Roadmap towards N-heterocyclic [2.2]paracyclophanes and their application in asymmetric catalysis

Article abstract of DOI:10.1002/ejoc.201300508

A novel family of [2.2]paracyclophane derivatives is described. Different substituted pyrazole, triazole and pyrimidine moieties were introduced to the [2.2]paracyclophane scaffold and the products were characterized spectroscopically and by X-ray structu

Full text of DOI:10.1002/ejoc.201300508

FULL PAPER
DOI: 10.1002/ejoc.201300508
Roadmap towards N-Heterocyclic [2.2]Paracyclophanes and Their Application
in Asymmetric Catalysis
Mark Busch,[a] Merve Cayir,[b] Martin Nieger,[c] Werner R. Thiel,[b] and Stefan Bräse*[a,d]
Keywords: Cyclophanes / Ligand design / Nitrogen heterocycles / Asymmetric catalysis
A novel family of [2.2]paracyclophane derivatives is de-
scribed. Different substituted pyrazole, triazole and pyrimid-
ine moieties were introduced to the [2.2]paracyclophane
scaffold and the products were characterized spectroscopi-
cally and by X-ray structure analysis. These compounds are
promising ligands for application in asymmetric catalysis. We
show here that one of these ligands can catalyze asymmetric
conjugate addition. Furthermore a palladium complex was
synthesized by using
phane ligand.
a hydroxy-pyrazolyl[2.2]paracyclo-
have been published by Gibson, Paradies and David.[6–8]
Further investigations, for example, by Noyori and
Soai,[9,10] showed that catalysis with [2.2]paracyclophane
zinc complexes having a nitrogen–oxygen coordination mo-
tif is feasible. In recent years, we combined the rigidity of
the [2.2]paracyclophane backbone with novel metal coordi-
nating moieties and described the asymmetric conjugate ad-
dition (ACA) of diethylzinc to cinnamaldehyde utilizing dif-
ferent [2.2]paracyclophane ligands.[11–13] In this publication
we present a series of new [2.2]paracyclophane derivatives
bearing N-heterocycles with various substitution patterns.
Such structures are possible candidates for the ACA of al-
dehydes. The synthesis and characterization of novel para-
cyclophane derivatives is discussed. A few years ago, Thiel
et al. published similar systems based on the phenyl ana-
logue.[14,15] We here transferred some of their methods to
the [2.2]paracyclophane backbone, improved their methods,
and expanded the product spectrum. The main goal of this
work was the synthesis of N-heterocycles of types 1, 2 and
3 (Figure 1). Because all the starting materials are accessible
as enantiopure paracyclophane derivatives, translation to
chiral, nonracemic products should be possible in all cases,
and one such example is discussed here.
Introduction
[2.2]Paracyclophane and its derivatives are a unique class
of compounds due to their rigidity. They can be function-
alized easily by following the established routes of arene
chemistry,[1] and their application ranges from asymmetric
catalysis all the way to surface modification through chemi-
cal vapour deposition (CVD). A first breakthrough in para-
cyclophane chemistry was worked out by Gorham in the
mid-1960s, who developed the use of pyrolysis and subse-
quent polymerization.[2] Those findings allowed the applica-
tion of [2.2]paracyclophane in surface modification chemis-
try. For example, coating methods with [2.2]paracyclophane
derivatives were reported that led to numerous publications
on CVD surface modification.[3] In addition, there are
many other applications of [2.2]paracyclophanes in polymer
chemistry and materials science.[4]
