride, and the in situ formed 4-

chloropyridine-2-formyl chloride was esteriﬁed with methanol

to aﬀord methyl 4-chloropyridine-2-carboxylate (7; conditions

slightly changed from those in the literature⁴⁵⁻⁴⁷), which was

reduced with sodium borohydride to the alcohol 8.^48,49This

benzylic alcohol was oxidized with selenium dioxide to the

aldehyde 9, as discussed above.

The methoxy, ethoxy, and thiomethoxy substituents as well

as the dimethylamino and pyrrolidino groups were introduced

by a nucleophilic ipso substitution according to known

methods (Scheme 3). Therefore, either (4-nitropyridin-2-

yl)methanol (3) or (4-chloropyridin-2-yl)methanol (8) as the

precursor was reacted with the sodium salt of methanol,

ethanol, or thiomethanol or the hydrochlorides of dimethyl-

amine or pyrrolidine as the starting materials to aﬀord the

substituted pyridine alcohols 10, 11, 12,⁵⁰13,^44,51or 14, which

were oxidized by selenium dioxide to the aldehydes 15, 16, 17,

18⁴⁴or 19⁵²in moderate to good yields (for related syntheses

of substituted pyridine methanols via ipso substitution of the

pyridine-N-oxide precursors. see also refs 34 and 44).

The methyl group for an example of a bispidine with an

aliphatic para substitutent was introduced in the pyridinyl

moiety as follows: 2,4-lutidine (20) was treated with hydrogen

peroxide to yield the N-oxide 21 (according to a published

procedure^35,53,54), which was transformed to the alcohol 22 in a

Boekelheide rearrangement, and this was afterward oxidized

with selenium dioxide to the aldehyde 23 (Scheme 4).

As the only nonpyridinyl compound of this series, methyl 2-

pyrazinecarboxylate (24) was directly reduced to the aldehyde

25 with lithium−aluminium hydride (Scheme 5).⁵⁵

RESULTS

■

Ligand and Copper(II) Complex Syntheses. The 4-

substituted picolinaldehydes required for the bispidone

syntheses are not commercially available and were accessible

in three- to four-step sequences. The 4-nitro- and 4-

bromopicolinaldehydes (4 and 5, respectively) were synthe-

sized with slight changes with respect to a literature-known

procedure (Scheme 1).³³Picoline-N-oxide (1) was nitrated in

The other starting materials, 6-methoxypicolinaldehyde (26),

3-methylpicolinaldehyde (27), and 3,5-dibromopicolinaldehyde

(28), are commercially available.

Scheme 1. Synthesis of 4-Nitro and 4-Promopicolinaledhyde

(4 and 5, Respectively)

The tetradentate bispidone ligands are formed by two

subsequent double Mannich reactions.⁵⁶Therefore, dimethyl

acetonedicarboxylate is reacted with methylamine and the

corresponding 4-substituted picolinaldehyde (or pyrazinealde-

hyde). The resulting piperidones P1−P11, obtained as the enol

tautomer (Figure 1; in solution, a complex syn/anti mixture

related to the aromatic moieties of the keto/enol tautomers is

observed),⁵⁷were isolated and then reacted with formaldehyde

and methylamine to the bispidones B1−B11 (see Table 1 and

Figure 2).⁵⁸

In most cases, the bispidones are isolated in the endo/endo

conﬁguration (syn isomer) concerning the aromatic 2,4-

substituents, i.e., the conﬁguration required for complexation

of transition-metal ions, because this structure constitutes the

thermodynamically favored isomer.^9,59However, for the

(p-NO₂)- and (p-Br)bispidones B1 and B3, both diastereomers

(endo/endo or syn and endo/exo or anti isomer) were

obtained as analytically pure samples by fractional crystal-

lization. Attempts to gain the pyrazine-based as well as the m,m-

dibromo-based bispidones B10 and B11 in the desired syn

conﬁguration failed (for related problems with hexadentate

bispidines, see ref 60).

position 4 using concentrated sulfuric acid and fuming nitric

acid to aﬀord 4-nitropicoline-N-oxide (2).^34,35A Boekelheide

rearrangement using triﬂuoroacetic anhydride leads to the

corresponding alcohol 3,^33,36−39which was oxidized with

selenium dioxide to 4 (for general conditions for the selenium

dioxide reaction, see 40−43; for related procedures using

Because of the possibility for retro-Mannich reactions, the

carbonyl group at position C⁹of the bispidone backbone is

responsible for the conversion of syn-bispidones to anti-

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Scheme 2. Synthesis of 4-Chloropicolinaldehyde (9)

Scheme 3. General Synthesis of 4-Methoxy-, 4-Ethoxy-, 4-(Thiomethoxy)-, 4-(Dimethylamino)-, and 4-

Pyrrolidinopicolinaldehyde (15−19, Respectively)

Scheme 4. Synthesis of 4-Methylpicolinaldehyde (23)

Scheme 5. Synthesis of Pyrazinecarbaldehyde (25)

bispidones and vice versa and complete decomposition of the

ligand. This can be prevented by reduction of the ketone to an

alcohol. This was also expected to lead to a decrease of the

redox potential of the corresponding copper(II) complexes and

therefore an increase of their copper(II) complex stabilities. To

further quantify the latter aspect, the p-Cl and p-MeO

derivatives B2 and B5, as well as the unsubstituted parent

ligand B12,⁶¹⁻⁶⁴were also stereoselectively reduced to their

secondary alcohol derivatives (Scheme 6).⁶³

With these new ligands at hand, complexation reactions with

Figure 1. Experimental structures of the substituted piperidones P2−

P7, P10, and P11. Ellipsoids are shown at the 30% probability level;

cocrystallized solvent molecules and hydrogen atoms are omitted for

clarity.

copper(II) perchlorate hexahydrate were made. In the cases of

B1−B5, B7, and B8, the resulting complexes were isolated

prior to their investigation; i.e., the ligand was reacted with

copper(II) perchlorate in acetonitrile at ambient temperature

overnight (Table 2). Isolation of the complexes was achieved by

ether diﬀusion. In some cases, insuﬃcient amounts of ligand

obtained from the multistep synthetic route complicated

attempts to isolate the complexes [i.e., with (p-EtO)N₂py₂

(B6) and (m-Me)N₂py₂(B9)]. In these cases, the correspond-

ing copper(II) complexes were prepared in situ by mixing the

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Table 1. Synthesis of the Substituted Tetradentate Bispidones (the Desired syn-Bispidone Is Depicted) via the Isolated

a

Piperidones

substituent X (aldehyde)

(p-NO₂)py

piperidone

bispidone

4

P1

P2

P3

P4

P5

P6

P7

P8

P9

P10

P11

18.0%

81.8%

55.2%

42.5%

51.3%

45.9%

67.6%

67.2%

54.6%

27.8%

62.4%

syn-B1

B2

8.2%

anti-B1

anti-B3

42.2%

55.2%

(p-Cl)py

9

57.0%

13.2%

48.3%

54.8%

9.2%

(p-Br)py

5

syn-B3

B4

(p-Me)py

23

15

16

17

26

27

25

28

(p-MeO)py

(p-EtO)py

(p-MeS)py

(o-MeO)py^c)

(m/3′-Me)py^c)

pyr

B5

B6

B7

31.4%

36.2%

46.8%

36.4%

49.7%

B8

B9

anti-B10

anti-B11

(m,m/3′,5′-di-Br)py^c)

a

Nonoptimized yields obtained by crystallization of the products.

Figure 2. Experimental structures of the bispidines: syn-bispidones B4, B7, and B9; anti-bispidones B3, B10, and B11; C⁹-reduced syn-bispidones

{C⁹OH}B2 and {C⁹OH}B5. Ellipsoids are shown at the 30% probability level; cocrystallized solvent molecules and hydrogen atoms are omitted for

clarity.

ligand and dry copper(II) perchlorate⁶⁵in a ratio of 6:5 in

acetonitrile.

moieties and the N³methyl group is minimized by adopting an

anti conﬁguration with respect to the pyridine rings. Each of the

piperidone structures presented shows that the pyridine moiety

closest to the enol double bond at C²(see Table 1 for

numbering) is located in the axial position [and, therefore, the

pyridine group at C⁴is located in the equatorial position, which

seems to be a prerequisite for the most stable form (Figure 1)].

The bispidones crystallize either in a chair−chair con-

formation [observed for syn-B4; syn-B7 and anti-B3; anti-B10,

syn-{C⁹OH}B2 and syn-{C⁹OH}B5] or in a boat−chair

Crystal Structures. As reported above, the piperidones

crystallize in their enol form because of the stabilizing hydrogen

bond formed by the enol hydroxy group and a carbonyl oxygen

atom of one adjacent ester group. This results in an envelope

conformation of the six-membered piperidone ring. The methyl

group of N³(numbering adopted from the corresponding

bispidones; see Table 1) of each compound is located in the

axial position. The steric hindrance caused by the pyridinyl

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Unfortunately, some bispidones only crystallized as the

undesired anti isomers. There is no clear evidence that strains

and stresses in the (hypothetical) syn isomer occur (e.g., in the

pyrazine derivate B10). It might be that solubility eﬀects are

responsible. Crystallizations of the bispidones are preferably

carried out in methanol as the solvent. Therefore, isomerization

via a retro-Mannich reaction is still possible, and the

thermodynamically more stable syn isomer may convert to

the less stable but also less soluble anti isomer. Slow

crystallization may then shift the equilibrium toward the anti

isomer.

Scheme 6. Stereoselective Reduction of the Bispidones B12,

B2, and B5 to the Bispidoles {C⁹OH}B12, {C⁹OH}B2, and

{C⁹OH}B5

The copper(II) complexes of these tetradentate bispidine

ligands are characterized by a tetragonal (square-pyramidal or

elongated octahedral) coordination geometry (see Figure 3 and

Table 3). The square plane is represented by the donors N³,

conformation (observed for syn-B9 and anti-B11) with N⁷as

part of the ring with boat conformation (Figure 2). Neglecting

heteroatoms, the chair−chair conformation of such a

condensed bicyclic system represents the energetically favored

structure. In a chair−chair conformation, the pyridinyl groups

can adopt the favored equatorial position with respect to the

six-membered N³ring, and the N⁷methyl group is able to point

away from the sterically crowded cavity of the rigid bispidine

backbone. Therefore, the lone-pair repulsion, emerging from

N³and N⁷, plays a minor role for the lowest-energy

conformation. However, lone-pair repulsion is the reason for

a rotation of the pyridinyl groups; i.e., the pyridine nitrogen

atoms are pointing out of the cavity. The boat−chair

conformation of syn-B9 and anti-B11 is a result of the speciﬁc

substitution pattern. In syn-B9, the methyl groups at the 3′/

meta position of the pyridine moieties force N³into an almost

trigonal-planar geometry. Therefore, the electron density of N³

is directly pointing into the cavity, and lone-pair repulsion of N³

and N⁷becomes vitally important (this phenomenom is known

as the hockey-sticks eﬀect).^1,66,67This is avoided by adopting a

boat−chair conformation. Similar eﬀects apply for anti-B11.

N

^py1, and N^py2and an equatorially coordinated acetonitrile

(complexation reactions were carried out in acetonitrile at

ambient temperature). N⁷is the axial donor, and the Cu−N⁷

axis displays the expected pseudo-Jahn−Teller elongation,

typical for Cu^II(d⁹). In some cases a perchlorate counterion

is axially coordinated and completes the coordination sphere of

Cu^IIto distorted octahedral. An exception of this typical Cu^II

tetradentate bispidine coordination geometry is the complex

resulting from ligand B8 (o-MeO substitution). In this case, a

water molecule instead of acetonitrile is equatorially coordi-

nated. This presumably is the result of two strong hydrogen

bonds formed with the ortho-substituted pyridine methoxy

groups. In addition, even with dry solvents (commercially

available absolute acetonitrile), traces of water suﬃce to form

the hydrate of the ligands at position C⁹upon complexation. It

is not obvious in which case the hydrate or keto form

crystallizes, and similar to the coordination of a sixth ligand

trans to N⁷, this might be fortuitous and based on crystal lattice

eﬀects.

Table 2. Synthesis of the Copper(II) Complexes of the Substituted Tetradentate Bispidine Ligands

X

Y

yield (%)

p-NO₂

p-Cl

O/(OH)₂

88.0

82.3

85.5

24.5

73.7

p-Br

p-Me

p-MeO

p-EtO

p-MeS

o-MeO

m-Me

H

a

in situ

91.0

48.0

a

in situ

73.0

91.5

88.5

91.5

p-MeO

p-Cl

Y = H, OH

H

a

The complexes were not isolated prior to measurements; see the Experimental Section for details.

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sharp band observed at around 630 nm (≈15800 cm⁻¹) is

2

attributed to the d_xy→ d_{x −y}(b_2g→ b_1g) transition. A second,

broader band observed at 900−1000 nm (≈11000−10000

−1

2

cm ) can be assigned to the d_z→ d_{x −y}(a_1g→ b_1g) transition.

The coordination geometries of these copper(II) complexes in

solution and the solid state are qualitatively identical, and this

emerges from comparative measurements of the parameters in

TiO₂of the copper(II) complexes of the p-Br, p-MeO, and p-

MeS ligands of B3, B5, and B7 (see the Supporting

Information).

The marginal spectroscopic variations are not surprising

because the bispidine scaﬀold is very rigid.⁵In the case of the

para-substituted bispidine copper(II) complexes, the N³···N⁷

distance (see Table 3), a measure of the bispidine cavity size,

varies by only about 0.04 Å (2.903−2.944 Å) in comparison to

approximately 0.07 Å (2.866−2.940 Å) for the metal-free

ligands (for syn isomers crystallizing in the chair−chair

conformation). The distances of the in-plane pyridine donors

py¹and py²in these complexes range from 3.89 to 3.96 Å (a

variation of only 0.07 Å; see Table 3). The experimental

structural analysis reveals that with regard to the Cu^II-donor

distances the main variability is observed for the Cu−N⁷bond

length (Jahn−Teller axis) that ranges from 2.236 to 2.353 Å, a

variation of 0.117 Å [for comparison: Cu−N³= 2.008−2.023 Å,

variation of 0.015 Å; Cu−NCCH₃(L) = 1.957−1.977 Å,

variation of 0.020 Å; Cu−N(py) = 1.973−2.014 Å, variation of

0.041 Å].⁶⁸Variation of the Cu−N⁷bond leads to diﬀerences in

Figure 3. Experimental structures of the copper(II) complexes with

the (substituted) bispidine ligands B1−B3, B5, B7, B8, B12, {C⁹OH}

B2, and {C⁹OH}B5. Ellipsoids are shown at the 30% probability level;

cocrystallized solvent molecules, counterions, and hydrogen atoms

(except for the equatorially coordinated water molecule in [Cu(B8)-

OH₂]²⁺) are omitted for clarity.

Electronic and EPR Spectra. The UV/vis spectra of the

copper(II) complexes with the newly synthesized bispidine

ligands were measured at 25 °C in acetonitrile. To ensure the

formation of identical forms of the ligand coordinated with

respect to the hydrate and keto forms at position C⁹, the

complexes under study were prepared in situ by taking the

advantage of the fast exchange velocity of Cu^II. The ligand and

dry copper(II) perchlorate were mixed in absolute acetonitrile

and stirred for 30 min in a sealed vial. An immediate color

change of the solution to blue/green indicated fast complex

formation. The UV/vis spectra of the copper(II) complexes of

the nine new ligands as well as of the bispidone with

unsubstituted pyridine groups and the three C⁹-reduced ligands

are given as Supporting Information, and the transitions are

reported in Table 4. Except for [Cu(B8)(NCCH₃)]²⁺, the UV/

vis spectra show qualitatively identical transitions: the rather

2

the perturbation of the d_zorbital of the metal center and

2

therefore has a signiﬁcant inﬂuence on the d_z→ d_{x −y}(a_1g

→

b_1g) transition. However, crystal structure analyses also reveal

that the Cu−N⁷distance largely is modulated by coordination

of perchlorate, and this does not necessarily translate to the

situation observed in solution. The transition assigned to d_xy→

2

d_{x −y}(b_2g→ b_1g) primarily arises from perturbation of the “in-

plane” donors, and small diﬀerences of the bonding parameters

do not seem to lead to a signiﬁcant shift in the dd transition.

EPR spectra of the complexes based on B2, B3, B5, and B7

have been recorded and simulated, and the corresponding

parameters and spectra are given in the Supporting

Information. As expected, the spin Hamiltonian parameters

are very similar, and as for the electronic spectra, this is largely

Table 3. Selected Bond Lengths (Å) and Angles (deg) of the Molecular Cations of the Copper(II) Complexes

CB1

CB7

(p-MeS)

CB8

(o-MeO)

CB12

(N₂py₂)

C{C⁹OH}

a

(p-NO₂) CB2 (p-Cl) CB3 (p-Br)

CB5 (p-MeO)

B2

B5

Cu−N³

2.008(3)

2.274(3)

2.023(2)

2.324(2)

2.011(3)

2.253(3)

2.011(4)/2.004(4)

2.236(4)/2.253(4)

2.015(2)

2.244(2)

1.993(3)

2.340(3)

2.022(2)

2.353(2)

2.023(2)

2.241(2)

2.014(2)

2.236(2)

Cu−N⁷

Cu−N(py)

1.987(3)/ 2.004(2)/

2.008(3)/

2.013(3)

1.973(4)/2.001(5) /

1.989(4)/1.981(5)

1.984(2)/

2.005(2)

2.066(3)/ 2.003(2)/

2.012(2)/

2.014(2)

1.986(2)/

1.996(2)

2.001(3)

1.995(2)

2.075(3)

1.994(2)

b

c

b

Cu−L

1.968(3)

1.977(3)

1.957(3)

1.965(4) /1.960(5)

1.964(2)

1.932(3)

1.972(2)

1.971(2)

1.966(2)

Cu−O(ClO₃)

2.610(3)

2.939(3)

3.942(4)

84.79(8)

2.582(4)

2.917(4)

4.084(4)

84.2(1)

2.757(2)

2.917(3)

3.946(3)

83.26(7)

N³---N⁷

2.923(4)

3.917

2.921(4)

3.963(4)

86.2(1)

2.91(2)/2.91(2)

3.89(2)/3.90(2)

86.3(2)/85.9(2)

2.903(2)

3.914(2)

85.79(6)

2.944(2)

3.961(2)

87.14(7)

2.908(2)

3.905(2)

86.19(5)

N(py1)···N(py2)

N³−Cu−N⁷

N³−Cu−N(py)

85.9(1)

81.8(1)/

82.2(1)

82.34(9)/

81.88(9)

82.0(1)/

82.1(1)

82.0(2)/81.6(2) /

81.6(2)/81.5(2)

82.13(7)/

81.65(7)

82.3(1)/

81.2(1)

81.67(8)/

82.56(8)

81.89(7)/

81.24(7)

81.96(6)/

81.63(6)

b

c

b

N³−Cu−L

173.8(1)

178.68(9)

160.67(9)

172.2(1)

169.9(2) /170.5(2)

169.35(7)

157.71(7)

177.3(1)

176.47(9)

161.79(9)

100.01(8)

175.26(7)

172.01(8)

168.38(6)

N(py1)−Cu−N(py2)

158.4(1)

160.50(1)

157.5(2)/156.5(2)

161.0(1)

159.31(7)

157.53(6)

b

c

b

N⁷−Cu−L

100.4(1)

96.51(9)

101.6(1)

103.8(2) /103.56(2) 104.84(7)

94.0(1)

100.84(7)

105.34(6)

N⁷−Cu−O(ClO₃)

173.31(8)

178.0(1)

a

b

c

Two independent molecules. L = NCCH₃. L = H₂O.