Another field of application of paracyclophane chemis-
try is in asymmetric reactions and catalysis. Unlike ferro-
cene, [2.2]paracyclophane derivatives exhibit planar chiral-
ity with just one substituent. A breakthrough in stereoselec-
tive paracyclophane chemistry came through the synthesis
of the enantiopure C2-symmetric paracyclophane ligand
PhanePhos.[5] Substantial reviews in the field of catalysis
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: stefan.braese@kit.edu
Homepage: https://www.ioc.kit.edu/braese/
[b] Department of Chemistry, TU Kaiserslautern,
Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern, Germany
[c] Department of Chemistry, University of Helsinki,
P. O. Box 55 (A.I. Virtasen aukio 1), 00014, Finland
[d] Institute of Toxicology and Genetics, Karlsruhe Institute of
Technology,
Hermann-von-Helmholtz-Platz 1,
76344 Eggenstein-Leopoldshafen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300508.
Figure 1. Target structures: pyrazole 1, triazole 2 and pyrimidine 3
derivatives.
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Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
Scheme 1. Synthesis of 3-dimethylaminopropen-2-onyl[2.2]paracyclophane (6) and its conversion into pyrazol-3-yl[2.2]paracyclophane
(1a).
Results and Discussion
Starting from commercially available [2.2]paracyclo-
phane, 4-acetyl[2.2]paracyclophane (4) is accessible in good
yields through Friedel–Crafts acylation following a reaction
pathway reported by Cram.[16] Inspired by Thiel’s method
to access pyrazole derivatives, 3-dimethyaminoprop-2-en-
one 6 was synthesized, which underwent ring-closure to
pyrazole 1a upon treatment with hydrazine (Scheme 1). The
reaction time could be reduced by conducting the reaction
under microwave conditions.
To fully explore the scope of this reaction, a range of
hydrazines were employed (Scheme 2, Table 1). As an exam-
ple for this class of compounds, the crystal structure of 8g
is shown in Figure 2.[17]
Figure 2. Molecular structure of 8g (displacement parameters are
drawn at 50% probability level).
(DMF–DMA; 5) leading to hydroxy-dimethylaminopro-
pen-2-onyl[2.2]paracyclophane (10). The molecular struc-
ture of 10 was determined by single-crystal structure analy-
sis (Figure 3). By implementing similar microwave reaction
conditions to those described above, hydroxy-pyrazolyl[2.2]-
paracyclophane (11a), as the next target structure, could be
Scheme 2. General procedure for the synthesis of pyrazolyl[2.2]-
paracyclophanes 8b–g.
accessed (Scheme 3).
Table 1. Summary of the synthesis of pyrazolyl[2.2]paracyclo-
phanes 8b–g.
Entry
Hydrazine
R
Yield [%]
Product
1
2
3
4
5
6
7b
7c
7d
7e
7f
Me
8
8b[a]
8c[a]
8d
CH2CF3
cHex
Ph
Bn
4-BrC6H4
92
32
71
61
74
8e
8f
7g
8g[a]
[a] Crystal structure given in the Supporting Information.
After the successful synthesis of monofunctionalized pyr-
azolyl[2.2]paracyclophane derivatives, we focused on hy-
droxy-pyrazolyl[2.2]paracyclophanes. Rozenberg et al. de-
veloped
a route to acetyl-hydroxy[2.2]paracyclophane
(AHPC, 9), which is one of the intermediate structures
towards hydroxy-pyrazolyl[2.2]paracyclophanes.[18] In this
three-step, racemic sequence, with a total yield of 62%,
AHPC (9) is accessible from formyl[2.2]paracyclophane
(Rieche formylation) and subsequent hydroxy[2.2]paracy-
clophane (Dakin oxidation).[19]
Figure 3. Molecular structure of 10 (displacement parameters are
drawn at 50% probability level).
As described for the above intermediates, other hydraz-
ines were applied under microwave conditions to yield fur-
Corresponding to the procedure by Thiel, AHPC (9) was ther substituted hydroxy-pyrazolyl[2.2]paracyclophanes.
treated with N,N-dimethylformamide–dimethyl acetal Depending on the nature of the hydrazine, two pyrazole
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Scheme 3. Synthesis of hydroxy-pyrazolyl[2.2]paracyclophane (11a).
Scheme 4. Synthesis of two pyrazole isomers.
isomers were obtained that could not always be separated
by using standard purification methods (Scheme 4,
1
Table 2).[20] The isomer ratios A/B were determined by H
NMR spectroscopic analysis.
Table 2. Comparison of hydroxy-pyrazolyl[2.2]paracyclophanes.
Entry Hydrazine
R
Yield OH shift Ratio
Major
product
[%][a] [δ, ppm] A/B[b]
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7h
7i
7j
H
Me
CH2CF3
cHex
Ph
Bn
tBu
2-Py
CH2-2-Py
95
99
90
57
79
43
47
4
10.70
5.41
5.35
5.34
5.47
1:0
1:13
1:5
11a
12b
12c
12d
12e
12f
11h
11i
0:1[d]
0:1
5.28
1:40[c]
13:1
22:1
0:1
11.25
10.71
[e]
63
–
12j
Figure 4. Molecular structure of 12e in the solid state (displacement
parameters are drawn at 50% probability level).
[a] Isolated yield of the major isomer or isomer mixture. [b] Isomer
ratio: A: substituent R at the α-nitrogen atom, B: at the β-nitrogen
atom (Scheme 4). [c] X-ray data of both isomers were obtained.
[d] No solid-state structure was determined; the nature of the iso-
1
mer was determined on the basis of H NMR spectroscopic analy-
sis. [e] No OH signal was detected; isomer structure determined by
X-ray crystallography.
As an example for a series of structurally characterized
N-functionalized pyrazoles with a [2.2]paracyclophane
backbone, the solid-state structures of compounds 12e and
11h are presented in Figure 4 and 5, respectively.
Carrying out the reaction with phenylhydrazine (7e) led
to the formation of isomer A (Entry 5), bearing the phenyl
residue at the α-nitrogen atom of the pyrazole with respect
to the [2.2]paracyclophane scaffold, whereas the use of hy-
drazine hydrate (7a) gave isomer B (Entry 1). Compounds
11a, 12d, 12e and 12j were isolated as pure regioisomers,
whereas all other derivatives were isolated as mixtures with
one dominant isomer. The structures were determined by
1H NMR spectroscopic analysis and supported by X-ray
structure analysis. In isomer A, one of the pyrazole nitrogen
Figure 5. Molecular structure of 11h in the solid state (displace-
ment parameters are drawn at 50% probability level, partial disor-
dering is omitted for clarity).
atoms is sterically capable of taking part in hydrogen bond- shift of the OH resonance to lower field (e.g., δ = 11.25 ppm
ing with the OH group (Figure 5), leading to a pronounced for 11h; Entry 7). This is no longer possible for isomer B,
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Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
for which this nitrogen atom is functionalized, leading to a and 17 and methyl ester 18 (Figure 8). Such systems may
high-field shift of the OH resonance (e.g., δ = 5.47 ppm for be relevant for the formation of various metal complexes.
11e).
Coordination of zinc to the hydroxyl group and the α-
nitrogen atom of the pyrazole ring is necessary for efficient
ACA catalysis, thus, isomers of type B are not suitable for
this reason because they cannot coordinate the zinc cation
in the required coordination environment. An alternative
route to isomers of type A is deprotonation of the NH-moi-
ety of 11a followed by alkylation (Scheme 5). In this case,
isomer A is exclusively formed, probably due to the forma-
tion of an O,N chelate complex with the sodium cation,
which blocks one of the nitrogen atoms for alkylation. By
doubling the amount of base and alkylating agent, this se-
quence also allows parallel alkylation of both the pyrazole
and the OH groups. The solid-state structure of compound
Figure 7. Molecular structure of 11k in the solid state (displace-
11b was elucidated by X-ray structure analysis (Figure 6).
ment parameters are drawn at 50% probability level).
Scheme 5. Synthesis of methylated pyrazolyl[2.2]paracyclophanes
(11b and 15).