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Table 4. pK_aValues of Substituted Pyridines, Hammett Coeﬃcients¹⁰⁹of the Substituents, and Electrochemical Potentials and

dd Transitions of the Copper(II) Bispidine Complexes

a

b

entry substituent at pyridine pK_aof the substituted pyridine Hammett’s σ coeﬃcient E_1/2(vs Fc/Fc⁺in ACN) dd transitions; λ/nm (ε/[L cm⁻¹mol⁻¹])

1

H (pyridine)

p-NO₂

p-Cl

5.33

1.23

3.97

3.87

6.08

6.55

0

−504 (−442)

−269

626 (77), 901 (15)

630 (80), 955 (15)

630 (115), 957 (21)

630 (120), 957 (21)

625 (106), 912 (20)

629 (116), 912 (21)

629 (82), 885 (15)

630 (126), 920 (19)

698 (64), 962 (30)

627 (127), 929 (27)

614 (sh), 699, 1010

638 (72)

2

0.778

3

0.227

−397 (−319)

−394 (−330)

−502 (−471)

−563 (−471)

− (−508.0)

−518 (−452)

−250 (−271)

4

p-Br

0.232

5

p-Me

−0.170

−0.268

−0.250

−0.047

6

p-MeO

p-EtO

7

8

p-MeS

o-MeO

9

3.28

4.90

6.03

5.77

0.81

2.81

5.33

3.97

6.55

c

10

11

12

13

14

15

16

17

18

m-MeO

0.115

−473

−184

d

o-Me

m-Me (3′-Me)

m-Me (5′-Me)

−0.069

− (−484.0)

c

−496

−30

−358

624 (122), 920 (25)

660 (52), 1091 (30)

633 (129), 970 (30)

626 (80), 912 (15)

628 (84), 954 (15)

c

o-Br

c

m-Br (5′-Br)

0.391

0

H {C⁹OH}

−475 (−474)

−385 (−371)

−564 (−548)

p-Cl {C⁹OH}

p-MeO {C⁹OH}

0.227

−0.268

628 (83), 900 (16)

b

a

Average values of literature-known protonation constants (see the Supporting Information for a detailed list). Values in parentheses are

measurements with in situ prepared complexes [6:5 ligand/copper(II) perchlorate in acetonitrile]; see the Experimental Section for details. Values

taken from ref 15; the counterions of these complexes are tetraﬂuoroborates instead of perchlorates. Values taken from ref 14 and 110; the

c

d

counterions of these complexes are tetraﬂuoroborates instead of perchlorates.

due to the rigidity of the bispidine backbone and, consequently,

very similar structural properties.

complexes. Indeed, comparative studies with the p-MeO- and p-

Cl-substituted as well as the parent unsubstituted ligand in its

unreduced and C⁹-reduced forms show that the redox

potentials are the same within an error of 10 mV (see Table

4). Therefore, we conclude that the in situ determined redox

potentials are from the keto forms.⁶⁹

Electrochemistry. Two diﬀerent series of cyclic voltammo-

grams (CVs) were measured at ambient temperature and in

acetonitrile as the solvent (see the Supporting Information for

details): (i) the isolated complexes were dissolved prior to

measurement and, due to insuﬃcient amounts of some of the

ligands, (ii) all of the complexes under study were prepared in

situ and directly subjected to CV measurements. Interestingly,

upon comparison of the potentials of the isolated and in situ

prepared copper(II) complexes of identical, C⁹-unreduced

ligands, a signiﬁcant shift in the redox potentials was observed

(see Table 4). There are two possible explanations for this

phenomenon. (i) Traces of water in the acetonitrile solution

may lead to ligand exchange (OH₂vs NCMe), and this would

be expected to lead to signiﬁcant shifts in the redox potentials.

The expectation would be that in situ prepared complexes have

water bound equatorially to the Cu^IIcenter instead of an

acetonitrile molecule. However, ligand exchange is expected to

be relatively fast, and no time-dependent shift was observed in

either of the spectra. (ii) The keto/hydrate equilibrium at C⁹of

the complexes might be another reason for the observed shift.

Several crystal structures of various transition-metal bispidine

complexes have been reported in either the keto or hydrate

form (see above); when using methanol as the solvent, crystal

structures of the C⁹methyl acetal were also observed.¹With

(Cu^II-B2), we are now able to present the ﬁrst example of a

copper(II) bispidine complex with both forms in the lattice,

indicating that the energies of these structures are very similar

(see Figure 3). While the hydrate form predominates in the

crystallized complexes because of the long isolation procedures,

the keto form might prevail in the in situ prepared complexes,

and this would be the case if the formation of hydrate is a slow

process. If that were the case, the complexes of the C⁹-reduced

derivates ({C⁹OH}L) should not show major discrepancies in

the redox potentials of the isolated and in situ prepared

Within the series of para-substituted bispidines, the redox

potential of the resulting copper(II) complex can be tuned in a

range of 300 mV from the derivative with the least stable

complex, [Cu^II(p-NO₂)N₂py₂](ClO₄)₂(CB1) with E_1/2

=

−269 mV, to that with the most stable complex, [Cu^II(p-

MeO)N₂py₂](ClO₄)₂(CB5) with E_1/2= −563 mV.

DISCUSSION

■

It is known that the redox potentials of Cu^II/Icouples in general

are linearly correlated to the thermodynamic stability of the

corresponding copper(II) complex, with a more negative

potential resulting in a more stable copper(II) complex,⁷⁰and

nice correlations have been found for the pyridine-based¹⁰and

second-generation bispidine complexes.²It therefore appears

that methods to predict the redox potentials can lead to a

rational design of ligands with speciﬁc and high stability

constants. This is of importance for various applications, in

particular also for PET imaging with ⁶⁴Cu-labeled antibodies or

nanoparticles, where the bispidine ligands have advantages

because of their easy functionalization and fast complex

formation and also because of their possibilities to modify the

complex charge.

The inﬂuence of diﬀerent substituents on the basicity of

pyridine is well-studied. There are mainly two eﬀects triggering

the basicity of the pyridine ring, the inductive (I) and

mesomeric (M) eﬀects. The former depends on the electro-

negativity of the substituent: a more electronegative substituent

decreases the basicity of pyridine. This eﬀect decreases with the

distance to the nitrogen donor from the ortho and meta to para

position. The latter eﬀect is caused by substituents with

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conjugated lone pairs. Because of the need for conjugation to

the nitrogen donor, the eﬀect is large with ortho and para

substitution. The same trend is valid for groups inﬂuencing the

basicity by hyperconjugation, which is of minor importance but

is still observed for alkyl substituents. All three eﬀects interact

with each other. However, with halides, the −I eﬀect

predominates. Thus, independent from the substitution

position, halides decrease the basicity of the pyridine ring (Cl

> Br). Introduction of a methyl group enhances the basicity of

the pyridine with the greatest eﬀect in the para position

followed by the ortho position. A methoxy group in the para

position greatly enhances the basicity of pyridine because of a

strong +M eﬀect that prevails over the −I eﬀect. Introduced at

the ortho or meta position, the methoxy group causes a

decrease of the basicity (stronger inﬂuence of the −I eﬀect and

a less important contribution of the +M eﬀect because of the

lower stability of the o-quinoid in comparison to the p-quinoid

resonance structure).^71,72

There are many examples in the literature that deal with a

systematic study of substitution eﬀects of pyridine moieties as a

simple ligand or as part of a more complex ligand system on the

pyridine-to-metal bond strength,^71,73−86and there have also

been reports of correlations of Hammett parameters with

electrochemical data.⁷³The correlation of the Hammett

coeﬃcients with the half-wave potentials of substituted metal

complexes is not limited to a substitution of aromatic donor

moieties.^87,88A linear relationship was reported of the

Hammett coeﬃcients and half-wave potentials of the cobalt-

(III) complexes of apically substituted hexaaza-cage ligands,

which can be explained by either a through-space Coulombic

mechanism or an interaction through the ligand’s σ frame-

work.⁸⁹

lying substituted pyridine groups as well as with the Hammett

coeﬃcients of the substituents (see Table 4 for the

corresponding data). There is an acceptable linear correlation;

i.e., the basicity of the substituted pyridine can be used to

predict the redox power and thermodynamic stability of

tetradentate bispidine ligands. Note that this is primarily

based on the constant and rigid ligand structure, and structural

variations such as those observed with sterically hindered

bispidine ligands with ortho-substituted pyridines do not fall

into this correlation and were therefore not included in the ﬁt

shown in Figure 4 (note that for the same reason Hammett

coeﬃcients for ortho substitution are not established) and

would need corrections for steric eﬀects.^28,29,90Hammett

coeﬃcients, which were introduced to evaluate the inﬂuence of

substituents at the benzene ring on the reaction rate of side-

chain reactions (e.g., the hydrolysis of benzoic esters),^91,92are

linearly correlated to the basicity of substituted pyridines and

can therefore also be used to estimate the stability of even more

complex, multisubstituted bispidine ligands.^93,94On the basis of

these observations, we predict a very low redox potential for a

tetradentate bispidine with para-substituted N,N-dimethylami-

nopyridine (DMAP) groups (p-Me₂N)N₂py₂, with a pK_avalue

of DMAP of 9.47 (see the Supporting Information) and the

corresponding Hammett coeﬃcient of σ_para= −0.6. Using these

correlations, a redox potential (E_1/2) of −710 or −664 mV,

respectively, lower than all others, can be expected.

The ligand-ﬁeld splitting of a transition-metal complex

depends on the metal center, the donor atoms, and the

coordination geometry, and with similar geometries, it is

approximately inversely proportional to the sixth power of the

metal−donor distance; i.e., with a given and known structure,

the spectra may be predicted based on the ligand-ﬁeld

properties of the donor groups.⁹⁵To do this, we have used a

known parametrization for the ligand-ﬁeld modeling, using the

angular overlap model approach (AOM),⁹⁶⁻⁹⁹in order to ﬁnd a

set of parameters that could also be used to predict the redox

potentials and complex stabilities.

Figure 4 shows the correlation of the experimentally

observed redox potentials of the substituted bispidine copper-

(II) complexes with literature-known basicities of the under-

Although some trends are observable (e_σstrength: p-MeO >

p-Br > p-NO₂), the obtained data, especially when ortho- and

meta-substituted groups are included, do not lead to a

consistent picture with respect to the strength of inductive

and mesomeric eﬀects and their dependencies on the position

of substitution. Altogether, as expected (see spectroscopy and,

in particular, Table 4), the spectroscopic parameters are too

similar and the structural variations are too small to lead to any

acceptable correlation (see the Supporting Information).

An interesting and promising possibility to screen the metal−

ligand bonding in these systems is EDA,^32,100because in a

series of structurally related complexes, this can give valuable

insight in metal−donor-bonding energy diﬀerences contribu-

ting to the complex stabilities. Because modiﬁcation of the

electron density at the pyridine nitrogen atom, emerging from

the para substituents, the total bonding energy E_totaland, in

particular, the electrostatic energy E_elstatshould be correlated

with the observed redox potentials. This could provide another

tool to predict the electrochemical properties and stability

constants of copper(II) complexes of novel bispidine ligands.

The calculations were performed with a slightly simpliﬁed

bispidine scaﬀold to minimize the computational cost and in

their hydrate form. In addition to the experimentally studied

complexes, others with potentially interesting substituted

bispidine ligands were also computed (Table 5 and the

Supporting Information).

Figure 4. Correlation of the pK_avalues (red squares) and Hammett’s σ

coeﬃcients (blue triangles) of the underlying substituted pyridines

with the redox potentials of the corresponding substituted bispidine

copper(II) complexes (redox potentials from Table 4, hydrate form/

isolated complexes, C⁹-reduced ligands not included; for correlation

with pK_avalues, entries 1−6, 9−11, and 13−15; for correlation with

Hammett coeﬃcients, entries 1−6, 8, 10, 13, and 15). Red hollow

squares indicate ortho-substituted bispidine copper(II) complexes that

were excluded from the linear ﬁt.¹¹¹

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a

Table 5. EDA of Substituted Bispidine copper(II) Complexes; Energies in [kcal/mol]

a

The asterisk indicates a pyrazine instead of a substituted pyridine moiety.

As expected, the main variation is due to the electrostatic

energy E_elstat(see Table 5), and correlations of the total and

electrostatic energies (E_totaland E_elstat) with the observed redox

potentials are shown in Figure 5. With the exception of the

for correlations with redox potentials (see the Supporting

Information for correlations of Mulliken charges with E_elstatof

EDA). The correlations shown in Figure 5 may be used to

compute properties of the copper(II) complexes with unknown

ligands. As shown in the section on Hammett’s σ coeﬃcients

above, the copper(II) complex of the p-dimethylamino-

substituted bispidine is expected to lead to an E_1/2of −664

mV. The estimation by EDA using either the correlation of

E

_elstator E_totalwith the redox potentials supports this prediction

with a computed E_1/2of −683 or −688 mV, respectively. As

expected, the more rigid “closed” pyrrolidino derivative gives

rise to an even more negative redox potential E_1/2of −705 mV

(E_elstatcorrelation) and −724 mV (E_totalcorrelation). This is in

agreement with the higher basicity of p-pyrrolidinopyridine

compared to p-DMAP.

The correlation of the copper(II) complex stabilities,

including all experimentally observed potentials and stability

constants (red squares), experimentally observed potentials,

and correlated stability constants (blue crosses) as well as

computed potentials and correlated stabilities (shown for the p-

DMAP analogue, black cross) is shown in Figure 6. The

methoxy derivative B5 with an observed potential of −563 mV

is estimated to lead to the highest copper(II) formation

constant known for a tetradentate bispidine-based ligand (log K

= 16 in comparison with the log K value of 15 for the

unsubstituted parent complex emerging from the correlation),

and the corresponding p-DMAP complex, which has not been

prepared so far, should have a copper(II) stability constant of

log K = 18 (see the Supporting Information for a detailed list of

predicted log K values).

Figure 5. Correlation of the calculated (EDA) electrostatic and total

bonding energies (E_elstatand E_total) of the simpliﬁed substituted

bispidine copper(II) complexes with the experimentally observed

redox potentials of the substituted bispidine copper(II) complexes

(redox potentials from Table 4; hydrate form/isolated complexes, C⁹-

reduced ligands not included; entries 1−6 and 8).¹¹²

.

pyrazine derivative (see Table 5), which has a slightly more

negative orbital interaction (E_orb) and a signiﬁcantly lower Pauli

repulsion (E_Pauli), which probably is due to diﬀerences in the

aromaticity (modiﬁcation of the nitrogen-donor orbitals), the

two correlations are both of very similar quality and accurate

enough to predict the redox potentials (and complex

stabilities). Therefore, Mulliken charges might also be used

CONCLUSION

■

A total of 11 new, substituted, tetradentate (syn-)bispidine

ligands and their copper(II) complexes are reported. The

copper(II) complexes are square-pyramidal or have elongated

octahedral geometries with N³, py¹, py², and acetonitrile in

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EXPERIMENTAL SECTION

■

Materials and Methods. All reactions in dry solvents were carried

out under an inert atmosphere of argon or nitrogen applying standard

Schlenk techniques. All glassware was heated and dried under vacuum

prior to use. Chemicals were purchased from Sigma-Aldrich Chemie

GmbH (Taufkirchen, Germany), ABCR GmbH & Co. KG (Karlsruhe,

Germany), and Merck KGaA (Darmstadt, Germany) and were of the

highest available purity. Dry solvents were used as delivered without

further puriﬁcation.

NMR spectra were recorded on a Bruker DRX 200, a Bruker Avance

II 400, or a Bruker Avance III 600 spectrometer. The latter

spectrometer was equipped with a direct detection cryoprobe for

maximum sensitivity in the detection of ¹³C. ¹H and ¹³C NMR

chemical shifts are referenced to the signals of the solvent (CDCl₃and

DMSO-d⁶). NMR assignments of the new piperidones and bispidones

are based on the known parent compounds.^{9,62,63,101,102}

UV/vis spectra were recorded on a Jasco V-570 UV/vis/near-IR

spectrophotometer. Solution spectra were measured from in situ

prepared complexes at ambient temperature in acetonitrile as the

solvent. For solid-state UV/vis spectra, the isolated complexes were

triturated with titanium(IV) oxide.

EPR measurements were performed on a Bruker ELEXSYS-E-500

instrument at 110 K, using methanol as the solvent. The spin-

Hamiltonian parameters were obtained by simulation of the spectra

with XSophe.^103,104

Figure 6. Correlation of the Cu^II/Iredox potential of the substituted

bispidine complexes to the formation constants of the corresponding

copper(II) complex (red squares: experimentally derived formation

constants).¹⁰The linear ﬁt follows the equation: y = −57.83176x +

360.98494; R²= 0.8707. See the Supporting Information for a detailed

list of estimated stability constants.

Electrochemical measurements were performed on a CH Instruments

CHI660D electrochemical workstation, equipped with a CH Instru-

ments Picoamp Booster and Faraday Cage, with a three-electrode

setup consisting of a glassy-carbon working electrode, a platinum wire

auxiliary electrode, and an Ag/AgNO₃reference electrode [0.01 M

Ag⁺; 0.1 M (Bu₄N)(BF₄) in MeCN]. The solutions were thoroughly

degassed, and a slight argon stream was set above the solution during

the measurement; a scan rate of 100 mV s⁻¹was used.

Mass spectra were recorded on Finnigan MAT8230 and Joel JMS-

700 spectrometers. Elemental analyses were performed on a CHN-O-

vario EL by the “Mikroanalytische Labor”, Department of Organic

Chemistry, University of Heidelberg.

X-ray Crystallography. Data were collected on a Bruker AXS

SMART 1000 CCD diﬀractometer (Mo Kα radiation, sealed tube, and

graphite monochromator) or an Agilent Technologies Supernova-E

CCD diﬀractometer (Mo or Cu Kα radiation, microfocus tube, and

multilayer mirror optics); see the Supporting Information for details

on the crystal structure determination.

Computational Methods Used. Ligand-ﬁeld calculations were done

with CAMMAG,¹⁰⁵using a published setup^95,96,105and ﬁtted

parameters for the substituted pyridine groups.⁹⁷

For quantum-chemical calculations, the complexes were optimized

by Gaussian 09¹⁰⁶(B3LYP, TZVP) with a dihedral constraint (see

Table 5 and the Supporting Information for a detailed list of the bond

lengths and angles of the calculated structures). The methyl group of

the equatorially coordinated acetonitrile was ﬁxed to avoid rotation,

which caused serious problems during optimization. EDA was

performed to obtain the total bonding energy with various bispidine

ligands, Cu^II, and acetonitrile as fragments; EDA was performed with

ADF.^107,108

−

equatorial positions and N⁷(and ClO₄) in the axial positions.

Because of the rigid backbone of the bispidines, there are no

signiﬁcant diﬀerences in the donor−Cu^IIbond distances, except

for the weak Cu^II−N⁷bond, which is long in six-coordinate

structures and short in ﬁve-coordinate structures. Further

evidence for these structural characteristics emerges from the

electronic spectra: the complexes of the para-substituted ligands

have a rather symmetric transition at 630 nm (unresolved

2

transitions from d_xy, d_xz, and d_yz) and the d_z-based transition at

850−1000 nm (see Table 4 and the Supporting Information).