Figure 8. Some further functionalized pyrazolyl[2.2]paracyclo-
phane derivatives 11k, 16, 17 and 18. Reagents and conditions: For
11k: 11a, DMF, NaH (1.1 equiv.), MOMCl (1.5 equiv.) 30 min,
room temp. For 16: 11b, DMSO, 1-fluoro-2-nitrobenzene
(1.5 equiv.), K2CO3 (3.0 equiv.), 180 °C, 5 h. For 17: 11a, 1-fluoro-
2-nitrobenzene (1.5 equiv.), K2CO3 (3.0 equiv.), 180 °C, 4 h. For 18:
12b, methyl bromoacetate (2.0 equiv.), 2 d, room temp.
As a minor side product appearing in most of the reac-
tions of hydroxyacetyl[2.2]paracyclophanes with hydrazines,
the yellow coloured chromone 20 could be identified
(Scheme 6). This compound was selectively accessible in
high yields by treatment of 10 with concentrated hydrochlo-
ric acid in dichloromethane heated to reflux.
Figure 6. Molecular structure of one of the two independent mo-
lecules of 11b in the solid state (displacement parameters are drawn
at 50% probability level).
Because reacting compound 10 with methylhydrazine
gave isomer A (12b) almost exclusively, we could directly
compare the OH resonances of both isomers: whereas 12b
gave an OH resonance at δ = 5.41 ppm, the corresponding
resonance of 11b appeared at δ = 10.90 ppm.
Scheme 6. Synthesis of the paracyclophane-chromone derivative
20.
A further example of the deprotonation–alkylation se-
quence leading to isomer A is the methoxymethyl (MOM)
protected pyrazole 11k (OH resonance at δ = 10.76 ppm).
Direct conversion AHPC (9) into another chromone de-
Figure 7 shows the molecular structure of compound 11k. rivative, 22, was observed by reacting the former with di-
Analogous arylations are possible by following protocols methylacetamide dimethylacetal (21) (Scheme 7); Figure 9
for SNAr reactions leading to the nitrophenyl derivatives 16 shows the molecular structure of 22.
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M. Busch, M. Cayir, M. Nieger, W. R. Thiel, S. Bräse
FULL PAPER
Scheme 7. Synthesis of the paracyclophane-chromone derivative
22.
Figure 10. Molecular structure of 2a in the solid state (displace-
ment parameters are drawn at 50% probability level).
Again, a range of hydrazines were used to explore the
scope of this reaction (Scheme 9), and triazole derivatives
25b–e, 25g and 25i could be obtained in acceptable yields
(Table 3).
Figure 9. Molecular structure of 22 in the solid state (displacement
parameters are drawn at 50% probability level).
Scheme 9. Synthesis of triazolyl[2.2]paracyclophanes 25b–e, 25g,
and 25i.
Table 3. Summary of the synthesis of triazolyl[2.2]paracyclophanes.
Starting with [2.2]paracyclophane amide (23), triazolyl
functionalized [2.2]paracyclophanes are accessible. Com-
pound 23 was synthesized by following a process developed
by Reich et al.,[21] involving treatment of racemic
bromo[2.2]paracyclophane with nBuLi and then with dry-
ice to give carboxy[2.2]paracyclophane.[22] The acid was ac-
tivated with SOCl2 and the acid chloride was quenched with
aqueous ammonia to give 23 in 92% yield.[23] Analogously
to AHPC (9), 23 was treated with DMF–DMA (5), to give
24, which could not be purified by column chromatography
due to decomposition. Reacting 24 with hydrazine 7a for
Entry
Hydrazine
R
Yield [%]
Product
1
2
3
4
5
6
7b
7c
7d
7e
7g
7i
Me
CH2CF3
cHex
Ph
4-BrC6H4
2-Py
53
45
64
59
47
49
25b
25c
25d[a]
25e[a]
25g
25i[a]
[a] Molecule structure given in the Supporting Information.