Cyclic voltammetry reveals reversible redox potentials that

vary widely depending on the electronic nature of the pyridine

substituent. These potentials are linearly correlated to the

copper(II) complex stabilities: the more negative the redox

potential, the more stable the complex. Importantly, there is

also a linear correlation of the redox potentials with the pK_a

values of the substituted pyridine groups and with the Hammett

coeﬃcients of the substituents, and this allows for the

prediction of bispidine derivatives with high copper(II)

complex stabilities. EDA calculations were used as a further

tool to develop new tetradentate bispidine ligands. The total

binding energy E_totalas well as the electrostatic interaction E_elstat

have been shown to correlate, as expected, linearly with the

redox potentials and therefore with the copper(II) complex

stabilities; as is also expected, E_elstatdepends on the charge

distribution (Mulliken charges on the pyridine nitrogen atom).

Therefore, with EDA, further promising copper(II) chelators

were predicted. On the basis of both the Hammett coeﬃcients

and EDA, we predict the p-dimethylamino-substituted

tetradentate bispidine as a very promising ligand for very stable

copper(II) complexes.

Syntheses. 4-Nitropicoline-N-oxide (2; C₆H₆N₂O₃, M_W= 154.12 g

mol⁻¹). Picoline-N-oxide (1; 27.3 g, 0.25 mol, 1.0 equiv) was dissolved

in sulfuric acid (122.6 g, 1.25 mol, 5.0 equiv) at 0 °C, and fuming nitric

acid (78.8 g, 1.25 mol, 5.0 equiv) was added dropwise at 0 °C over 30

min. The reaction mixture was stirred for 2 h at 115 °C. After cooling,

the reaction mixture was poured onto 400 mL of crushed ice. This

slurry was neutralized by the portionwise addition of K₂CO₃and

ﬁltered. The solid was washed with chloroform (3 × 50 mL), the

phases were separated, and the aqueous phase was extracted with

chloroform (3 × 100 mL). The combined organic phases were dried

over Na₂SO₄and concentrated in vacuo to aﬀord a yellow solid as the

Because these methods are not limited to tetradentate

bispidines and to copper(II) chemistry, we now have a simple

and eﬃcient method for the rational design of new bispidine-

based ligands for use in various areas, from medicinal chemistry

and bioinorganic model systems to oxidation and aziridination

catalysis.

1

pure product in a yield of 73.1% (28.15 g, 182.7 mmol). H NMR

3

(200 MHz, CDCl₃): δ 2.57 (s, 3H, CH₃), 8.00 (dd, J_H,H= 7.08 Hz,

4

⁴J_H,H= 3.07 Hz, 1H, H⁵), 8.14 (d, J_H,H= 2.99 Hz, 1H, H³), 8.32 (d,

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³J_H,H= 7.08 Hz, 1H, H⁶). ¹³C NMR (50 MHz, CDCl₃): δ 18.01,

mL). This solid was dissolved in 200 mL of chloroform and washed

with a saturated NaHCO₃solution (3 × 250 mL). The combined

organic phases were dried over MgSO₄, ﬁltered, and concentrated. The

pale-brown oil that crystallized was obtained as the fairly pure product

118.05, 120.62, 140.01, 141.59, 150.59. HR-EI (positive mode, [M]⁺).

calcd: m/z 154.0378. Obsd: m/z 154.0386. Elem anal (report 31055,

[M]). Calcd: C, 46.76; H, 3.92; N, 18.18. Obsd: C, 46.62; H, 3.90; N,

18.06.

1

in a yield of 66.3% (22.18 g, 129.27 mmol). H NMR (400 MHz,

3

4

CDCl₃): δ 4.03 (s, 3H, CH₃), 7.51 (dd, J_H,H= 5.21 Hz, J_H,H= 1.82

(4-Nitropyridin-2-yl)methanol (3; C₆H₆N₂O₃, M_W= 154.12 g

mol⁻¹). 2 (5.00 g, 32.6 mmol, 1.0 equiv) was dissolved in 140 mL of

dichloromethane (DCM), and triﬂuoroacetic anhydride (20.44 g,

13.54 mL, 97.32 mmol, 3.0 equiv) dissolved in 30 mL of DCM was

added dropwise to the solution. After complete addition, the reaction

mixture was stirred for 3 days at ambient temperature. Then the

solution was concentrated in vacuo, and 100 mL of methanol and 50

mL of a saturated K₂CO₃solution were added to the residue and

vigorously stirred for 4 h at ambient temperature, whereupon a white

solid formed. Methanol was removed in vacuo, and the resulting

aqueous solution was extracted with DCM (3 × 200 mL). The

combined organic phases were washed with brine (3 × 200 mL), dried

over MgSO₄, ﬁltered, and concentrated to aﬀord a yellow solid in a

Hz, 1H, H⁵), 8.15 (d, J_H,H= 1.76 Hz, 1H, H³), 8.66 (d, J_H,H= 5.27

Hz, 1H, H⁶). ¹³C NMR (100 MHz, CDCl₃): δ 53.23, 125.68, 127.16,

145.50, 149.17, 150.60, 164.62. HR-EI (positive mode, [M]⁺). Calcd:

m/z 171.0087. Obsd: m/z 171.0080. HR-EI (positive mode, [M −

COCH₂]⁺). Calcd: m/z 113.0032. Obsd: m/z113.0021. Elem anal

(report 29274, [M]). Calcd: C, 49.00; H, 3.52; N, 8.16. Obsd: C,

49.00; H, 3.52; N, 8.16.

3

(4-Chloropyridin-2-yl)methanol (8; C₆H₆ClNO, M_W= 143.57 g

mol⁻¹). In a ﬂame-dried ﬂask, ﬁnely crushed CaCl₂(14.0 g, 126.2

mmol, approximately 4.0 equiv) and 7 (5.36 g, 31.2 mmol, 1.0 equiv)

were suspended in a mixture of 30 mL of methanol and 18 mL of

tetrahydrofuran (THF) and cooled to 0 °C. Then NaBH₄(2.36 g, 62.5

mmol, 2.0 equiv) was added portionwise, and this suspension was

vigorously stirred for 1.5 h at 0 °C. The reaction was quenched by the

addition of 50 mL of aqua dest.; the suspension was stirred for another

2 h at ambient temperature and afterward extracted with ethyl acetate

(3 × 150 mL). The combined organic phases were dried over Na₂SO₄

and concentrated to aﬀord a white-to-pale-yellow solid as the fairly

1

yield of 65.8% (3.29 g, 21.4 mmol). H NMR (400 MHz, CDCl₃): δ

4.94 (s, 2H, CH₂OH), 7.94 (dd, ³J_H,H= 5.40 Hz, ⁴J_H,H= 1.88 Hz, 1H,

4

3

H⁵), 8.11 (d, J_H,H= 1.51 Hz, 1H, H³), 8.85 (d, J_H,H= 5.40 Hz, 1H,

H⁶). ¹³C NMR (100 MHz, CDCl₃): δ 64.36 (CH₂OH), 113.13 (C3),

114.86 (C5), 150.95 (C4), 154.37 (C6), 163.49 (C2).

4-Nitropicolinaldehyde (4; C₆H₄N₂O₃, M_W= 152.11 g mol⁻¹). 3

(6.98 g, 45.29 mmol, 2.0 equiv) and selenium dioxide (2.51 g, 22.65

mmol, 1.0 equiv) were dissolved in 100 mL of 1,4-dioxane and heated

to 85 °C for 5 h. After the reaction mixture cooled, it was ﬁltered

through Celite 545 and concentrated in vacuo. The crude product was

puriﬁed by Kugelrohr distillation (0.65 mbar, 165 °C) to aﬀord a clear

orange, viscous oil as the pure product in a yield of 41.4% (2.85 g,

1

pure product in a yield of 88.3% (3.96 g, 27.6 mmol). H NMR (600

3

MHz, CDCl₃): δ 4.72 (s, 2H, CH₂OH), 7.18 (dd, J_H,H= 5.35 Hz,

⁴J_H,H= 1.85 Hz, 1H, H⁵), 7.36 (br s, 1H, H³), 8.38 (d, ³J_H,H= 5.15 Hz,

1H, H⁶). ¹³C NMR (150 MHz, CDCl₃): δ 64.01 (C6), 121.01 (C2),

122.65 (C4), 144.95 (C3), 149.36 (C5), 161.62 (C1). HR-EI (positive

mode, [M]⁺). Calcd: m/z 143.0138. Obsd: m/z 143.0101. HR-EI

(positive mode, [M − H]⁺). Calcd: m/z 142.0060. Obsd: m/z

142.0029. Elem anal (report 30863, [M]). Calcd: C, 50.19; H, 4.21; N,

9.76. Obsd: C, 50.64; H, 4.53; N, 9.82.

1

3

18.74 mmol). H NMR (200 MHz, CDCl₃): δ 8.27 (dd, J_H,H= 5.25

Hz, J_H,H= 2.18 Hz, 1H, H⁵), 8.64 (dd, J_H,H= 2.22 Hz, J_H,H= 0.68

Hz, 1H, H³), 9.12 (dd, ³J_H,H= 5.29 Hz, ⁵J_H,H= 0.60 Hz, 1H, H⁶), 10.19

(s, 1H, CHO). ¹³C NMR (50 MHz, CDCl₃): δ 114.21, 119.84, 152.51,

154.77, 155.26, 191.00. HR-EI (positive mode, [M]⁺). Calcd: m/z

152.0222. Obsd: m/z 152.0207. HR-EI (positive mode, [M − CO]⁺).

Calcd: m/z 124.0273. Obsd: m/z 124.0284. Elem anal (report 30422,

[M]). Calcd: C, 47.38; H, 2.65; N, 18.42. Obsd: C, 47.23; H, 2.86; N,

18.22.

4

5

4-Chloropicolinaldehyde (9; C₆H₄ClNO, M_W= 141.56 g mol⁻¹). 8

(6.21 g, 43.3 mmol, 2.0 equiv) was dissolved in 100 mL of 1,4-dioxane.

Then selenium dioxide (2.40 g, 21.6 mmol, 1.0 equiv) was added, and

the resulting mixture was heated to 95 °C for 4 h. A brown precipitate

formed and was ﬁltered using Celite 545 and washed with 1,4-dioxane.

The solution was concentrated in vacuum to aﬀord a pale-yellow-to-

brown solid as the fairly pure product in a yield of 82.2% (5.03 g, 35.53

mmol). Further puriﬁcation could be done by distillation (0.4 mbar, 75

4-Bromopicolinaldehyde (5; C₆H₄BrNO, M_W= 186.01 g mol⁻¹). In

a ﬂame-dried two-necked ﬂask with condenser, acetyl bromide (30

mL) was rapidly added to 4 (1.83 g, 12.0 mmol) under an atmosphere

of argon. The red solution was stirred at 60−70 °C for 15 h. A red

solid formed. The suspension was poured onto crushed ice and slowly

basiﬁed with Na₂CO₃to pH = 8 by frequently adding ice to the

mixture. This aqueous solution (200 mL) was extracted with diethyl

ether (3 × 120 mL). The combined organic phases were dried over

Na₂SO₄, ﬁltered, and concentrated to aﬀord an orange oil as the fairly

pure product in a yield of 77.7% (1.74 g, 9.35 mmol), which was

°C). ¹H NMR (600 MHz, CDCl₃): δ 7.54 (dd, ³J_H,H= 5.25 Hz, ⁴J_H,H

=

2.12 Hz, 1H, H⁵), 7.96 (dd, ⁴J_H,H= 2.07 Hz, ⁵J_H,H= 0.56 Hz, 1H, H³),

3

5

8.70 (dd, J_H,H= 5.25 Hz, J_H,H= 0.51 Hz, 1H, H⁶), 10.06 (s, 1H,

CHO). ¹³C NMR (150 MHz, CDCl₃): δ 122.06, 127.89, 145.68,

151.02, 153.88, 192.11.

(4-Methoxypyridin-2-yl)methanol (10; C₇H₉NO₂, M_W= 139.15 g

mol⁻¹). 3 (12.13 g, 78.71 mmol, 1.0 equiv) was dissolved in 200 mL of

methanol, and a methanolic solution of sodium methoxide (25 wt %,

64.26 g, 68.0 mL, 297.4 mmol, 3.8 equiv) was added dropwise at

ambient temperature. The resulting solution was heated under reﬂux

(80 °C) for 1 day. After the reaction mixture was allowed to cool to

ambient temperature, the solution was neutralized using concentrated

hydrochloric acid. The solid material was removed by ﬁltration, the

methanol was removed in vacuum, and the aqueous solution was

extracted with DCM (4 × 250 mL), dried over Na₂SO₄, ﬁltered, and

concentrated to aﬀord a red-brown oily solid in a yield of 72.0% (7.88

1

directly used in the next step. H NMR (200 MHz, CDCl₃): δ 7.70

3

4

(dd, J_H,H= 5.21 Hz, J_H,H= 1.96 Hz, 1H, H⁵), 8.12 (dd, J_H,H= 1.96

5

3

5

Hz, J_H,H= 0.68 Hz, H³), 8.61 (dd, J_H,H= 5.21 Hz, J_H,H= 0.60 Hz,

H⁶), 10.05 (s, 1H, CHO). ¹³C NMR (50 MHz, CDCl₃): δ 125.13,

130.93, 134.18, 150.87, 153.61, 192.04. HR-EI (positive mode, [M]⁺).

Calcd: m/z 184.9476. Obsd: m/z 184.9488. HR-EI (positive mode,

[M − CO]⁺). Calcd: m/z 156.9527. Obsd: m/z 156.9504.

Methyl 4-chloropicolinate (7; C₇H₆ClNO₂, M_W= 171.58 g mol⁻¹).

Under an atmosphere of argon, thionyl chloride (75 mL, 122.3 g, 1.03

mol, approximately 10 equiv) was heated to 50 °C and N,N-

dimethylformamide (2.50 mL, 2.36 g, 32.29 mmol, 0.17 equiv) was

added carefully. The mixture was stirred for 10 min at 50 °C,

whereupon picolinic acid (6; 24.00 g, 194.95 mmol, 1.0 equiv) was

added portionwise to the reaction mixture. The color of the mixture

changed from green to red. This mixture was stirred at 70 °C for 2

days. The formation of an orange precipitate was observed. After

cooling to ambient temperature, 50 mL of toluene was added and the

excess thionyl chloride was coevaporated in vacuo. The resulting

precipitate was suspended in 150 mL of toluene, cooled to 0 °C, and

treated dropwise with methanol (6.50 mL). A pale-yellow precipitate

formed and was ﬁltered and thoroughly washed with toluene (200

1

g, 56.6 mmol). H NMR (400 MHz, CDCl₃): δ 3.86 (s, 3H, OCH₃),

4.71 (s, 2H, CH₂OH), 6.73 (dd, ³J_H,H= 5.77 Hz, ⁴J_H,H= 2.38 Hz, 1H,

4

3

H⁵), 6.80 (d, J_H,H= 2.38 Hz, 1H, H³), 8.36 (d, J_H,H= 5.77 Hz, 1H,

H⁶). ¹³C NMR (100 MHz, CDCl₃): δ 55.17, 64.24, 105.78, 109.09,

149.63, 161.11, 166.31. Elem anal (report 29621, [M]). Calcd: C,

60.42; H, 6.52; N, 10.07. Obsd: C, 60.30; H, 6.62; N, 10.14.

(4-Ethoxypyridin-2-yl)methanol (11; C₈H₁₁NO₂, M_W= 153.18 g

mol⁻¹). 3 (5.77 g, 37.4 mmol, 1.0 equiv) was dissolved in 100 mL of

ethanol at ambient temperature, and 41.9 mL of an ethanolic solution

of sodium ethoxide (21 wt %; 36.40 g, 112.32 mmol, 3.0 equiv) was

added dropwise to the reaction mixture within 20 min. The red

solution was reﬂuxed for 1 day. After the reaction mixture was allowed

to cool to ambient temperature, 50 mL of aqua dest. was added, and

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the mixture was neutralized using concentrated hydrochloric acid. The

ethanol was removed in vacuo, and another 100 mL of aqua dest. and

200 mL of DCM were added to the mixture and separated. The

aqueous phase was further extracted with DCM (3 × 100 mL). The

combined organic phases were dried over Na₂SO₄, ﬁltered, and

concentrated. The dark-red oil was puriﬁed by Kugelrohr distillation

(1.5 mbar, 170 °C) to aﬀord a pale-yellow oil in a yield of 42.0% (2.41

g, 15.7 mmol) as the fairly pure product. ¹H NMR (200 MHz,

[M]). Calcd: C, 67.39; H, 7.92; N, 15.72. Obsd: C, 67.36; H, 7.91; N,

15.36.

4-Methoxypicolinaldehyde (15; C₇H₇NO₂, M_W= 137.14 g mol⁻¹).

10 (19.03 g, 136.8 mmol, 2.0 equiv) and selenium dioxide (7.59 g,

68.38 mmol, 1.0 equiv) were dissolved in 300 mL of 1,4-dioxane and

heated to 85 °C for 4 h. After cooling, the solution was ﬁltered

through Celite 545 and concentrated in vacuo. The resulting brown

viscous oil was puriﬁed by distillation (1.4−1.5 mbar, 140 °C) to

aﬀord a yellow oil in a yield of 55.3% (10.37 g, 75.62 mmol). ¹H NMR

(400 MHz, CDCl₃): δ 3.92 (s, 3H, OCH₃), 7.03 (dd, ³J_H,H= 5.65 Hz,

3

CDCl₃): δ 1.44 (t, J_H,H= 7.04 Hz, 3H, OCH₂CH₃), 3.52 (s, 1H,

3

CH₂OH), 4.10 (q, J_H,H= 7.00 Hz, 2H, OCH₂CH₃), 4.71 (s, 2H,

4

⁴J_H,H= 2.63 Hz, 1H, H⁵), 7.48 (d, J_H,H= 2.64 Hz, 1H, H³), 8.59 (d,

CH₂OH), 6.72 (dd, ³J_H,H= 5.80 Hz, ⁴J_H,H= 2.47 Hz, 1H, H⁵), 6.78 (d,

⁴J_H,H= 1.88 Hz, 1H, H³), 8.34 (d, ³J_H,H= 5.80 Hz, 1H, H⁶). ¹³C NMR

³J_H,H= 5.65 Hz, 1H, H⁶), 10.04 (s, 1H, CHO). ¹³C NMR (100 MHz,

CDCl₃): δ 55.59, 106.69, 114.57, 151.22, 154.65, 166.54, 193.37. HR-

EI (positive mode, [M]⁺). Calcd: m/z 137.0477. Obsd: m/z 137.0460.

HR-EI (positive mode, [M − CO]⁺). Calcd: m/z 109.0528. Obsd: m/z

109.0526.

(50 MHz, CDCl₃): δ 14.42, 63.67, 64.14, 106.30, 109.53, 149.40,

160.94, 165.79. HR-EI (positive mode, M⁺). Calcd: m/z 153.0790.

Obsd: m/z 153.0781. Elem anal (report 31992, [M + ¹/₂H₂O]).

Calcd: C, 59.24; H, 7.46; N, 8.64. Obsd: C, 58.86; H, 7.22; N, 8.79.

[4-(Methylthio)pyridin-2-yl]methanol (12; C₇H₉NOS, M_W= 155.22

g mol⁻¹). 8 (3.21 g, 22.36 mmol, 1.0 equiv) and sodium

thiomethoxide (2.35 g, 33.54 mmol, 1.5 equiv) were dissolved in 50

mL of ethanol and reﬂuxed for 16 h. After cooling to ambient

temperature, the excess of methylthiolate and most of the ethanol was

removed in vacuum. The resulting yellow oil was portioned between

100 mL of DCM and 100 mL of aqua dest. The aqueous phase was

further extracted with 100 mL of DCM. The combined organic phases

were dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to aﬀord a

light-brown solid as the fairly pure product in a yield of 97.67% (3.39

g, 21.84 mmol). ¹H NMR (400 MHz, CDCl₃): δ 2.50 (s, 3H, SCH₃),

4.72 (s, 2H, CH₂OH), 7.02 (dd, ³J_H,H= 5.40 Hz, ⁴J_H,H= 1.76 Hz, 1H,

4-Ethoxypicolinaldehyde (16; C₈H₉NO₂, M_W= 151.16 g mol⁻¹).