We then wanted to develop a method with which to ac-
1 h at 80 °C in a high-pressure vessel with acetic acid as the cess pyrimidine and pyridine derivatives of [2.2]paracyclo-
solvent led to the formation of triazole 2a (Scheme 8).[24] phanes. Treating AHPC (9) with a range of aldehydes 26a–
Figure 10 shows the molecular structure of triazolyl[2.2]- f in a base-catalyzed aldol reaction generated the six com-
paracyclophane (2a).
pounds 27a–f in quite low yields (Scheme 10, Table 4).[25]
Scheme 8. Synthesis of compound 2a from amide[2.2]paracyclophane (23).
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Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
One illustrative molecular structure of compound 27e is
presented in Figure 11.
Scheme 11. Synthesis of pyrimidine derivatives.
Scheme 10. Base-catalyzed aldol reaction with AHPC (9).
Table 4. Summary of the base-catalyzed aldol reactions.
Entry Aldehyde
R
Yield [%]
Product
1
2
3
4
5
6
26a
26b
26c
26d
26e
26f
Ph
4-FC6H4
4-CF3C6H4
4-tBuC6H4
3,5-(OMe)2-C6H3
[2.2]PC
28
11
16
15
19
3
27a[a]
27b[a]
27c
27d[a]
27e[a]
27f
[a] Molecular structure given in the Supporting Information.
Figure 12. Molecular structure of 29a in the solid state (displace-
ment parameters are drawn at 50% probability level).
Treating hydroxy-pyrazolyl[2.2]paracyclophane (11a)
with PdCl2(PhCN)2 (30) gave two diastereomers of the pal-
ladium chloride complex 31, which were characterized by
mass spectrometry (see Scheme 12 and the Supporting In-
formation).
The next target was to synthesize an enantiomerically
pure ligand for asymmetric conjugate addition (ACA). We
focused on isomers A of the pyrazole type ligands 11. This
option gave us three possible structures 11a, 11h and 11i.
Although we achieved very good yield in synthesizing 11a,
Figure 11. Molecular structure of 27e in the solid state (displace-
ment parameters are drawn at 50% probability level).
We expected to prepare pyrimidine derivatives from ami- the application of this compound was ruled out by the pos-
dines,[26] and pyridines from malononitrile, respectively.[27] sibility that the NH group might interfere in catalysis. The
Unfortunately it was not possible to purify the products by yield of 11i was too low to continue with this compound as
using conventional separation methods or HPLC. To elim- the model catalyst. Therefore, synthesis of (Sp)-11h, bearing
inate the possibility of rotamers, which can complicate the a tBu group on the pyrazole, was carried out starting from
1
NMR spectra, H NMR experiments at increased tempera- enantiopure (Sp)-formyl[2.2]paracyclophane,[19] following
tures were carried out, however, with no satisfying outcome. the steps described earlier (Schemes 3 and 4).
In all reactions, chromone 20 was formed as a side product.
To prove the catalytic activity of this new class of com-
However, reacting precursors 6 and 10 with guanidine (28a) pounds, one representative ACA was carried out with (Sp)-
or benzamidine (28b) resulted in the formation of com- 11h. Cinnamaldehyde (32) was treated with diethylzinc (33)
pounds 3 and 29 in good to excellent yields (Scheme 11).[28] and a catalytic amount of (Sp)-11h (Scheme 13). The 1,2-
Due to steric hindrance and the fact that guanidine (28a) is product was obtained with (Sp)-11h in excellent yields; no
a better nucleophile than benzamidine (28b), the yields of side product from 1,4-addition was observed. Chiral phase
the aminopyrimidines were superior to those of the phenyl- HPLC analysis revealed 24% of enantiomeric excess (ee).
pyrimidines. These compounds will form part of further re- Although the ee value was not as high as expected, ligand
search in asymmetric catalysis. Figure 12 shows the molecu- (Sp)-11h still acted as a catalyst, which opens up possibil-
lar structure of 29a.
ities to optimize structures and reaction conditions.