11 (2.24 g, 14.62 mmol, 1.0 equiv) and selenium dioxide (0.81 g, 7.31

mmol, 0.5 equiv) were suspended in 20 mL of 1,4-dioxane and heated

to 90 °C for 4 h. After cooling to ambient temperature, the solution

was decanted from the solid material and concentrated in vacuo. The

residue was puriﬁed by distillation (145 °C, 1.8 mbar) to aﬀord a

1

colorless oil in a yield of 84.1% (1.86 g, 12.30 mmol). H NMR (600

3

MHz, CDCl₃): δ 1.47 (t, J_H,H= 7.01 Hz, 3H, OCH₂CH₃), 4.16 (q,

3

4

³J_H,H= 7.03 Hz, 3H, OCH₂CH₃), 7.01 (dd, J_H,H= 5.60 Hz, J_H,H

=

2.57 Hz, 1H, H⁵), 7.46 (d, J_H,H= 2.52 Hz, 1H, H³), 8.58 (d, J_H,H

4

3

5.65 Hz, 1H, H⁶), 10.04 (s, 1H, CHO). ¹³C NMR (150 MHz, CDCl₃):

δ 14.35, 64.15, 107.13, 114.94, 151.22, 154.59, 165.87, 193.45.

4-(Methylthio)picolinaldehyde (17; C₇H₇NOS, M_W= 153.20 g

mol⁻¹). 12 (3.54 g, 22.81 mmol, 1.0 equiv) and selenium dioxide (1.27

g, 11.41 mmol, 0.5 equiv) were suspended in 40 mL of 1,4-dioxane

and heated to 100 °C for 2.5 h. After cooling, the solution was

decanted from the solid material and concentrated. The resulting

brown oil was puriﬁed by distillation (145 °C, 1.0 mbar) to aﬀord a

pale-brown oil as the pure product in a yield of 79.8% (2.79 g, 18.21

mmol). ¹H NMR (400 MHz, CDCl₃): δ 2.55 (s, 3H, SCH₃), 7.31 (dd,

³J_H,H= 5.33 Hz, ⁴J_H,H= 2.07 Hz, 1H, H⁵), 7.75 (d, ⁴J_H,H= 1.88 Hz, 1H,

3

H⁵), 7.07 (s, 1H, H³), 8.33 (d, J_H,H= 5.27 Hz, 1H, H⁶). ¹³C NMR

(100 MHz, CDCl₃): δ 13.70 (SCH₃), 64.14 (CH₂OH), 116.13 (C3),

118.68 (C5), 147.76 (C4), 151.18 (C6), 158.79 (C2). HR-EI (positive

mode, [M]⁺). Calcd: m/z 155.0405. Obsd: m/z 155.0413. HR-EI

(positive mode, [M − H]⁺). Calcd: m/z 154.0327. Obsd: m/z

154.0349. Elem anal (report 30501, [M]). Calcd: C, 54.17; H, 5.84; N,

9.02. Obsd: C, 54.43; H, 5.93; N, 9.25.

[4-(Dimethylamino)pyridin-2-yl]methanol (13; C₈H₁₂N₂O, M_W

=

152.19 g mol⁻¹). 8 (2.30 g, 16.02 mmol, 1.0 equiv), dimethylamine

hydrochloride (6.53 g, 80.1 mmol, 5.0 equiv), and sodium hydroxide

(3.00 g, 75.0 mmol, 4.68 equiv) were put into a pressure tube, 1 mL of

aqua dest. was added, and the apparatus was sealed. The reaction

mixture was stirred at 155 °C for 1 day. After cooling to ambient

temperature, the reaction mixture was ﬁltered, diluted with 50 mL of

aqua dest., and extracted with DCM (3 × 100 mL). The combined

organic phases were dried over Na₂SO₄, ﬁltered, and concentrated in

vacuo. The resulting brown solid was recrystallized from hot acetone

to aﬀord brown crystals, which were washed with further cold acetone.

The product was obtained in a yield of 57.0% (1.39 g, 9.13 mmol). ¹H

NMR (200 MHz, CDCl₃): δ 3.02 (s, 6H, N(CH₃)₂), 4.65 (s, 2H,

CH₂OH), 6.41−6.46 (m, 2H, H^ar), 8.15−8.20 (m, 1H, H^ar). ¹³C NMR

(50 MHz, CDCl₃): δ 39.18 (2C, N(CH₃)₂), 64.41 (CH₂OH), 102.51

(C3), 105.75 (C5), 148.36 (C4), 154.89 (C6), 159.05 (C2).

H³), 8.55 (d, ³J_H,H= 5.27 Hz, 1H, H⁶), 10.04 (s, 1H, CHO). ¹³C NMR

(100 MHz, CDCl₃): δ 13.81, 117.20, 123.80, 149.24, 152.27, 152.45,

193.33. HR-EI (positive mode, [M]⁺). Calcd: m/z 153.0248. Obsd:

m/z 153.0245. HR-EI (positive mode, [M − CO]⁺). Calcd: m/z

125.0299. Obsd: m/z 125.0318. Elem anal (report 30502, [M]).

Calcd: C, 54.88; H, 4.61; N, 9.14. Obsd: C, 54.85; H, 4.63; N, 9.32.

4-(Dimethylamino)picolinaldehyde (18; C₈H₁₀N₂O, M_W= 150.18

g mol⁻¹). 13 (1.32 g, 8.67 mmol, 1.0 equiv) and selenium dioxide

(0.48 g, 4.34 mmol, 0.5 equiv) were suspended in 15 mL of 1,4-

dioxane and heated to 100 °C for 3 h. After cooling, the solution was

decanted from the solid material and concentrated. The resulting oil

was puriﬁed by Kugelrohr distillation (1.1 mbar, 185 °C) to aﬀord a

pale-yellow oil as the pure product in a yield of 80.6% (1.05 g, 6.99

1

mmol). H NMR (200 MHz, CDCl₃): δ 3.05 (s, 6H, N(CH₃)₂), 6.64

3

4

(4-Pyrrolidinopyridin-2-yl)methanol (14; C₁₀H₁₄N₂O, M_W= 178.23

g mol⁻¹). 8 (1.77 g, 12.33 mmol, 1.0 equiv) and pyrrolidine (5.26 g,

6.17 mL, 73.98 mmol, 6.0 equiv) were heated to 155 °C for 1 day in a

pressure tube. After the reaction mixture was allowed to cool to

ambient temperature, it was concentrated under vacuum. The residue

was taken up in 20 mL of DCM and 20 mL of aqua dest., and the

phases were separated. The organic phase was washed with further

aqua dest. (20 mL), dried over Na₂SO₄, ﬁltered, and concentrated in

vacuo. The resulting pale-brown solid was recrystallized from hot

acetone to aﬀord pale-brown crystals as the pure product in a yield of

43.6% (0.96 g, 5.38 mmol). ¹H NMR (200 MHz, CDCl₃): δ 2.02 (td,

³J_H,H= 6.55 Hz, ³J_H,H= 3.40 Hz, 4H, H⁹), 3.25−3.35 (m, 4H, H⁸), 4.62

(dd, J_H,H= 5.89 Hz, J_H,H= 2.82 Hz, 1H, H⁵), 7.16 (d, J_H,H= 2.82

Hz, 1H, H³), 8.36 (d, J_H,H= 5.89 Hz, 1H, H⁶), 9.97 (s, 1H, CHO).

3

¹³C NMR (50 MHz, CDCl₃): δ 39.20, 104.31, 109.84, 150.08, 153.05,

154.71, 194.62. HR-EI (positive mode, [M − CO]⁺). Calcd: m/z

122.0844. Obsd: m/z 122.0835. Elem anal (report 30359, [M +

¹/₄H₂O]). Calcd: C, 62.12; H, 6.84; N, 18.11. Obsd: C, 61.96; H, 7.06;

N, 18.19.

4-Pyrrolidinopicolinaldehyde (19; C₁₀H₁₂N₂O, M_W= 176.22 g

mol⁻¹). 14 (907.4 mg, 5.09 mmol, 1.0 equiv) and selenium dioxide

(282.9 mg, 2.55 mmol, 0.5 equiv) were suspended in 15 mL of 1,4-

dioxane and heated to 100 °C for 3 h. After cooling, the solution was

decanted from the solid material and concentrated. The resulting oil

was puriﬁed by Kugelrohr distillation (1.3 mbar, 230 °C) to aﬀord a

pale-yellow oil as the pure product in a yield of 62.5% (0.56 g, 3.18

(s, 2H, CH₂OH), 6.28 (dd, ³J_H,H= 5.80 Hz, ⁴J_H,H= 2.50 Hz, 1H, H⁵),

4

3

6.33 (d, J_H,H= 2.10 Hz, 1H, H³), 8.12 (d, J_H,H= 5.80 Hz, 1H, H⁶).

¹³C NMR (50 MHz, CDCl₃): δ 25.26, 46.97, 64.45, 102.98, 105.98,

148.25, 152.31, 159.25. HR-EI (positive mode, [M]⁺). Calcd: m/z

178.1106. Obsd: m/z 178.1125. HR-EI (positive mode, [M − H]⁺).

Calcd: m/z 177.1028. Obsd: m/z 177.1043. Elem anal (report 32378,

1

3

mmol). H NMR (400 MHz, CDCl₃): δ 2.07 (dt, J_H,H= 6.53 Hz,

³J_H,H= 3.39 Hz, 4H, H⁹), 3.38 (dt, J_H,H= 5.80 Hz, J_H,H= 3.70 Hz,

3

4H, H⁸), 6.54 (dd, ³J_H,H= 5.77 Hz, ⁴J_H,H= 2.64 Hz, 1H, H⁵), 7.06 (d,

⁴J_H,H= 2.64 Hz, 1H, H³), 8.36 (d, J_H,H= 5.77 Hz, 1H, H⁶), 9.99 (s,

3

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1H, CHO). ¹³C NMR (100 MHz, CDCl₃): δ 25.32, 47.24, 104.79,

110.27, 149.91, 152.20, 152.92, 194.76. HR-EI (positive mode, [M]⁺).

Calcd: m/z 176.0950. Obsd: m/z 176.0937. HR-EI (positive mode,

[M − H]⁺). Calcd: m/z 175.0871. Obsd: m/z 175.0885. HR-EI

(positive mode, [M − CO]⁺). Calcd: m/z 148.1001. Obsd: m/z

148.1012. Elem anal (report 30488, [M]). Calcd: C, 68.16; H, 6.86; N,

15.90. Obsd: C, 68.02; H, 6.96; N, 15.91.

and extracted with chloroform (8 × 20 mL). The combined organic

phases were washed with a saturated NaHCO₃solution (1 × 50 mL),

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo to aﬀord a

dark-red oil as the fairly pure product in a yield of 53.4% (0.84 g, 7.77

mmol). This oil was used for the next step without further

puriﬁcation.¹H NMR (600 MHz, CDCl₃): δ 8.78 (br s, 1H, H^ar),

3

8.82 (d, J_H,H= 2.22 Hz, 1H, H^ar), 9.19 (s, 1H, H^ar), 10.18 (s, 1H,

2,4-Lutidine-N-oxide (21; C₇H₉NO, M_W= 123.15 g mol⁻¹). To 20

(10.80 g, 0.101 mol) was slowly added 30 mL of glacial acetic acid with

stirring. Then 16 mL of an aqueous solution of hydrogen peroxide

(30%) was added portionwise. This solution was stirred at 70 °C for 1

day. After the mixture was allowed to cool to ambient temperature, a

small amount of Na₂SO₃was added in order to destroy unreacted

hydrogen peroxide and stirring was continued for 10 min. An aqueous

solution of sodium hydroxide (20%) was added until pH = 12, and the

solution was extracted with DCM (3 × 100 mL). The combined

organic phases were dried over Na₂SO₄, ﬁltered, and concentrated. A

colorless, smelly, and viscous oil was obtained as the pure product in a

yield of 82.3% (10.24 g, 83.15 mmol). ¹H NMR (400 MHz, CDCl₃): δ

2.30 (s, 3H, CH₃), 2.48 (s, 3H, CH₃), 6.93 (dd, ³J_H,H= 6.50 Hz, ⁴J_H,H

= 2.00 Hz, 1H, H⁵), 7.05 (br s, 1H, H³), 8.13 (d, ³J_H,H= 6.53 Hz, 1H,

H⁶). ¹³C NMR (100 MHz, CDCl₃): δ 17.72, 20.18 (2C, CH₃), 124.28,

127.11, 136.97, 138.68, 148.20 (5C, C^ar). Elem anal (report 30781, [M

CHO). ¹³C NMR (150 MHz, CDCl₃): δ 143.57, 144.89, 146.94,

148.54 (4C, C^ar), 192.47 (CHO). HR-EI (positive mode, [M]⁺).

Calcd: m/z 108.0324. Obsd: m/z 108.0310.

Piperidone (p-NO₂)Npy₂P1 (C₂₀H₁₉N₅O₉, M_W= 473.39 g mol⁻¹). 4

(2.54 g, 16.70 mmol, 2.0 equiv) was dissolved in 10 mL of methanol at

0 °C, and then an aqueous solution of methylamine (40%, 0.65 g, 0.72

mL, 8.35 mmol, 1.0 equiv) and 26 (1.45 g, 1.21 mL, 8.35 mmol, 1.0

equiv) was added dropwise. After stirring at 0 °C for 10 min, the

reaction mixture was allowed to stand at 0 °C for several days until a

brown slimy precipitate formed. The solution was decanted, and a

small amount of methanol was added to the precipitate, whereupon a

yellow solid appeared. This yellow solid was ﬁltered and washed with

cold methanol to aﬀord the pure product in a yield of 18.0% (0.71 g,

1

1.50 mmol). H NMR (400 MHz, CDCl₃): δ 2.31 (s, 3H, NCH₃),

3.65 (s, 3H, COOCH₃), 3.82 (s, 3H, COOCH₃), 4.19 (d, ³J_H,H= 9.03

3

Hz, 1H, NCHCH), 4.69 (d, J_H,H= 9.16 Hz, 1H, NCHCH), 5.00 (s,

1

1H, NCH), 7.91 (dd, ³J_H,H= 5.40 Hz, ⁴J_H,H= 2.01 Hz, 1H, H^ar), 7.96−

+ /₅H₂O]). Calcd: C, 66.33; H, 7.47; N, 11.05. Obsd: C, 66.54; H,

7.99 (m, 2H, H^ar), 8.35 (d, ⁴J_H,H= 1.88 Hz, 1H, H^ar), 8.81 (d, ³J_H,H

=

7.69; N, 11.25.

3

5.40 Hz, 1H, H^ar), 8.93 (d, J_H,H= 5.40 Hz, 1H, H^ar), 12.51 (s, 1H,

enol OH). ¹³C NMR (100 MHz, CDCl₃): δ 37.92, 45.01, 52.03, 52.98,

61.03, 64.60, 97.55, 115.04, 115.27, 115.54, 115.78, 150.96, 151.13,

154.46, 154.57, 161.56, 164.61, 166.84, 170.24, 171.36. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 474.12610. Obsd: m/z

474.12541. HR-ESI (positive mode, [M + Na]⁺). Calcd: m/z

496.10805. Obsd: m/z 496.10739. Elem anal (report 30780, [M]).

Calcd: C, 50.74; H, 4.05; N, 14.79. Obsd: C, 50.76; H, 4.11; N, 14.74.

Piperidone (p-Cl)Npy₂P2 (C₂₀H₁₉Cl₂N₃O₅, M_W= 452.29 g mol⁻¹). 9

(5.05 g, 35.67 mmol, 2.0 equiv) was diluted in 30 mL of methanol, and

an ethanolic solution of methylamine (8 M, 17.84 mmol, 2.23 mL, 1.0

equiv) was added at 0 °C. At this temperature, dimethylacetone

dicarboxylate (3.11 g, 2.60 mL, 17.84 mmol, 1.0 equiv) was added

dropwise to the solution and stirred for 10 min and furthermore for 2

h at ambient temperature. The resulting solution was stored at −6 °C.

A white-to-pale-purple solid formed and was ﬁltered, washed with cold

methanol, and dried in vacuo to aﬀord a pure product in a mixture of

isomers in a yield of 81.8% (6.60 g, 14.6 mmol). Further crystallization

from hot methanol aﬀords a white crystalline solid as a single isomer.

¹H NMR (600 MHz, CDCl₃): δ 2.24 (s, 3H, NCH₃), 3.64 (s, 3H,

(4-Methylpyridin-2-yl)methanol (22; C₇H₉NO, M_W= 123.15 g

mol⁻¹). To 21 (9.88 g, 80.23 mmol, 1.0 equiv) dissolved in 200 mL of

DCM was added dropwise triﬂuoroacetic anhydride (50.55 g, 33.45

mL, 240.7 mmol, 3.0 equiv) dissolved in a further 50 mL of DCM.

The red solution was stirred at ambient temperature for 3.5 days. Then

triﬂuoroacetic anhydride and DCM were removed under vacuum, and

200 mL of methanol and 250 mL of a saturated K₂CO₃solution were

added to the residue. After stirring for 3 h, methanol was removed and

the aqueous phase was extracted with DCM (3 × 200 mL). The

combined organic phases were washed with brine (2 × 250 mL), dried

over Na₂SO₄, ﬁltered, and concentrated. A brown oil was obtained as

the fairly pure product containing traces of educt in a yield of 29.3%

1

(2.89 g, 23.5 mmol). H NMR (200 MHz, CDCl₃): δ 2.36 (s, 3H,

CH₃), 4.72 (s, 2H, CH₂OH), 7.03 (d, ³J_H,H= 5.12 Hz, 1H, H⁵), 7.07−

3

7.09 (m, 1H, H³), 8.41 (d, J_H,H= 5.12 Hz, 1H, H⁶). ¹³C NMR (50

MHz, CDCl₃): δ 21.02, 64.05, 121.22, 123.39, 147.90, 148.18, 158.84.

HR-EI (positive mode, M⁺). Calcd: m/z 123.0684. Obsd: m/z

1

123.0682. Elem anal (report 30855, [M + /₃H₂O]). Calcd: C, 65.09;

H, 7.54; N, 10.84. Obsd: C, 64.80; H, 7.56; N, 10.87.

4-Methylpicolinaldehyde (23; C₇H₇NO, M_W= 121.14 g mol⁻¹). 22

(2.68 g, 21.76 mmol, 1.0 equiv) and selenium dioxide (1.21 g, 10.9

mmol, 0.5 equiv) were suspended in 40 mL of 1,4-dioxane and heated

to 100 °C for 3 h. After cooling to ambient temperature, the solution

was decanted from the solid material and concentrated. The residue

was puriﬁed by Kugelrohr-distillation (105 °C, 1.0 mbar) to aﬀord a

3

COOCH₃), 3.76 (s, 3H, COOCH₃), 4.19 (d, J_H,H= 9.69 Hz, 1H,

3

NCHCH), 4.47 (d, J_H,H= 9.69 Hz, 1H, NCHCH), 4.83 (s, 1H,

NCH), 7.16 (dd, ³J_H,H= 5.25 Hz, ⁴J_H,H= 1.61 Hz, 1H, H^ar), 7.24 (dd,

³J_H,H= 5.30 Hz, ⁴J_H,H= 1.56 Hz, 1H, H^ar), 7.27 (m, 1H, H^ar), 7.56 (d,

3

⁴J_H,H= 1.41 Hz, 1H, H^ar), 8.38 (d, J_H,H= 5.35 Hz, 1H, H^ar), 8.54 (d,

1

colorless oil in a yield of 54.2% (1.43 g, 11.80 mmol). H NMR (200

³J_H,H= 5.25 Hz, 1H, H^ar), 12.48 (s, 1H, enol OH). ¹³C NMR (150

MHz, CDCl₃): δ 37.65, 44.73, 51.92, 52.66, 60.36, 64.60, 97.53,

122.74, 123.08, 123.17, 123.64, 144.47, 144.59, 149.46, 150.02, 159.74,

162.42, 167.19, 170.67, 171.64. HR-ESI (positive mode, [M + H]⁺).

Calcd: m/z 452.07800. Obsd: m/z 452.07770. HR-ESI (positive mode,

[M + Na]⁺). Calcd: m/z 474.05995. Obsd: m/z 474.05994. HR-ESI

(positive mode, [M + K]⁺). Calcd: m/z 490.03388. Obsd: m/z

490.03395. Elem anal (report 30807, [M]). Calcd: C, 53.11; H, 4.23;

N, 9.29. Obsd: C, 53.29; H, 4.25; N, 9.44.

MHz, CDCl₃): δ 2.43 (s, 3H, CH₃), 7.33 (ddd, ³J_H,H= 4.95 Hz, ⁴J_H,H

=

4

1.75 Hz, J_H,H= 0.73 Hz, 1H, H⁵), 7.75−7.79 (m, 1H, H³), 8.62 (d,

³J_H,H= 4.95 Hz, 1H, H⁶), 10.05 (s, 1H, CHO). ¹³C NMR (50 MHz,

CDCl₃): δ 20.98 (CH₃), 122.46, 128.68, 148.53, 149.92, 152.68 (5C,

C^ar), 193.64 (CHO). HR-EI (positive mode, [M]⁺). Calcd: m/z

121.0528. Obsd: m/z 121.0554. HR-EI (positive mode, [M − CO]⁺).

Calcd: m/z 93.0579. Obsd: m/z 93.0586. Elem anal (report 30861, [M

1

+ /₅H₂O]). Calcd: C, 67.40; H, 5.98; N, 11.23. Obsd: C, 67.52; H,

5.95; N, 11.26.

Piperidone (p-Br)Npy₂P3 (C₂₀H₁₉Br₂N₃O₅, M_W= 541.19 g mol⁻¹).

To 5 (1.57 g, 8.44 mmol, 2.0 equiv) dissolved in 10 mL of methanol

was subsequently added an ethanolic solution of methylamine (8 M,

0.58 mL, 4.64 mmol, 1.1 equiv) followed by dimethylacetone

dicarboxylate (0.74 g, 0.62 mL, 4.22 mmol, 1.0 equiv). The solution

was stirred at 0 °C for 1 h and at ambient temperature for another 1 h.

The solution was concentrated to half of its volume and freed from

minor particles by ﬁltration into a hot ﬂask. Crystallization took place

immediately. A pale-yellow crystalline solid was obtained as the pure

product in a yield of 55.2% (1.26 g, 2.33 mmol). ¹H NMR (400 MHz,

Pyrazine-2-carboxaldehyde (25; C₅H₄N₂O, M_W= 108.10 g mol⁻¹).

Methyl-2-pyrazinecarboxylate (24; 2.01 g, 14.55 mmol, 1.0 equiv) was

dissolved in 40 mL of dry THF at −78 °C under an atmosphere of

argon. To this solution was added 7.28 mL of a 1 M solution of

lithium−aluminium hydride in THF over 20 min. The mixture was

stirred at −78 °C for a further 1.5 h. Then 2 mL of glacial acid was

added to the mixture at low temperature. The mixture was then stirred

for 0.5 h, allowing it to warm to ambient temperature. The solvent was

removed in vacuo, and the resulting residue was taken up in diluted

hydrochloric acid (3 mL of concentrated HCl/12 mL of aqua dest.)

6493

dx.doi.org/10.1021/ic4004214 | Inorg. Chem. 2013, 52, 6481−6501

Inorganic Chemistry

Article

CDCl₃): δ 2.24 (s, 3H, NCH₃), 3.65 (s, 3H, COOCH₃), 3.77 (s, 3H,

dicarboxylate (1.02 g, 0.85 mL, 5.86 mmol, 1.0 equiv) were added

dropwise consecutively. The mixture was stirred at 0 °C for 2 h and

afterward at ambient temperature overnight. The product was

crystallized by slow evaporation of the solvent at ambient temperature,

ﬁltered, washed with further cold methanol, and dried under vacuum.

A white, crystalline solid was obtained as the pure product in a yield of

3

COOCH₃), 4.19 (d, J_H,H= 9.54 Hz, 1H, NCHCH), 4.47 (d, J_H,H

=

9.66 Hz, 1H, NCHCH), 4.83 (s, 1H, NCH), 7.33 (dd, ³J_H,H= 5.21 Hz,

3

4

⁴J_H,H= 1.44 Hz, 1H, H^ar), 7.40 (dd, J_H,H= 5.21 Hz, J_H,H= 1.44 Hz,

1H, H^ar), 7.44 (d, J_H,H= 0.75 Hz, 1H, H^ar), 7.73 (d, ⁴J_H,H= 1.25 Hz,

4

3

1H, H^ar), 8.31 (d, J_H,H= 5.27 Hz, 1H, H^ar), 8.46 (d, ³J_H,H= 5.27 Hz,

1

1H, H^ar), 12.48 (s, 1H, enol OH). ¹³C NMR (100 MHz, CDCl₃): δ

37.71, 44.86, 51.93, 52.69, 60.37, 64.58, 97.58, 125.74, 126.07, 126.23,

126.69, 133.26, 133.33, 149.35, 149.89, 159.62, 162.29, 167.16, 170.62,

171.63. HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 541.97492.

Obsd: m/z 541.97475. HR-ESI (positive mode, [M + Na]⁺). Calcd:

m/z 563.95687. Obsd: m/z 563.95700. HR-ESI (positive mode, [M +

K]⁺). Calcd: m/z 579.93081. Obsd: m/z 579.93092. Elem anal (report

30963, [M]). Calcd: C, 44.39; H, 3.54; N, 7.76. Obsd: C, 44.59; H,

3.62; N, 8.04.

45.9% (1.27 g, 2.69 mmol). H NMR (400 MHz, CDCl₃): δ 1.39 (t,

3

³J_H,H= 6.90 Hz, 3H, pyOCH₂CH₃), 1.45 (t, J_H,H= 7.15 Hz, 3H,

pyoCH₂CH₃), 2.21 (s, 3H, N³CH₃), 3.64 (s, 3H, COOCH₃), 3.74 (s,

3

3H, COOCH₃), 3.98−4.19 (m, 4H, pyOCH₂CH₃), 4.21 (d, J_H,H

=

9.54 Hz, 1H, N³CHCH), 4.41 (d, J_H,H= 9.54 Hz, 1H, N³CHCH),

3

4.88 (br s, 1H, N³CH), 6.65 (d, ³J_H,H= 5.65 Hz, 1H, H^ar), 6.70−6.78

(m, 2H, H^ar), 7.08 (s, 1H, H^ar), 8.30 (d, J_H,H= 5.65 Hz, 1H, H^ar),

3

8.43−8.47 (m, 1H, H^ar), 12.43 (s, 1H, enol OH). ¹³C NMR (100

MHz, CDCl₃): δ 14.40, 14.49, 37.96, 46.42, 51.87, 52.51, 61.21, 63.48,

63.66, 98.50, 109.13, 109.21, 109.50, 149.96, 150.46, 155.73, 157.22,

159.91, 163.28, 165.44, 167.35, 169.09, 171.26, 171.76. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 472.20838. Obsd: m/z

472.20791. HR-ESI (positive mode, [M + Na]⁺). Calcd: m/z

494.19032. Obsd: m/z 494.19015. Elem anal (report 30808, [M]).

Calcd: C, 61.14; H, 6.20; N, 8.91. Obsd: C, 61.17; H, 6.16; N, 8.92.

Piperidone (p-MeS)Npy₂P7 (C₂₂H₂₅N₃O₅S₂, M_W= 475.58 g mol⁻¹).

17 (2.65 g, 17.30 mmol, 2.0 equiv) was dissolved in 30 mL of

methanol at 0 °C, and an ethanolic solution of methylamine (8 M,

1.08 mL, 8.65 mmol, 1.0 equiv) and dimethylacetone dicarboxylate

(1.51 g, 1.26 mL, 8.65 mmol, 1.0 equiv) were added dropwise

consecutively. The solution was stirred for 1.5 h at 0 °C. During that

time, a precipitate formed. The suspension was stirred for another 3.5

h at ambient temperature. Afterward, the mixture was stored at −6 °C

overnight to complete precipitation. Then the white solid was ﬁltered,

washed with cold methanol, and dried under vacuum to aﬀord the

product in a yield of 67.6% (2.78 g, 5.85 mmol). Crystals could be

obtained by recrystallization from hot methanol. ¹H NMR (400 MHz,

CDCl₃): δ 2.21 (s, 3H, N³CH₃), 2.42 (s, 3H, pySCH₃), 2.53 (s, 3H,

pySCH₃), 3.64 (s, 3H, COOCH₃), 3.72 (s, 3H, COOCH₃), 4.21 (d,

Piperidone (p-Me)Npy₂P4 (C₂₂H₂₅N₃O₅, M_W= 411.45 g mol⁻¹). 23

(1.01 g, 8.34 mmol, 2.0 equiv) was dissolved in 10 mL of methanol at

0 °C, and an ethanolic solution of methylamine (8 M, 0.39 g, 0.52 mL,

4.17 mmol, 1.0 equiv) and dimethylacetone dicarboxylate (0.73 g, 0.61

mL, 4.17 mmol, 1.0 equiv) were added dropwise consecutively. The

solution was stirred at 0 °C for 2 h and further on at ambient

temperature overnight. The solvent was then allowed to evaporate

slowly at ambient temperature. After 2 days, big colorless crystals were

obtained as the pure product in a yield of 42.5% (723.0 mg, 1.77

mmol). ¹H NMR (400 MHz, CDCl₃): δ 2.22 (s, 3H, N³CH₃/pyCH₃),

2.26 (s, 3H, N³CH₃/pyCH₃), 2.40 (s, 3H, N³CH₃/pyCH₃), 3.63 (s,

3H, COOCH₃), 3.73 (s, 3H, COOCH₃), 4.29 (d, ³J_H,H= 9.91 Hz, 1H,

3

N³CHCH), 4.44 (d, J_H,H= 9.91 Hz, 1H, N³CHCH), 4.88 (s, 1H,

N³CH), 6.95 (d, ³J_H,H= 5.02 Hz, 1H, H^ar), 7.02 (s, 1H, H^ar), 7.05 (d,

³J_H,H= 4.89 Hz, 1H, H^ar), 7.34 (br s, 1H, H^ar), 8.34 (d, ³J_H,H= 5.02 Hz,

3

1H, H^ar), 8.53 (d, J_H,H= 5.02 Hz, 1H, H^ar), 12.48 (s, 1H, enol OH).

¹³C NMR (100 MHz, CDCl₃): δ 20.90, 21.34, 37.71, 45.40, 51.84,

52.47, 60.47, 64.73, 98.02, 123.33, 123.63, 123.70, 124.34, 147.53,

148.36, 148.98, 157.76, 159.82, 167.55, 169.14, 171.28, 171.88. HR-

ESI (positive mode, [M + H]⁺). Calcd: m/z 412.18725. Obsd: m/z

412.18665. HR-ESI (positive mode, [M + Na]⁺). Calcd: m/z

434.16919. Obsd: m/z 434.16880. HR-ESI (positive mode, [M +

K]⁺). Calcd: m/z 450.14313. Obsd: m/z 450.14274. Elem anal (report

30952, [M]). Calcd: C, 64.22; H, 6.12; N, 10.21. Obsd: C, 64.16; H,

6.16; N, 10.14.

³J_H,H= 9.41 Hz, 1H, N³CHCH), 4.40 (d, J_H,H= 9.54 Hz, 1H,

3

4

N³CHCH), 4.86 (s, 1H, N³CH), 6.94 (dd, J_H,H= 5.33 Hz, J_H,H

=

4

1.82 Hz, 1H, H⁵′), 7.01−7.05 (m, 2H, H^ar), 7.37 (d, J_H,H= 1.13 Hz,

1H, H³′), 8.28 (d, ³J_H,H= 5.27 Hz, 1H, H⁶′), 8.41 (d, ³J_H,H= 5.40 Hz,

1H, H⁶′), 12.44 (s, 1H, enol OH). ¹³C NMR (100 MHz, CDCl₃): δ

13.63, 13.72, 37.85, 45.80, 51.88, 52.53, 60.92, 66.62, 98.17, 118.61,

118.70, 119.37, 119.44, 148.10, 150.71, 157.65, 159.65, 159.71, 167.20,

168.98, 171.01, 171.69. HR-ESI (positive mode, [M + H]⁺). Calcd: m/

z 476.13139. Obsd: m/z 476.13116. Elem anal (report 30806, [M]).

Calcd: C, 55.56; H, 5.30; N, 8.84. Obsd: C, 55.92; H, 5.34; N, 8.93.

Piperidone (o-MeO)Npy₂P8 (C₂₂H₂₅N₃O₇, M_W= 443.45 g mol⁻¹).

26 (0.97 g, 7.07 mmol, 2.0 equiv) was dissolved in 10 mL of methanol

at 0 °C, and then an ethanolic solution of methylamine (8 M, 0.44 mL,

3.54 mmol, 1.0 equiv) and dimethylacetone dicarboxylate (0.62 g, 0.52

mL, 3.54 mmol, 1.0 equiv) were added dropwise. The solution was

stirred at 0 °C for 1 h and at ambient temperature for another 2.5 h.

Then 20 mL of diethyl ether was added to the solution, and

crystallization was performed at −6 °C. After storage for 3 months at

−6 °C, a colorless solid crystallized and was ﬁltered and washed with

cold methanol. The mother liquor was concentrated to aﬀord further

white solid. The clean product was obtained in a yield of 67.2% (1.06

g, 2.38 mmol). ¹H NMR (600 MHz, CDCl₃): δ 2.24 (s, 3H, N³CH₃),

3.66 (s, 3H, COOCH₃), 3.70 (s, 3H, COOCH₃), 3.89 (s, 3H,

Piperidone (p-MeO)Npy₂P5 (C₂₂H₂₅N₃O₇, M_W= 443.45 g mol⁻¹).

15 (10.27 g, 74.89 mmol, 2.0 equiv) was diluted in 50 mL of methanol

and cooled to 0 °C. Then an ethanolic solution of methylamine (8 M,

4.68 mL, 37.45 mmol, 1.0 equiv) and dimethylacetone dicarboxylate

(6.52 g, 5.46 mL, 37.45 mmol, 1.0 equiv) was added dropwise. This

solution was stirred at 0 °C for 10 min and at ambient temperature

overnight. The solution was concentrated to approximately 40 mL and

another 40 mL of diethyl ether was added. This solution was stored at

−6 °C for several days. The colorless crystals were ﬁltered and further

washed with cold methanol. This procedure was repeated with the

reaction mixture for several times to increase the yield. The pure

product was obtained as colorless-to-white crystals (to white powder)

in a yield of 51.3% (8.52 g, 19.2 mmol). ¹H NMR (400 MHz, CDCl₃):

δ 2.22 (s, 3H, N³CH₃), 3.64 (s, 3H, COOCH₃), 3.73 (s, 3H,

COOCH₃), 3.79 (s, 3H, pyOCH₃), 3.91 (s, 3H, pyOCH₃), 4.22 (d,

3

³J_H,H= 9.54 Hz, 1H, N³CHCH), 4.42 (d, J_H,H= 9.54 Hz, 1H,

N³CHCH), 4.92 (br s, 1H, N³CH), 6.68 (dd, ³J_H,H= 5.65 Hz, ⁴J_H,H

=

2.51 Hz, 1H, H⁵′), 6.75−6.79 (m, 2H, H^ar), 7.13 (d, J_H,H= 2.01 Hz,

1H, H³′), 8.31 (d, ³J_H,H= 5.65 Hz, 1H, H⁶′), 8.46 (d, ³J_H,H= 5.77 Hz,

1H, H⁶′), 12.44 (s, 1H, enol OH). ¹³C NMR (100 MHz, CDCl₃): δ

37.95, 46.37, 51.91, 52.55, 55.14, 55.39, 61.26, 66.81, 108.73, 108.80,

108.93, 109.22, 109.63, 149.96 (2C), 159.92, 161.51, 166.13, 167.39,

167.41, 171.30, 171.68. HR-ESI (positive mode, [M + H]⁺). Calcd: m/

z 444.17708. Obsd: m/z 444.17660. Elem anal (report 30891, [M]).

Calcd: C, 59.59; H, 5.68; N, 9.48. Obsd: C, 59.48; H, 5.69; N, 9.41.

Piperidone (p-EtO)Npy₂P6 (C₂₄H₂₉N₃O₇, M_W= 471.50 g mol⁻¹).

16 (1.77 g, 11.71 mmol, 2.0 equiv) was dissolved in 20 mL of

methanol at 0 °C, and an ethanolic solution of methylamine (8 M,

0.55 g, 0.73 mL, 5.86 mmol, 1.0 equiv) and dimethylacetone

4

3

pyOCH₃), 3.91 (s, 3H, pyOCH₃), 4.25 (d, J_H,H= 9.99 Hz, 1H,

N³CHCH), 4.69 (d, ³J_H,H= 9.99 Hz, 1H, N³CHCH), 4.72 (s, N³CH),

3

6.59 (d, J_H,H= 8.17 Hz, 1H, H^ar), 6.63 (d, ³J_H,H= 8.07 Hz, 1H, H^ar),

3

6.89 (d, J_H,H= 7.37 Hz, 1H, H^ar), 7.17 (d, ³J_H,H= 7.27 Hz, 1H, H^ar),

3

7.49 (t, J_H,H= 7.72 Hz, 1H, H^ar), 7.59 (t, J_H,H= 7.67 Hz, 1H, H^ar),

12.44 (s, 1H, enol OH). ¹³C NMR (150 MHz, CDCl₃): δ 37.41, 44.44,

51.60, 52.19, 53.30, 53.42, 60.02, 64.24, 98.61, 108.68, 109.27, 115.51,

116.25, 138.65, 138.84, 155.88, 158.66, 163.09, 163.22, 166.57, 171.06,

172.29. Elem anal (report 31192, [M]). Calcd: C, 59.59; H, 5.68; N,

9.48. Obsd: C, 59.36; H, 5.61; N, 9.40.

Piperidone (m/3′-Me)Npy₂P9 (C₂₂H₂₅N₃O₅, M_W= 411.45 g mol⁻¹).