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Scheme 12. Reaction of racemic 11a to form two diastereomers of the 1-hydroxy(2-pyrazol-3-yl)[2.2]paracyclophane palladium complex
31 (only the rac-isomer is shown for clarity).
Scheme 13. Asymmetric conjugate addition with ligand (Sp)-11h and diethylzinc of cinnamaldehyde (32).
General Procedure E for (1-Hydroxy-2-pyrimidine-4-yl)[2.2]paracy-
clophanes: A 5 mL high-pressure vessel was charged with either 6
or 10 (1.00 equiv.), phenylamidine (1.30 equiv.), sodium
and pyrimidine substituted [2.2]paracyclophane derivatives. (2.00 equiv.) and anhydrous ethanol (3 mL). The mixture was
Conclusions
We successfully synthesized various pyrazole, triazole
1
heated to 80 °C overnight, then the mixture was dried with MgSO4
and purified by column chromatography.
The X-ray structure analyses and H NMR spectra of the
pyrazole products proved that different isomers are formed,
suggesting that two mechanistic pathways are possible. Re- Compound 1a: According to general procedure C with 10 (220 mg,
720 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 1:1) to give 1a (188 mg, 95%) as
a white crystalline solid. Rf = 0.45 (cyclohexane/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 2.71–2.80 (m, 1 H, HPc), 2.86–
3.18 (m, 6 H, HPc), 3.75–3.82 (m, 1 H, HPc), 6.47–6.50 (m, 1 H, Pc-
garding the pyrazole structures, we correlated the substitu-
tion pattern with the 1H NMR signal of the hydroxyl group.
Hydroxy-pyrazolyl[2.2]paracyclophane 11a is feasible as a
ligand for metal complexes and, with one example, we
showed that these ligand systems can be used as catalysts
in asymmetric conjugate addition.
HAr), 6.56–6.70 (m, 7 H, Pc-HAr), 7.68–7.69 (m, 1 H, Pc-HAr),
12.35 (br. s, 1 H, NH) ppm. IR (DRIFT): ν = 3098 (w), 2921 (w),
˜
2848 (w), 1594 (vw), 1540 (vw), 1499 (vw), 1450 (w), 1434 (w), 1399
(w), 1342 (vw), 1299 (vw), 1204 (vw), 111 (w), 1095 (w), 1076 (vw),
1049 (w), 989 (vw), 937 (w), 903 (w), 838 (w), 770 (w), 714 (w), 670
(w), 639 (w), 618 (w), 581 (w), 517 (w), 491 (w) cm–1. MS (70 eV,
EI): m/z (%) = 274 (36) [M+], 170 (47) [C11H10N2+], 104 (16)
[C8H8+]. HRMS: calcd. for C19H18N2 274.1469; found 274.1468.
Experimental Section
General Procedure A for Aldol Derivatives: AHPC (9; 1.00 equiv.)
and aldehyde (1.00 equiv.) were dissolved in 2-propanol (2 mL) and
cooled to 0 °C, then 50% aq. KOH (2.00 equiv.) was added and the
mixture was stirred at room temperature for 12 h. The red residue
was filtered off, washed with cold 2-propanol and purified by col-
umn chromatography (cyclohexane/ethyl acetate, 50:1).