27 (2.23 g, 18.41 mmol, 2.0 equiv) was dissolved in 15 mL of

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methanol and cooled to 0 °C. Then an aqueous solution of

methylamine (40%, 1.04 g, 1.38 mL, 11.05 mmol, 1.2 equiv) and

dimethylacetone dicarboxylate (1.60 g, 1.34 mL, 9.21 mmol, 1.0 equiv)

were added to the solution dropwise. The solution was stirred at 0 °C

for 2 h, whereupon a precipitate formed, and furthermore at ambient

temperature overnight. The white solid was ﬁltered, washed with cold

methanol, and dried on air. The pure product was obtained in a yield

of 54.6% (2.07 g, 5.03 mmol). ¹H NMR (200 MHz, CDCl₃): δ 1.50 (s,

3H, N³CH₃/pyCH₃), 2.24 (s, 3H, N³CH₃/pyCH₃), 2.46 (s, 3H,

N³CH₃/pyCH₃), 3.57 (s, 3H, COOCH₃), 3.64 (s, 3H, COOCH₃),

4.72 (m, 1H, CH), 4.77 (s, 1H, CH), 4.82 (br s, 1H, CH), 7.02 (dd,

1.2 equiv) were added dropwise to the suspension consecutively, and

the mixture was reﬂuxed for 1 h. After cooling to ambient temperature,

the solvent was removed in vacuo. The resulting foam was taken up in

hot methanol. A yellow solid formed. For further precipitation, the

suspension was stored at 6 °C overnight. The solid material was

ﬁltered and washed with a small amount of cold methanol. The solid

material consists of a ﬁne powdery white solid and a more crystalline

yellow solid, which could be separated manually. The former white

solid turned out to be syn-bispidone (endo/endo isomer) and was

obtained in a yield of 8.2% (0.06 g, 0.11 mmol); the yellow solid

turned out to be anti-bispidone (endo/exo isomer) and was obtained

in a yield of 42.2% (0.30 g, 0.57 mmol). syn-B1. ¹H NMR (400 MHz,

3

³J_H,H= 7.64 Hz, J_H,H= 4.74 Hz, 1H, H⁵′), 7.12 (dd, J_H,H= 7.45 Hz,

CDCl₃): δ 2.10 (s, 3H, N³CH₃), 2.33 (s, 3H, N⁷CH₃), 2.59 (d, ²J_H,H

=

³J_H,H= 4.67 Hz, 1H, H⁵′), 7.27 (ddd, ³J_H,H= 7.55 Hz, ⁴J_H,H= 1.65 Hz,

2

⁴J_H,H= 0.69 Hz, 1H, H⁴′), 7.49 (ddd, ³J_H,H= 7.55 Hz, ⁴J_H,H= 1.61 Hz,

12.55 Hz, 2H, CH_axH_eq), 2.81 (d, J_H,H= 12.80 Hz, 2H, CH_axH_eq),

3.85 (s, 6H, COOCH₃), 5.04 (s, 2H, NCH), 8.01 (dd, ³J_H,H= 5.33 Hz,

⁴J_H,H= 2.07 Hz, 2H, H⁵′), 8.84 (d, ³J_H,H= 5.27 Hz, 2H, H⁶′), 8.94 (d,

⁴J_H,H= 1.63 Hz, 2H, H³′). ¹³C NMR (100 MHz, CDCl₃): δ 43.62,

44.23, 52.82, 60.74, 61.72, 73.03, 115.77, 116.23, 151.60, 154.86,

162.85, 167.68, 201.79. anti-B1. ¹H NMR (400 MHz, CDCl₃): δ 2.06

3

⁴J_H,H= 0.69 Hz, 1H, H⁴′), 8.30−8.35 (m, 1H, H⁶′), 8.45 (dd, J_H,H

=

4.80 Hz, ⁴J_H,H= 1.39 Hz, 1H, H⁶′), 12.50 (s, 1H, enol OH). ¹³C NMR

(50 MHz, CDCl₃): δ 16.46, 18.37, 36.56, 41.52, 51.49, 52.11, 56.03,

62.09, 96.52, 121.97, 122.27, 132.66, 133.56, 137.59, 138.10, 145.35,

145.67, 155.50, 158.73, 167.83, 170.95, 172.10. Elem anal (report

IPMB-MM455, [M]). Calcd: C, 64.22; H, 6.12; N, 10.21. Obsd: C,

64.20; H, 6.33; N, 10.17.

(s, 3H, N³CH₃), 2.28 (s, 3H, N⁷CH₃), 2.77 (d, J_H,H= 12.27 Hz, 1H,

2

N⁷CH_axH_eq), 2.92 (dd, J_H,H= 12.60 Hz, J_H,H= 1.6 Hz, 1H,

2

4

N⁷CH_axH_eq), 3.17 (d, ²J_H₂_,H= 11.04 Hz, 1H, N⁷CH_axH_eq), 3.58 (s, 3H,

Piperidone NPyr₂P10 (C₁₈H₁₉N₅O₅, M_W= 385.37 g mol⁻¹). 25 (25;

0.91 g, 8.42 mmol, 2.0 equiv) was dissolved in 10 mL of methanol at 0

°C, and then an ethanolic solution of methylamine (8 M, 0.48 g, 0.63

mL, 5.05 mmol, 1.2 equiv) followed by dimethylacetone dicarboxylate

(0.73 g, 0.61 mL, 4.21 mmol, 1.0 equiv) were added to the solution

and stirred at 0 °C for 2 h and afterward at ambient temperature

overnight. A yellow crystalline solid was obtained as the pure product

by slow evaporation of the solvent at ambient temperature in a yield of

4

COOCH₃), 3.69 (dd, J_H,H= 11.04 Hz, J_H,H= 1.51 Hz, 1H,

N⁷CH_axH_eq), 3.88 (s, 3H, COOCH₃), 5.05 (br s, 1H, N³CH), 5.21 (br

s, 1H, N³CH), 7.92 (dd, J_H,H= 5.14 Hz, J_H,H= 2.20 Hz, 1H, H⁵′),

3

4

7.93 (dd, J_H,H= 5.14 Hz, J_H,H= 2.26 Hz, 1H, H⁵′), 8.07 (d, J_H,H

=

3

4

1.88 Hz, 1H, H³′), 8.69 (br s, 1H, H³′), 8.79 (d, J_H,H= 5.40 Hz, 1H,

3

H⁶′), 8.88 (d, J_H,H= 5.27 Hz, 1H, H⁶′). ¹³C NMR (100 MHz,

3

CDCl₃): δ 40.33, 44.05, 52.55, 52.82, 61.71, 61.76, 61.88, 65.67, 70.12,

72.51, 114.47, 115.21, 115.90, 116.88, 150.46, 151.12, 153.94, 154.40,

161.03, 162.37, 168.62, 168.86, 200.77. HR-ESI (positive mode, [M +

H]⁺). Calcd: m/z 529.16830. Obsd: m/z 529.16749. HR-ESI (positive

mode, [M + MeOH + H]⁺). Calcd: m/z 561.19452. Obsd: m/z

561.19372. Elem anal (report 29622, [M]). Calcd: C, 52.27; H, 4.58;

N, 15.90. Obsd: C, 52.37; H, 4.70; N, 15.62.

1

27.8% (0.45 g, 1.17 mmol). H NMR (600 MHz, CDCl₃): δ 2.28 (s,

3H, N³CH₃), 3.64 (s, 3H, COOCH₃), 3.74 (s, 3H, COOCH₃), 4.21

3

(d, J_H,H= 8.78 Hz, 1H, N³CHCH), 4.68 (br s, 1H, N³CHCH), 4.89

(s, 1H, N³CH), 8.46 (s, 1H, H^ar), 8.47 (s, 1H, H^ar), 8.52 (s, 1H, H^ar),

8.54 (s, 1H, H^ar), 8.59 (s, 1H, H^ar), 8.87 (s, 1H, H^ar), 12.52 (s, 1H,

enol OH). ¹³C NMR (150 MHz, CDCl₃): δ 37.54 (NCH₃), 43.82,

51.96, 52.78, 58.71, 62.82, 96.98, 143.26 (2C), 143.35, 143.62, 145.22,

145.63, 153.29, 156.19, 166.86, 170.15, 171.42. HR-ESI (positive

mode, [M + H]⁺). Calcd: m/z 386.14644. Obsd: m/z 386.14582. HR-

ESI (positive mode, [M + Na]⁺). Calcd: m/z 408.12839. Obsd: m/z

408.12777. HR-ESI (positive mode, [M + K]⁺). Calcd: m/z

424.10233. Obsd: m/z 424.10173. Elem anal (report 30951, [M]).

Calcd: C, 56.10; H, 4.97; N, 18.17. Obsd: C, 56.09; H, 5.04; N, 18.12.

Piperidone (m,m-di-Br)Npy₂P11 (C₂₀H₁₇Br₄N₃O₅, M_W= 698.98 g

mol⁻¹). 28 (1.04 g, 3.93 mmol, 2.0 equiv) was dissolved in 5 mL of

methanol at 0 °C, and an ethanolic solution of methylamine (33 wt %,

0.22 g, 0.29 mL, 2.36 mmol, 1.2 equiv) and dimethylacetone

dicarboxylate (0.34 g, 0.28 mL, 1.97 mmol, 1.0 equiv) were added

dropwise subsequently to the solution, which was then stirred for 2 h

at 0 °C and another 4 h at ambient temperature. A white solid

precipitated. The resulting solid was removed by ﬁltration, washed

with a small amount of cold methanol, and dried on air. The pure

Bispidone (p-Cl)N₂py₂B2 (C₂₃H₂₄Cl₂N₄O₅, M_w= 507.37 g mol⁻¹).

Piperidone P2 (2.00 g, 4.42 mmol, 1.0 equiv) was suspended in 30 mL

of methanol and heated to 50 °C. At this temperature, an aqueous

solution of methylamine (40%, 0.34 g, 0.38 mL, 4.42 mmol, 1.0 equiv)

and an aqueous solution of formaldehyde (37%, 0.72 g, 0.66 mL, 8.84

mmol, 2.0 equiv) were added to the suspension and heated to reﬂux

for 3 h. The newly formed suspension was allowed to stand at ambient

temperature overnight and ﬁltered. The solid was washed with cold

methanol to aﬀord a white crystalline solid as the pure product in a

1

yield of 57.0% (1.28 g, 2.52 mmol). H NMR (400 MHz, CDCl₃): δ

2.08 (s, 3H, N³CH₃), 2.30 (s, 3H, N⁷CH₃), 2.53 (d, ²J_H,H= 12.30 Hz,

2

2H, CH_axH_eq), 2.90 (d, J_H,H= 12.80 Hz, 2H, CH_axH_eq), 3.83 (s, 6H,

COOCH₃), 4.78 (s, 2H, NCH), 7.27 (dd, ³J_H,H= 5.27 Hz, ⁴J_H,H= 2.01

Hz, 2H, H⁵′), 8.10 (d, ⁴J_H,H= 1.88 Hz, 2H, H³′), 8.42 (d, ³J_H,H= 5.27

Hz, 2H, H⁶′). ¹³C NMR (100 MHz, CDCl₃): δ 43.46, 44.24, 52.61,

60.74, 61.86, 73.31, 123.57, 123.77, 144.95, 150.14, 160.71, 168.11,

202.72. HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 507.12020.

Obsd: m/z 507.11987. Elem anal (report 29806, [M]). Calcd: C,

54.45; H, 4.77; N, 11.04. Obsd: C, 54.30; H, 4.74; N, 10.93.

1

product was obtained in a yield of 62.4% (0.86 g, 1.23 mmol). H

NMR (enol form; 200 MHz, CDCl₃): δ 2.25 (s, 3H, N³CH₃), 3.61 (s,

3

3H, COOCH₃), 3.67 (s, 3H, COOCH₃), 4.62 (d, J_H,H= 11.24 Hz,

Bispidone (p-Br)N₂py₂B3 (C₂₃H₂₄Br₂N₄O₅, M_W= 596.27 g mol⁻¹).

Piperidone P3 (0.94 g, 1.74 mmol, 1.0 equiv) was dissolved in 10 mL

of THF and heated to 50 °C, whereupon 0.16 mL of an aqueous

solution of methylamine (40%, 0.14 g, 1.74 mmol, 1.0 equiv) followed

by 0.26 mL of an aqueous solution of formaldehyde (37%, 0.28 g, 3.48

mmol, 2.0 equiv) were added. The suspension was heated to reﬂux for

1 h. After the mixture was allowed to cool to ambient temperature, the

solvent was removed in vacuo. The residue was taken up in hot

methanol, whereupon a white solid crystallized. The suspension was

allowed to stand at −6 °C for further crystallization. The white solid

was ﬁltered and washed with methanol. The solution was furthermore

concentrated, whereupon yellow crystals formed. The white solid (ﬁrst

crystallization), which turned out to be syn-bispidone (endo/endo

isomer), was obtained in a yield of 13.2% (0.14 g, 0.23 mmol). The

yellow needles (second crystallization), which turned out to be anti-

bispidone (endo/exo isomer), were obtained in a yield of 55.2% (0.57

3

1H, N³CHCH), 5.07 (br s, 1H, N³CH), 5.24 (d, J_H,H= 11.24 Hz,

4

N³CHCH), 7.93 (d, J_H,H= 2.02 Hz, 1H, H^ar), 8.07 (d, J_H,H= 2.02

Hz, 1H, H^ar), 8.52−8.56 (m, 1H, H^ar), 8.61 (d, J_H,H= 2.02 Hz, 1H,

4

H^ar), 12.50 (s, 1H, enol OH). ¹³C NMR (keto and enol forms; 50

MHz, CDCl₃): δ 30.40, 36.49, 41.44, 51.88, 52.19, 52.52, 54.95, 57.05,

62.47, 66.72, 96.15, 118.99, 119.91, 120.10, 123.01, 123.52, 123.58,

142.21, 143.14, 143.22, 147.76, 147.95, 147.98, 148.16, 153.15, 167.49,

168.38, 169.82, 171.40, 200.39. HR-ESI (positive mode, [M + H]⁺).

Calcd: m/z 699.79390. Obsd: m/z 699.79389. Elem anal (report

IPMB_MM405, [M]). Calcd: C, 34.37; H, 2.45; N, 6.01. Obsd: C,

34.56; H, 2.83; N, 6.01.

Bispidone (p-NO₂)N₂py₂B1 (C₂₃H₂₄N₆O₉, M_W= 528.47 g mol⁻¹).

Piperidone P1 (0.64 g, 1.35 mmol, 1.0 equiv) was suspended in 10 mL

of THF and heated to 50 °C. At this temperature, an aqueous solution

of formaldehyde (37%, 0.22 g, 0.20 mL, 2.70 mmol, 2.0 equiv) and an

aqueous solution of methylamine (40%, 0.13 g, 0.14 mL, 1.62 mmol,

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1

g, 0.96 mmol). syn-B3. H NMR (200 MHz, CDCl₃): δ 2.07 (s, 3H,

of THF and heated to 50 °C. At this temperature, an aqueous solution

of methylamine (40%, 0.16 g, 0.18 mL, 2.09 mmol, 1.2 equiv) and an

aqueous solution of formaldehyde (37%, 0.28 g, 0.26 mL, 3.48 mmol,

2.0 equiv) were added dropwise to the mixture consecutively. The

mixture was reﬂuxed for 1 h and then concentrated in vacuo after

cooling to ambient temperature. The residue was taken up in methanol

and precipitated by slow evaporation of the solvent. The resulting

white solid was ﬁltered and washed with a small amount of cold

methanol (product is fairly soluble in methanol) to aﬀord the pure

product in a yield of 9.2% (83.7 mg, 0.16 mmol). ¹H NMR (400 MHz,

N³CH₃), 2.30 (s, 3H, N⁷CH₃), 2.51 (d, 2H, J_H,H= 12.13 Hz, 1H,

2

N⁷CH_axH_eq), 2.88 (d, J_H,H= 12.88 Hz, 2H, CH_axH_eq), 3.81 (s, 6H,

2

COOCH₃), 4.76 (s, 2H, N³CH), 7.42 (dd, J_H,H= 5.31 Hz, J_H,H

=

3

4

1.89 Hz, 2H, H⁵′), 8.27 (d, ⁴J_H,H= 1.64 Hz, 2H, H³′), 8.32 (d, ³J_H,H

5.31 Hz, 2H, H⁶′). ¹³C NMR (50 MHz, CDCl₃): δ 43.43, 44.07, 52.54,

60.70, 61.90, 73.26, 126.45, 126.95, 133.59, 149.98, 160.58, 168.04,

202.58. anti-B3. ¹H NMR (400 MHz, CDCl₃): δ 2.05 (s, 3H, N³CH₃),

2.28 (s, 3H, N⁷CH₃), 2.76 (br d, J_H,H= 12.05 Hz, N⁷CH_axH_eq), 3.08

2

(d, J_H,H= 10.92, N⁷CH_ax₂H_eq), 3.49 (br s, 1H, N⁷CH_axH_eq), 3.54 (s,

2

3H, COOCH₃), 3.65 (d, J_H,H= 10.79 Hz, N⁷CH_axH_eq), 3.85 (s, 3H,

COOCH₃), 4.79 (s, 1H, N³CH), 5.07 (s, 1H, N³CH), 7.33−7.37 (m,

CDCl₃): δ 1.49 (t, J_H,H= 6.96 Hz, 6H, OCH₂CH₃), 2.06 (s, 3H,

3

2

N³CH₃), 2.27 (s, 3H, N⁷CH₃), 2.51 (d, J_H,H= 11.92 Hz, 2H,

2H, H^ar), 7.48 (s, 1H, H^ar), 8.04 (br s, 1H, H^ar), 8.30 (d, J_H,H= 5.27

CH_axH_eq), 3.02 (d, J_H,H= 11.42 Hz, 2H, CH_axH_eq), 3.81 (s, 6H,

3

2

Hz, 1H, H^ar), 8.38 (d, ³J_H,H= 5.27 Hz, 1H, H^ar). ¹³C NMR (100 MHz,

CDCl₃): δ 40.22, 44.08, 52.28, 52.64, 61.38, 62.06, 65.90, 69.76, 69.79,

72.39, 125.24, 125.96, 126.48, 127.47, 132.86, 133.16, 149.00, 149.66,

158.73, 160.05, 169.08, 169.36, 201.41. HR-ESI (positive mode, [M +

H]⁺). Calcd: m/z 597.01712. Obsd: m/z 597.01684. HR-ESI (positive

mode, [M + MeOH + H]⁺). Calcd: m/z 629.04334. Obsd: m/z

629.04301. Elem anal (report 30487, [M]). Calcd: C, 46.33; H, 4.06;

N, 9.40. Obsd: C, 46.54; H, 4.20; N, 9.35.

COOCH₃), 4.15 (m, 4H, pyOCH₂CH₃), 4.68 (s, 2H, N³CH), 6.72

3

4

(dd, J_H,H= 5.65 Hz, J_H,H= 2.38 Hz, 2H, H⁵′), 7.65 (br s, 2H, H³′),

8.29 (d, J_H,H= 5.65 Hz, 2H, H⁶′). ¹³C NMR (100 MHz, CDCl₃): δ

3

14.54 (2C, OCH₂CH₃), 43.27 (N³CH₃), 44.54 (N⁷CH₃), 52.47 (2C,

COOCH₃), 60.85 (2C, C^6/8H₂), 61.94, 63.38 (OCH₂CH₃), 73.49 (2C,

C

^2/4H), 109.63 (4C, C⁴′^/6′), 150.33 (2C, C³′), 160.62, 165.54, 168.53,

203.57. HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 527.25057.

Obsd: m/z 527.24987. HR-ESI (positive mode, [M + Na]⁺). Calcd:

m/z 549.23252. Obsd: m/z 549.23210. Elem anal (report IPMB23,

[M]). Calcd: C, 61.58; H, 6.51; N, 10.64. Obsd: C, 61.18; H, 6.56; N,

10.55.

Bispidone (p-Me)N₂py₂B4 (C₂₅H₃₀N₄O₅, M_W= 466.53 g mol⁻¹).