Compound 2a: According to general procedure D with 24 (38.7 mg,
130 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 2a (14.6 mg, 41%) as
1
a white solid. Rf = 0.30 (cyclohexane/ethyl acetate, 1:1). H NMR
General Procedure B for 1-Hydroxy-2-pyrazol-3-yl)[2.2]paracyclo-
(400 MHz, CDCl3): δ = 2.86–3.20 (m, 7 H, HPc), 3.92–4.01 (m, 1 H,
HPc), 6.44–6.52 (m, 2 H, Pc-HAr), 6.55–6.59 (m, 2 H, Pc-HAr),
6.60–6.65 (m, 2 H, Pc-HAr), 7.01 (s, 1 H, Pc-HAr), 8.23 (s, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 34.9, 35.0, 35.2, 35.4
(–, 4ϫ CH2), 128.7 (Cquat), 131.0, 132.4, 132.9, 132.9, 133.0, 134.4,
135.6, 136.2 (+, 8ϫ CH), 138.8, 139.4, 139.6, 140.4, 148.8 (5ϫ
phanes:
A 10 mL microwave vessel was charged with 10
(1.00 equiv.), hydrazine (8.00 equiv.) and 2-propanol (2 mL) and
the mixture was heated under microwave conditions (140 °C) for
2 h, dried with MgSO4, and purified by column chromatography.
General Procedure C for Pyrazol-3-yl[2.2]paracyclophanes: A 10 mL
microwave vessel was charged with 4 (1.00 equiv.), hydrazine
(8.00 equiv.) and 2-propanol (2 mL), and the mixture was heated
under microwave conditions (160 °C) for 2.5 h, dried with MgSO4,
and purified by column chromatography.
Cquat) ppm. IR (DRIFT): ν = 3109 (vw), 2926 (vw), 2850 (vw),
˜
1757 (vw), 1593 (vw), 1511 (vw), 1481 (vw), 1450 (vw), 1433 (vw),
1409 (vw), 1383 (vw), 1305 (vw), 1263 (vw), 1177 (vw), 1081 (vw),
1060 (vw), 983 (vw), 940 (vw), 906 (w), 881 (vw), 844 (w), 806 (w),
794 (vw), 765 (vw), 716 (w), 640 (w), 583 (vw), 514 (w), 496 (vw),
479 (vw), 3017 (vw) cm–1. MS (70 eV, EI): m/z (%) = 275 (18) [M+],
171 (5) [C10H9N3+], 104 (39) [C8H8+], 103 (2) [C8H7+], 91 (6)
[C7H7+]. HRMS: calcd. for C18H17N3 275.1422; found 275.1420.
General Procedure D for Triazol-3-yl[2.2]paracyclophanes: A 5 mL
high-pressure vessel was charged with 24 (1.00 equiv.), hydrazine
(8.00 equiv.) and glacial acetic acid (1 mL). The mixture was heated
to 80 °C for 1 h, then water was added and the mixture was ex-
tracted with ethyl acetate. The combined organic phases were dried
with MgSO4 and purified by column chromatography.
Compound 3a: According to general procedure E with 6 (43.0 mg,
140 μmol). The crude product was purified by column chromatog-
6114
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6108–6123

Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
raphy (cyclohexane/ethyl acetate, 1:1) to give 3a (41.3 mg, 98%) as
a white solid. Rf = 0.44 (cyclohexane/ethyl acetate, 1:1). H NMR
(400 MHz, CDCl3): δ = 2.79–2.85 (m, 1 H, HPc), 2.94–3.01 (m, 2 H,
Compound 8b: According to general procedure C with 6 (519 mg,
1.70 mmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 3:1) to give 8b (39.0 mg, 8%) as