Piperidone P4 (620.7 mg, 1.51 mmol, 1.0 equiv) was suspended in 15

mL of THF and heated to 50 °C, whereupon 0.13 mL of an aqueous

solution of methylamine (40%, 0.12 g, 1.51 mmol, 1.0 equiv) and then

0.23 mL of an aqueous solution of formaldehyde (37%, 0.25 g, 3.02

mmol, 2.0 equiv) were added. The suspension was heated to reﬂux for

1 h. After the mixture was allowed to cool to ambient temperature, the

solvent was removed under vacuum. Methanol was added to the

resulting white foam. The solution was allowed to stand at −6 °C for

crystallization. The white solid was ﬁltered and washed with cold

methanol. A white crystalline solid was obtained as the pure product in

a yield of 48.3% (0.34 g, 0.73 mmol). ¹H NMR (400 MHz, CDCl₃): δ

2.02 (s, 3H, N³CH₃), 2.29 (s, 3H, N⁷CH₃), 2.45 (s, 6H, pyCH₃), 2.55

Bispidone (p-MeS)N₂py₂B7 (C₂₅H₃₀N₄O₅S₂, M_w= 530.66 g mol⁻¹).

Piperidone P7 (1.74 g, 3.66 mmol, 1.0 equiv) was suspended in THF

and heated to 50 °C. At this temperature, an aqueous solution of

methylamine (40%, 0.28 g, 0.31 mL, 3.66 mmol, 1.0 equiv) and an

aqueous solution of formaldehyde (37%, 0.59g, 0.54 mL, 7.32 mmol,

2.0 equiv) were added consecutively to the suspension and heated to

reﬂux for 1 h. After allowed to cool to ambient temperature, the

solvent was removed under vacuum, and the resulting residue was

taken up in ethanol. A solid was obtained by slow evaporation of the

solvent at ambient temperature and was recrystallized from hot

methanol to aﬀord a white solid as the pure product in a yield of 31.4%

2

(d, J_H,H= 12.05 Hz, 2H, CH_axH_eq), 3.06 (d, J_H,H= 11.92 Hz, 2H,

CH_axH_eq), 3.81 (s, 6H, COOCH₃), 4.66 (s, 2H, CH), 7.04 (d, ³J_H,H

=

(0.61 g, 1.15 mmol). H NMR (600 MHz, CDCl₃): δ 2.08 (s, 3H,

1

4.89 Hz, 2H, H⁵′), 7.85 (s, 2H, H³′), 8.36 (d, J_H,H= 5.02 Hz, 2H,

H⁶′). ¹³C NMR (100 MHz, CDCl₃): δ 21.49, 43.14, 44.36, 52.43,

60.66, 62.20, 73.91, 123.99, 124.28, 147.32, 148.92, 158.61, 168.62,

203.57. HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 467.22945.

Obsd: m/z 467.22914. HR-ESI (positive mode, [M + MeOH + H]⁺).

Calcd: m/z 499.25566. Obsd: m/z 499.25526. Elem anal (report

30486, [M]). Calcd: C, 64.36; H, 6.48; N, 12.01. Obsd: C, 64.58; H,

6.54; N, 12.14.

N³CH₃), 2.26 (s, 3H, N⁷CH₃), 2.49 (d, J_H,H= 12.01 Hz, 2H,

3

2

CH_axH_eq), 2.58 (s, 6H, pySCH₃), 2.89 (d, J_H,H= 11.91 Hz, 2H,

CH_axH_eq), 3.83 (s, 6H, COOCH₃), 4.74 (s, 2H, N³CH), 7.02 (d, ³J_H,H

= 5.25 Hz, H⁵′), 8.01 (s, 2H, H³′), 8.29 (d, ³J_H,H= 5.35 Hz, 2H, H⁶′).

¹³C NMR (150 MHz, CDCl₃): δ 13.68, 43.38, 44.49, 52.54, 60.83,

61.82, 73.25, 118.94, 119.16, 148.61, 150.74, 158.65, 168.39, 203.38.

HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 531.17359. Obsd:

m/z 531.17355. HR-ESI (positive mode, [M + MeOH + H]⁺). Calcd:

m/z 563.19980. Obsd: m/z 563.19977. Elem anal (report 30544,

[M]). Calcd: C, 56.58; H, 5.70; N, 10.56. Obsd: C, 56.65; H, 5.75; N,

10.59.

Bispidone (p-MeO)N₂py₂B5 (C₂₅H₃₀N₄O₇, M_W= 498.53 g mol⁻¹).

Piperidone P5 (3.00 g, 6.77 mmol, 1.0 equiv) was suspended in 40 mL

of methanol and heated to 50 °C. Then an aqueous solution of

methylamine (40%, 0.53 g, 0.59 mL, 6.77 mL, 1.0 equiv) and an

aqueous solution of formaldehyde (37%, 1.10 g, 1.01 mL, 13.54 mmol,

2.0 equiv) were added, and the suspension was heated to reﬂux for 3 h.

The solution was concentrated to one-third of its original volume and

stored at −6 °C for several days. The precipitate formed was ﬁltered

and washed with cold methanol. This procedure can be repeated with

the mother liquor to increase the yield. The pure product was obtained

as a white solid in a yield of 54.8% (1.85 g, 3.71 mmol). ¹H NMR (400

MHz, CDCl₃): δ 2.07 (s, 3H, N³CH₃), 2.28 (s, 3H, N⁷CH₃), 2.50 (d,

Bispidone (o-MeO)N₂py₂B8 (C₂₅H₃₀N₄O₇, M_W= 498.53 g mol⁻¹).

Piperidone P8 (336.0 mg, 0.76 mmol, 1.0 equiv) was suspended in 5

mL of THF and heated to 50 °C. At this temperature, an aqueous

solution of methylamine (40%, 0.07 g, 0.08 mL, 0.91 mmol, 1.2 equiv)

and an aqueous solution formaldehyde (37%, 0.12 g, 0.11 mL, 1.52

mmol, 2.0 equiv) were added. The mixture was reﬂuxed for 2 h. The

solvent was removed in vacuo, and the resulting white foam was taken

up in methanol. Slow evaporation of the solvent aﬀorded a white

1

crystalline solid in a yield of 36.1% (0.137 g, 0.274 mmol). H NMR

²J_H,H= 12.17 Hz, 2H, CH_axH_eq), 3.00 (d, J_H,H= 12.55 Hz, 2H,

2

(600 MHz, CDCl₃): δ 2.14 (2s, 6H, N^3/7CH₃), 2.52 (d, J_H,H= 11.71

2

CH_axH_eq), 3.83 (s, 6H, COOCH₃), 3.92 (s, 6H, pyOCH₃), 4.71 (s, 2H,

Hz, 2H, CH_axH_eq), 2.90 (d, J_H,H= 10.29 Hz, 2H, CH_axH_eq), 3.83 (s,

N³CH), 6.75 (dd, ³J_H,H= 5.77 Hz, ⁴J_H,H= 2.63 Hz, 2H, H⁵′), 7.69 (d,

6H, COOCH₃/pyOCH₃), 3.85 (s, 6H, COOCH₃/pyOCH₃), 4.67 (s,

2H, N³CH), 6.64 (dd, ³J_H₃_,H= 7.20 Hz, ⁴J_H,H= 1.40 Hz, 2H, H^ar), 7.64

(br s, 2H, H^ar), 7.66 (t, J_H,H= 7.27 Hz, 2H, H^ar). ¹³C NMR (150

MHz, CDCl₃): δ 43.46, 44.25, 52.26, 53.11, 60.73, 61.99, 72.72,

109.65, 116.05, 138.73, 156.85, 163.37, 168.80, 204.46. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 499.21927. Obsd: m/z

499.21845. HR-ESI (positive mode, [M + MeOH + H]⁺). Calcd: m/z

531.24549. Obsd: m/z 531.24416. Elem anal (report 31250, [M +

¹/₃H₂O]). Calcd: C, 59.51; H, 6.13; N, 11.10. Obsd: C, 59.60; H, 6.13;

N, 10.98.

⁴J_H,H= 2.51 Hz, 2H, H³′), 8.32 (d, J_H,H= 5.65 Hz, 2H, H⁶′). ¹³C

3

NMR (100 MHz, CDCl₃): δ 43.36, 44.49, 52.48, 54.99, 60.93, 61.91,

73.53, 108.96, 109.41, 150.43, 160.70, 166.23, 168.52, 203.57. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 499.21927. Obsd: m/z

499.21893. HR-ESI (positive mode, [M + Na]⁺). Calcd: m/z

521.20122. Obsd: m/z 521.20113. HR-ESI (positive mode, [M +

MeOH + H]⁺). Calcd: m/z 531.24549. Obsd: m/z 531.24493. Elem

anal (report 29809, [M]). Calcd: C, 60.23; H, 6.07; N, 11.24. Obsd: C,

60.44; H, 6.00; N, 11.26.

Bispidone (p-EtO)N₂py₂B6 (C₂₇H₃₄N₄O₇, M_W= 526.58 g mol⁻¹).

Piperidone P6 (0.82 g, 1.74 mmol, 1.0 equiv) was suspended in 10 mL

Bispidone (m/3′-Me)N₂py₂B9 (C₂₅H₃₀N₄O₅, M_W= 466.53 g mol⁻¹).

Piperidone P9 (1.03 g, 2.50 mmol, 1.0 equiv) was suspended in THF

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and heated to 50 °C. At this temperature, an aqueous solution of

methylamine (40%, 0.19 g, 0.21 mL, 2.50 mmol, 1.0 equiv) and an

aqueous solution of formaldehyde (37%, 0.41 g, 0.38 mL, 5.00 mmol,

2.0 equiv) were added consecutively. The mixture was heated to reﬂux

for 2 h. After allowed to cool to ambient temperature, the solvent was

removed in vacuo. The residue was recrystallized from hot methanol

twice to aﬀord the pure product in a yield of 46.8% (0.55 g, 1.17

temperature, sodium borohydride (16.7 mg, 0.44 mmol, 0.5 equiv)

dissolved in a further 10 mL of a 2:1 mixture of 1,4-dioxane/water was

slowly added dropwise to the suspension. The reaction mixture was

stirred for 1 h at −6 °C and at ambient temperature for 18 h. Then the

pH was adjusted to 2 by slowly adding concentrated sulfuric acid and

stirring of the mixture was continued for 2 h at ambient temperature.

Afterward, the pH of the mixture was adjusted to 12 by slowly adding

an aqueous solution of sodium hydroxide (20 wt %) and stirring of the

mixture was continued for another 2 h at ambient temperature. The

solvent was removed in vacuo, and the resulting white residue was

taken up in methanol for crystallization. If this procedure failed, the

crude product was puriﬁed as follows: the aqueous phase was extracted

with DCM (3 × 50 mL), the combined organic phases were dried over

Na₂SO₄, ﬁltered, and concentrated, and the resulting residue was

recrystallized from hot methanol. A white crystalline solid was

obtained as the pure product in a yield of 47.1% (0.21 g, 0.41 mmol)

mmol). ¹H NMR (200 MHz, CDCl₃): δ 2.05 (s, 3H, N³CH₃), 2.47 (s,

2

6H, pyCH₃), 2.49 (N⁷CH₃), 3.57 (s, 6H, COOCH₃), 3.87 (d, J_H,H

=

12.63 Hz, 2H, N⁷CH_axH_eq), 4.25 (d, J_H,H= 12.63 Hz, 2H,

2

3

N⁷CH_axH_eq), 4.85 (s, 2H, N³CH), 7.08 (dd, J_H,H= 7.58 Hz, J_H,H

=

4.67 Hz, 2H, H⁵′), 7.45 (br d, J_H,H= 7.20 Hz, 2H, H⁴′), 8.34 (br d,

³J_H,H= 3.66 Hz, 2H, H⁶′). ¹³C NMR (50 MHz, CDCl₃): δ 18.94 (2C,

C^arCH₃), 35.50 (N³CH₃), 45.62 (N⁷CH₃), 51.99 (2C, COOCH₃),

60.00 (2C, CH₂), 65.74 (2C, C^1/5), 69.39 (2C, CH), 122.56 (2C, C^ar),

133.40 (2C, C^ar), 138.07 (2C, C^ar), 146.18 (2C, C^ar), 155.71 (2C, C^ar),

170.80 (2C, COOCH₃), 205.09 (C⁹O). HR-ESI (positive mode, [M +

H]⁺). Calcd: m/z 467.22945. Obsd: m/z 467.22895. HR-ESI (positive

mode, [M + MeOH + H]⁺). Calcd: m/z 499.25566. Obsd: m/z

499.25513. Elem anal (report IPMB_Mimo456b, [M]). Calcd: C,

64.36; H, 6.48; N, 12.01. Obsd: C, 64.33; H, 6.57; N, 11.93.

3

1

by slow evaporation of the solvent. H NMR (200 MHz, CDCl₃): δ

1.93 (s, 3H, N³CH₃), 2.26 (s, 3H, N⁷CH₃), 2.36 (d, ²J_H,H= 12.25 Hz,

2

2H, CH_axH_eq), 2.49 (d, J_H,H= 12.51 Hz, 2H, CH_axH_eq), 3.67 (s, 6H,

3

COOCH₃), 4.13 (s, 2H, N³CH), 4.78 (d, J_H,H= 5.56 Hz, 1H,

3

4

C⁹HOH), 7.23 (dd, J_H,H= 5.31 Hz, J_H,H= 2.15 Hz, 2H, H⁵′), 7.94

4

3

Bispidone N₂pyr₂anti-B10 (C₂₁H₂₄N₆O₅, M_W= 440.45 g mol⁻¹).

Piperidone P10 (0.34 g, 0.88 mmol, 1.0 equiv) was suspended in 5 mL

of THF and heated to 60 °C, and then an aqueous solution of

methylamine (40%, 0.08 g, 0.09 mL, 1.06 mmol, 1.2 equiv) and an

aqueous solution of formaldehyde (37%, 0.14 g, 0.13 mL, 1.76 mmol,

2.0 equiv) were added dropwise to the suspension consecutively. The

mixture was heated to reﬂux for 3 h. After cooling to ambient

temperature, the solvent was removed in vacuo, and the resulting

residue was recrystallized from ethyl acetate to aﬀord yellow crystals as

(d, J_H,H= 1.77 Hz, 2H, H³′), 8.38 (d, J_H,H= 5.31 Hz, 2H, H⁶′). ¹³C

NMR (50 MHz, CDCl₃): δ 43.93, 45.58, 50.58, 52.16, 52.70, 71.74,

74.38, 123.25, 123.41, 144.70, 149.40, 161.99, 172.15. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 509.13585. Obsd: m/z

509.13533. Elem anal (report 32466, [M]). Calcd: C, 54.23; H, 5.14;

N, 11.00. Obsd: C, 54.31; H, 5.42; N, 10.93.

Bispidone {C⁹OH}B5 (C₂₅H₃₂N₄O₇; M_W= 500.54 g mol⁻¹).

Bispidone B5 (0.75 g, 1.5 mmol, 1.0 equiv) was suspended in 70

mL of a 3:1 mixture of 1,4-dioxane/water and cooled to −6 °C. At this

temperature, sodium borohydride (28.4 mg, 0.75 mmol, 0.5 equiv)

dissolved in a further 10 mL of a 3:1 mixture of 1,4-dioxane/water was

slowly added dropwise to the suspension. The reaction mixture was

stirred for 1 h at −6 °C and at 0 °C overnight. Then the pH was

adjusted to 1−2 by slowly adding concentrated sulfuric acid and

stirring of the mixture was continued for 1 h at ambient temperature.

Afterward, the pH of the mixture was adjusted to 12 by slowly adding

an aqueous solution of sodium hydroxide (20 wt %) and stirring of the

mixture was continued for another 2 h at ambient temperature. The

solvent was removed in vacuo, and the resulting white residue was

taken up in 50 mL of water. The aqueous phase was extracted with

DCM (4 × 50 mL), and the combined organic phases were dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo. A white crystalline solid

was obtained as the pure product in a yield of 64.7% (485.0 mg, 0.97

mmol). ¹H NMR (200 MHz, CDCl₃): δ 1.93 (s, 3H, N³CH₃), 2.25 (s,

1

the pure anti-bispidone in a yield of 36.4% (0.14 g, 0.32 mmol). H

NMR (600 MHz, CDCl₃): δ 2.09 (s, 3H, N³CH₃), 2.26 (s, 3H,

2

N⁷CH₃), 2.93 (d, J_H,H= 11.91 Hz, 1H, N⁷CH_axH_eq), 3.17 (d, J_H,H

=

10.80 Hz, 1H, N⁷CH_axH_eq), 3.27 (d, J_H,H= 11.50 Hz, 1H,

2

N⁷CH_axH_eq), 3.54 (s, 3H, COOCH₃), 3.63 (d, J_H,H= 10.80 Hz,

2

N⁷CH_axH_eq), 3.82 (s, 3H, COOCH₃), 4.98 (br s, 1H, N³CH), 5.20 (br

s, 1H, N³CH), 8.45 (d, ³J_H,H= 2.60 Hz, 2H, H^ar), 8.46 (d, ³J_H,H= 2.65

Hz, 2H, H^ar), 8.49 (m, 1H, H^ar), 8.54 (m, 1H, H^ar), 8.63 (m, 1H, H^ar),

8.88 (br s, 1H, H^ar). ¹³C NMR (150 MHz, CDCl₃): δ 39.96, 44.25,

52.37, 52.74, 60.84, 61.24, 62.07, 65.80, 67.76, 69.62, 142.88, 142.93,

143.53, 143.58, 144.90, 146.08, 153.26, 153.56, 169.06, 169.20, 201.24.

HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 441.18864. Obsd: m/

z 441.18798. HR-ESI (positive mode, [M + Na]⁺). Calcd: m/z

463.17059. Obsd: m/z 463.16998.

Bispidone (m,m-di-Br)N₂py₂anti-B11 (C₂₃H₂₂Br₄N₄O₅, M_W

=

754.06 g mol⁻¹). Piperidone P11 (1.08 g, 1.55 mmol, 1.0 equiv)

was dissolved in 10 mL of methanol and heated to 50 °C. At this

temperature, an aqueous solution of methylamine (40%, 0.12 g, 0.13

mL, 1.55 mmol, 1.0 equiv) and an aqueous solution of formaldehyde

(37%, 0.25 g, 0.23 mL, 3.10 mmol, 2.0 equiv) were added to the

mixture. The reaction mixture was stirred at reﬂux for 1 h. After

cooling to ambient temperature, the solution was slowly concentrated

by evaporation of the solvent at ambient temperature. A yellow

crystalline solid was obtained, ﬁltered, and washed with cold methanol

to aﬀord the pure anti-bispidone in a yield of 49.7% (0.58 g, 0.77

mmol). ¹H NMR (200 MHz, CDCl₃): δ 2.20 (s, 3H, N³CH₃), 2.45 (s,

3H, N⁷CH₃), 2.36 (d, ²J_H,H= 12.26 Hz, 2H, CH_axH_eq), 2.59 (d, ²J_H,H

=

12.25 Hz, 2H, CH_axH_eq), 3.67 (s, 6H, COOCH₃), 3.89 (s, 6H,

3

pyOCH₃), 4.08 (s, 2H, N³CH), 4.78 (d, J_H,H= 5.56 Hz, 1H,

3

4

C⁹HOH), 6.72 (dd, J_H,H= 5.68 Hz, J_H,H= 2.65 Hz, 2H, H⁵′), 7.53

(d, J_H,H= 2.53 Hz, 2H, H³′), 8.28 (d, J_H,H= 5.81 Hz, 2H, H⁶′). ¹³C

NMR (50 MHz, CDCl₃): δ 43.76, 45.82, 50.72, 52.04, 52.69, 54.84,

72.04, 74.58, 108.47, 109.16, 149.66, 162.05, 166.09, 172.44. HR-ESI

(positive mode, [M + H]⁺). Calcd: m/z 501.23492. Obsd: m/z

501.23432. Elem anal (report 32193, [M]). Calcd: C, 59.99; H, 6.44;

N, 11.19. Obsd: C, 59.97; H, 6.57; N, 11.19.

4

3

General Procedure for the Complexation of Tetradentate

Bispidines with Cu²⁺. A total of 0.2 mmol of the bispidine was

suspended in 2.5 mL of acetonitrile at ambient temperature, and

Cu(ClO₄)₂·6H₂O dissolved in 2.5 mL of acetonitrile was added to the

suspension. The appearance of a dark-blue solution indicated

immediate complexation. The solution was stirred for 2 h or overnight

at ambient temperature, respectively. Crystallization was performed by

ether diﬀusion at ambient temperature. The crystals were ﬁltered,

washed with a small amount of cold acetonitrile, and dried on air.

[Cu^IIB1(NCCH₃)](ClO₄)₂(C₂₅H₂₇Cl₂CuN₇O₁₇; M_W= 831.97 g mol⁻¹).

The synthesis was performed according to the general procedure with

0.2 mmol of ligand (105.7 mg, 1.0 equiv) and 0.2 mmol of

Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of 3.5 mL

of acetonitrile. Dark-blue crystals were obtained in a yield of 88.0%

(146.7 mg, 0.176 mmol). FAB (positive mode, [B1 + Cu^II+ H₂O]⁺).

2

3H, N⁷CH₃), 3.47 (m, 2H, N⁷CH), 3.61 (d, J_H,H= 12.00 Hz, 1H,

N⁷CH), 3.65 (s, 3H, COOCH₃), 3.66 (s, 3H, COOCH₃), 4.44 (d,

²J_H,H= 11.62 Hz, N⁷CH), 5.08 (s, 1H, N³CH), 5.98 (s, 1H, N³CH),

7.96 (d, ⁴J_H,H= 2.02 Hz, 1H, H^ar), 8.06 (d, ⁴J_H,H= 2.02 Hz, 1H, H^ar),

8.54 (d, ⁴J_H,H= 2.02 Hz, 1H, H^ar), 8.55 (d, ⁴J_H,H= 2.02 Hz, 1H, H^ar).

¹³C NMR (50 MHz, CDCl₃): δ 38.45, 45.14, 52.23, 52.38, 60.25,

60.45, 60.54, 63.57, 66.99, 68.99, 118.51, 119.61, 122.24, 124.06,

142.09, 142.71, 147.39, 148.70, 154.46, 154.66, 170.16, 170.47, 199.20.

HR-ESI (positive mode, [M + H]⁺). Calcd: m/z 754.83610. Obsd: m/

z 754.83380. Elem anal (report IPMB-MM457, [M]). Calcd: C, 36.63;

H, 2.94; N, 7.43. Obsd: C, 36.75; H, 3.28; N, 7.37.

Bispidone {C⁹OH}B2 (C₂₃H₂₆Cl₂N₄O₅; M_W= 509.38 g mol⁻¹).

Bispidone B2 (0.44 g, 0.87 mmol, 1.0 equiv) was suspended in 35 mL

of a 2:1 mixture of 1,4-dioxane/water and cooled to −6 °C. At this

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Calcd: m/z 609.1. Obsd: m/z 608.9. FAB (positive mode, [B1 + Cu^II

+ H₂O + ClO₄⁻¹]⁺). Calcd: m/z 708.1. Obsd: m/z 707.9. Elem anal

(report 32380, [B1+ Cu(ClO₄)₂+ CH₃CN + 2H₂O]). Calcd: C,

34.59; H, 3.60; N, 11.30. Obsd: C, 34.72; H, 3.83; N, 11.29. UV/vis

[CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 630 (80), 955 (15). CV

(CH₃CN, rt): E_1/2= −268.5 mV (vs Fc/Fc⁺).

of acetonitrile. Blue crystals were obtained as the pure product in a

yield of 48.0% (75.0 mg, 0.096 mmol). HR-FAB (positive mode, [B8

+ Cu^I]⁺). Calcd: m/z 561.1411. Obsd: m/z 561.1400. HR-FAB

(positive mode, [B8 + Cu^I+ H₂O]⁺). Calcd: m/z 579.1516. Obsd:

m/z 579.1497. Elem anal (report 33067, [B8 + Cu(ClO₄)₂+ H₂O]).

Calcd: C, 38.55; H, 4.14; N, 7.19. Obsd: C, 38.41; H, 4.20; N, 7.12.

UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 698 (64), 962 (30).

CV (CH₃CN, rt): E_1/2= −250.0 mV (vs Fc/Fc⁺).

[Cu^IIB2(NCCH₃)](ClO₄)₂(C₂₅H₂₇Cl₄CuN₅O₁₃; M_W= 810.87 g mol⁻¹).

The synthesis was performed according to the general procedure with

0.3 mmol of ligand (152.21 mg, 1.0 equiv) and 0.3 mmol of

Cu(ClO₄)₂·6H₂O (111.16 mg, 1.0 equiv) in a total volume of 6 mL of

acetonitrile. Blue crystals were obtained in a yield of 82.3% (200.7 mg,

0.247 mmol). HR-FAB (positive mode, [B2 + Cu^I+ H₂O]⁺). Calcd:

m/z 587.0525. Obsd: m/z 587.0549. HR-FAB (positive mode, [B2 +

[Cu^IIB12(NCCH₃)](ClO₄)₂(C₂₅H₂₉Cl₂CuN₅O₁₃; M_W= 741.98 g

mol⁻¹). The synthesis was performed according to the general

procedure with 0.2 mmol of ligand (87.7 mg, 1.0 equiv) and 0.2 mmol

of Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of 4.0 mL

of acetonitrile. Blue crystals were obtained in a yield of 73.0% (108.0

mg, 0.146 mmol). HR-FAB (positive mode, [B12 + Cu^I]⁺). Calcd:

m/z 501.1200. Obsd: m/z 501.1202. HR-FAB (positive mode, [B12 +

Cu^I+ H₂O]⁺). Calcd: m/z 519.1305. Obsd: m/z 519.1349. Elem anal

(report 32467, [B12 + Cu(ClO₄)₂+ CH₃CN + H₂O]). Calcd: C,

39.51; H, 4.11; N, 9.22. Obsd: C, 39.88; H, 4.14; N, 9.61. UV/vis

[CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 626 (77), 901 (15). CV

(CH₃CN, rt): E_1/2= −410.0 mV (vs Fc/Fc⁺) proposed keto form/

−504.0 mV (vs Fc/Fc⁺) proposed hydrate form.

−

Cu^II+ ClO₄+ H₂O]⁺). Calcd: m/z 686.0011. Obsd: m/z 686.0025.

Elem anal (report 31095, [B2 + Cu(ClO₄)₂+ 2CH₃CN + H₂O]).

Calcd: C, 37.28; H, 3.71; N, 9.66. Obsd: C, 37.21; H, 3.74; N, 9.70.

UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 630 (115), 957 (21).

CV (CH₃CN, rt): E_1/2= −397.0 mV (vs Fc/Fc⁺).

[Cu^IIB3(NCCH₃)](ClO₄)₂(C₂₅H₂₇Br₂Cl₂CuN₅O₁₃; M_W= 899.77 g

mol⁻¹). The synthesis was performed according to the general

procedure with 0.2 mmol of ligand (119.25 mg, 1.0 equiv) and 0.2

mmol of Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of

5 mL of acetonitrile. Dark-blue crystals were obtained in a yield of

85.5% (154.2 mg, 0.171 mmol). HR-FAB (positive mode, [B3 + Cu^II

+ H₂O]). Calcd: m/z 676.9495. Obsd: m/z 676.9462. HR-FAB

[Cu^II{C⁹OH}B12(NCCH₃)](ClO₄)₂(C₂₅H₃₁Cl₂CuN₅O₁₃; M_W= 743.99

g mol⁻¹). The synthesis was performed according to the general

procedure with 0.2 mmol of ligand (88.1 mg, 1.0 equiv) and 0.2 mmol

of Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of 3.5 mL

of acetonitrile. Dark-blue crystals were obtained in a yield of 91.5%

(136.1 mg, 0.183 mmol). FAB (positive mode, [{C⁹OH}B12+Cu^I]⁺).

Calcd: m/z 503.1. Obsd: m/z 503.0. FAB (positive mode, [{C⁹OH}

−

(positive mode, [B3 + Cu^II+ ClO₄]⁺). Calcd: m/z 757.8874. Obsd:

m/z 757.8820. Elem anal (report 31193, [B3 + Cu(ClO₄)₂+ CH₃CN

+ H₂O]). Calcd: C, 32.72; H, 3.18; N, 7.63. Obsd: C, 32.67; H, 3.34;

N, 7.91. UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 630 (120),

957 (21). CV (CH₃CN, rt): E_1/2= −394.0 mV (vs Fc/Fc⁺).

[Cu^IIB4(NCCH₃)](ClO₄)₂(C₂₇H₃₃Cl₂CuN₅O₁₃; M_W= 770.03 g mol⁻¹).

The synthesis was performed according to the general procedure with

0.2 mmol of ligand (93.31 mg, 1.0 equiv) and 0.2 mmol of

Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of 5 mL

of acetonitrile. Dark-blue crystals were obtained in a yield of 24.5%

(38.1 mg, 0.049 mmol). HR-FAB ([B4 + Cu^I+ H₂O]). Calcd: m/z

547.1618. Obsd: m/z 547.1585. HR-FAB ([B4 + Cu^I]). Calcd: m/z

529.1512. Obsd: m/z 529.1500. Elem anal (report 31094, [B4 +

Cu(ClO₄)₂+ CH₃CN]). Calcd: C, 42.11; H, 4.32; N, 9.09. Obsd: C,

41.56; H, 4.64; N, 9.79. UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹

mol⁻¹)]: 625 (106), 912 (20). CV (CH₃CN, rt): E_1/2= −501.5 mV

(vs Fc/Fc⁺).

II

B12 + Cu⁻¹+ ClO₄]⁺). Calcd: m/z 602.1. Obsd: m/z 601.9. Elem

anal (report 32381, [{C⁹OH}B12 + Cu(ClO₄)₂+ 2H₂O]). Calcd: C,

37.38; H, 4.36; N, 7.58. Obsd: C, 37.74; H, 4.36; N, 7.66. UV/vis

[CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 626 (80), 912 (15). CV

(CH₃CN, rt): E_1/2= −475.0 mV (vs Fc/Fc⁺).

[Cu^II{C⁹OH}B2(NCCH₃)](ClO₄)₂(C₂₅H₂₉Cl₄CuN₅O₁₃; M_W= 812.88 g

mol⁻¹). The synthesis was performed according to the general

procedure with 0.056 mmol of ligand (28.4 mg, 1.0 equiv) and 0.056

mmol of Cu(ClO₄)₂·6H₂O (20.75 mg, 1.0 equiv) in a total volume of

3.0 mL of acetonitrile. Dark-blue crystals were obtained in a yield of

98.2% (44.6 mg, 0.055 mmol). FAB (positive mode, [{C⁹OH}B2 +

Cu^I]⁺). Calcd: m/z 571.1. Obsd: m/z 570.9. FAB (positive mode,

[{C⁹OH}B2 + Cu^II+ ClO₄⁻¹]⁺). Calcd: m/z 670.0. Obsd: m/z 669.8.

UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)}: 628 (84), 954 (15).

CV (CH₃CN, rt): E_1/2= −384.5 mV (vs Fc/Fc⁺).

[Cu^IIB5(NCCH₃)](ClO₄)₂(C₂₇H₃₃Cl₂CuN₅O₁₅; M_W= 802.03 g mol⁻¹).

The synthesis was performed according to the general procedure with

0.3 mmol of ligand (149.6 mg, 1.0 equiv) and 0.3 mmol of

Cu(ClO₄)₂·6H₂O (111.16 mg, 1.0 equiv) in a total volume of 5 mL

of acetonitrile. Blue crystals were obtained in a yield of 73.7% (177.3

mg, 0.221 mmol). FAB (positive mode, [B5 + Cu^I+ H₂O]⁺). Calcd:

[Cu^II{C⁹OH}B5(NCCH₃)](ClO₄)₂(C₂₇H₃₅Cl₂CuN₅O₁₅; M_W= 804.04 g

mol⁻¹). The synthesis was performed according to the general

procedure with 0.2 mmol of ligand (100.1 mg, 1.0 equiv) and 0.2

mmol of Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of

3.5 mL of acetonitrile. Dark-blue crystals were obtained in a yield of

88.5% (142.1 mg, 0.177 mmol). HR-ESI (positive mode, [{C⁹OH}B5

+ Cu^II+ MeO⁻]⁺). Calcd: m/z 594.17509. Obsd: m/z 594.17489.

Elem anal (report 32379, [{C⁹OH}B5 + Cu(ClO₄)₂+ 2H₂O]). Calcd:

C, 37.58; H, 4.54; N, 7.01. Obsd: C, 37.51; H, 4.46; N, 6.97. UV/vis

[CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 628 (83), 900 (16). CV

(CH₃CN, rt): E_1/2= −563.5 mV (vs Fc/Fc⁺).

General in Situ Preparation of the Copper(II) Complexes

with Tetradentate Bispidines. Commercially available Cu-

(ClO₄)₂·6H₂O was dried in vacuo for 1 day and was considered dry.

A stock solution of Cu^IIwas prepared by dissolving 131.23 mg (0.5

mmol) of Cu(ClO₄)₂in 100 mL of absolute acetonitrile. Then 1 mL of

the Cu^IIstock solution (5 μmol) was added to 6 μmol of the

(substituted) N₂py₂ligand (approximately 3−4 mg, depending on the

substituent); i.e., Cu^IIand ligand are dissolved in a ratio of 5:6. An

immediate dissolution of the ligand and a pale-blue color of the

solution indicate complex formation. The solution was stirred for 30

min at ambient temperature. Then UV/vis spectra and CV

measurements were subsequently undertaken using the same solution

for both experiments.

m/z 579.2. Obsd: m/z 579.0. FAB (positive mode, [B5 + Cu^II

+

−

ClO₄+ H₂O]⁺). Calcd: m/z 678.1. Obsd: m/z 677.9. Elem anal

(report 31072, [B5 + Cu(ClO₄)₂+ CH₃CN + H₂O]). Calcd: C, 39.55;

H, 4.30; N, 8.54. Obsd: C, 39.42; H, 4.30; N, 8.50. UV/vis [CH₃CN,

rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 629 (116), 912 (21). CV (CH₃CN, rt):

E_1/2= −563.0 mV (vs Fc/Fc⁺).

[Cu^IIB7(NCCH₃)](ClO₄)₂(C₂₇H₃₅Cl₂CuN₅O₁₄S₂; M_W= 852.17 g

mol⁻¹). The synthesis was performed according to the general

procedure with 0.2 mmol of ligand (106.13 mg, 1.0 equiv) and 0.2

mmol of Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of

6 mL of acetonitrile. Dark-blue crystals were obtained in a yield of

91.0% (151.8 mg, 0.182 mmol). HR-ESI (positive mode, [B7 + Cu^II+

−

ClO₄+ MeOH]⁺). Calcd: m/z 724.07009. Obsd: m/z 724.09040.

HR-FAB (positive mode, [B7 + Cu^I+ H₂O]⁺). Calcd: m/z 611.1059.

Obsd: m/z 611.1094. Elem anal (report 31073, [B7 + Cu(ClO₄)₂+

2CH₃CN + H₂O]). Calcd: C, 38.99; H, 4.29; N, 9.41. Obsd: C, 39.12;

H, 4.31; N, 9.42. UV/vis [CH₃CN, rt; λ, nm (ε, L cm⁻¹mol⁻¹)]: 630

(126), 920 (19). CV (CH₃CN, rt): E_1/2= −517.5 mV (vs Fc/Fc⁺).

[Cu^IIB8(NCCH₃)](ClO₄)₂(C₂₇H₃₃Cl₂CuN₅O₁₅; M_W= 802.03 g mol⁻¹).

The synthesis was performed according to the general procedure with

0.2 mmol of ligand (100.0 mg, 1.0 equiv) and 0.2 mmol of

Cu(ClO₄)₂·6H₂O (74.11 mg, 1.0 equiv) in a total volume of 5.0 mL

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(21) Blower, P. J.; Lewis, J. S.; Zweit, J. Nucl. Med. Biol. 1996, 23,

957−980.

ASSOCIATED CONTENT

* Supporting Information

■

S

(22) Schmidt-Ott, W.-D. Z. Phys. 1959, 154, 286−293.

(23) Shokeen, M.; Anderson, C. J. Acc. Chem. Res. 2009, 42, 832−

841.

UV/vis/near-IR and EPR spectra as well as CVs of the reported

copper(II) complexes, a list of pK_avalues of substituted

pyridine groups, details of the AOM calculations, structural data

of the DFT calculations, details of the EDA analyses, Mulliken

charges, details of the crystallographic work (CCDC 921801−

921825 contains the supplementary crystallographic data; these

data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_

request/cif), and all relevant NMR and mass spectra. This

material is available free of charge via the Internet at http://

pubs.acs.org.

(24) Paterson, B. M.; Donnelly, P. S. Chem. Soc. Rev. 2011, 40,

3005−3018.

(25) Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J.

Chem. Rev. 2010, 110, 2858−2902.

(26) Juran, S.; Walther, M.; Stephan, H.; Bergmann, R.; Steinbach, J.;

Kraus, W.; Emmerling, F.; Comba, P. Bioconjugate Chem. 2009, 20,

347−359.

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(28) Comba, P.; Sickmuller, A. F. Inorg. Chem. 1997, 36, 4500−4507.

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(32) von Hopffgarten, M.; Frenking, G. WIREs Comput. Mol. Sci.

2012, 2, 43−62.

AUTHOR INFORMATION

Corresponding Author

*E-mail: peter.comba@aci.uni-heidelberg.de. Fax: +49-6221-

546617.

■

(33) Zaman, N.; Guillot, R.; Sen

Tetrahedron Lett. 2008, 49, 7274−7275.

(34) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;

Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446−

2458.

́ ́

echal-David, K.; Boillot, M.-L.

Notes

The authors declare no competing ﬁnancial interest.

(35) Tamura, M.; Urano, Y.; Kikuchi, K.; Higuchi, T.; Hirobe, M.;

Nagano, T. Chem. Pharm. Bull. 2000, 48, 1514−1518.

(36) Fontena, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A.

Synth. Commun. 1995, 25, 629−633.

ACKNOWLEDGMENTS

■

Financial support by the German Science Foundation (DFG),

the University of Heidelberg, and the Helmholtz Virtual

Institute NanoTracking is gratefully acknowledged.

(37) Furukawa, S. Yakugaku Zasshi 1959, 79, 492−499.

(38) Kobayashi, G.; Furukawa, S.; Kawada, Y. Yakugaku Zasshi 1954,

74, 790.

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complexes follows the equation y = −0.01839x − 3.57837; R²

=

0.96934; the linear correlation of the Hammett coeﬃcient of the

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dx.doi.org/10.1021/ic4004214 | Inorg. Chem. 2013, 52, 6481−6501

Inorganic Chemistry

Article

substituents and the redox potential of the copper(II) complexes

follows the equation y = 0.00332x + 1.60334; R²= 0.94536.

(112) The linear correlation of the calculated electrostatic energy

(E_elstat) and the redox potential of the corresponding copper(II)

complexes follows the equation y = 0.1393x − 271.76983; R²

=

0.9666; the linear correlation of the calculated total bonding energy

(E_total) and the redox potential of the copper(II) complexes follows the

equation y = 0.13196x − 447.59138; R²= 0.93564.

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dx.doi.org/10.1021/ic4004214 | Inorg. Chem. 2013, 52, 6481−6501

Article Doi

Tuning of the properties of transition-metal bispidine complexes by variation of the basicity of the aromatic donor groups

DOI: 10.1021/ic4004214

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Full text of DOI:10.1021/ic4004214

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