1
HPc), 3.02–3.10 (m, 2 H, HPc), 3.12–3.22 (m, 2 H, HPc), 3.73–3.83 a light-yellow crystalline solid. Rf = 0.28 (cyclohexane/ethyl acetate,
(m, 1 H, HPc), 5.30 (br. s, 2 H, NH2), 6.49–6.56 (m, 2 H, Pc-HAr), 3:1). 1H NMR (300 MHz, CDCl3): δ = 2.82–2.91 (m, 3 H, HPc),
6.58–6.61 (m, 4 H, Pc-HAr), 6.83 (s, 1 H, Pc-HAr), 6.86 (d, J =
5.27 Hz, 1 H, Pc-HAr), 8.36 (d, J = 5.27 Hz, 1 H, Pc-HAr) ppm. 13
2.99–3.15 (m, 5 H, HPc), 3.65 (s, 3 H, Me), 6.46 (dd, J = 7.8, 1.3 Hz,
1 H, Pc-HAr), 6.50–6.52 (m, 2 H, Pc-HAr), 6.57–6.59 (m, 2 H, Pc-
C
NMR (100 MHz, CDCl3): δ = 34.6, 35.2, 35.3, 35.4 (–, 4ϫ CH2),
111.4, 130.8 (+, 2ϫ CH), 132.0 (Cquat), 132.3, 132.6, 132.8, 133.0,
134.5, 136.4 (+, 6ϫ CH), 138.2, 138.9, 139.4, 139.7, 139.9 (5ϫ
HAr), 6.62 (dq, J = 7.9, 1.5 Hz, 2 H, Pc-HAr), 6.70 (dd, J = 7.9,
1.5 Hz, 1 H, Pc-HAr), 7.63 (d, J = 1.5 Hz, 1 H, Pc-HAr) ppm. 13C
NMR (100 MHz, CDCl3): δ = 33.6, 35.0, 35.2, 35.4 (–, 4ϫ CH2),
36.7 (+, CH3), 105.9, 129.9 (+, 2ϫ CH), 130.2 (Cquat), 132.3, 132.4,
Cquat), 157.4 (+, CH), 162.5 (Cquat) ppm. IR (DRIFT): ν = 3302
˜
(w), 3138 (w), 3000 (w), 2920 (w), 2849 (w), 1651 (w), 1561 (m), 133.4, 134.2, 135.1 (+, 5ϫ CH), 138.5 (Cquat), 138.7 (+, CH), 139.4,
1544 (w), 1475 (w), 1452 (w), 1433 (w), 1343 (w), 1289 (w), 1217
(w), 1084 (w), 1000 (vw), 931 (vw), 901 (w), 837 (w), 813 (w), 742
139.5, 140.3, 144.4 (4ϫ Cquat) ppm. IR (DRIFT): ν = 3105 (vw),
2920 (m), 2850 (w), 1894 (vw), 1672 (w), 1592 (w), 1500 (w), 1478
˜
(w), 714 (w), 678 (w), 644 (w), 634 (w), 897 (w), 574 (w), 518 (w), (w), 1451 (w), 1432 (w), 1411 (w), 1397 (m), 1272 (w), 1228 (w),
506 (w), 485 (w), 440 (w) cm–1. MS (70 eV, EI): m/z (%) = 301 (79)
[M+], 197 (100) [C12H11N3+], 104 (2) [C8H8+]. HRMS: calcd. for
C20H19N3 301.1579; found 301.1578.
1184 (w), 1092 (w), 1069 (w), 998 (w), 951 (vw), 928 (w), 899 (m),
839 (m), 813 (m), 793 (m), 733 (m), 710 (m), 679 (w), 666 (w), 649
(m), 638 (m), 585 (m), 518 (m), 494 (m), 466 (w), 403 (w) cm–1. MS
(70 eV, EI): m/z (%) = 288 (100) [M+], 184 (86) [C12H12N2+], 169
(21) [C11H9N2+], 104 (42) [C8H8+], 103 (9) [C8H7+], 78 (5)
[C5H4N+], 77 (5) [C6H5+]. HRMS: calcd. for C20H20N2 288.1626;
found 288.1628.
Compound 3b: According to general procedure E with 6 (43.0 mg,
140 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 3b (30.0 mg, 60%) as
1
a white solid. Rf = 0.68 (cyclohexane/ethyl acetate, 3:1). H NMR
Compound 8c: According to general procedure C with 6 (35.0 mg,
110 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 8c (36 mg, 92%) as a
white crystalline solid. Rf = 0.53 (cyclohexane/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 2.73–2.79 (m, 1 H, HPc), 2.86–
2.92 (m, 2 H, HPc), 2.94–3.06 (m, 2 H, HPc), 3.08–3.18 (m, 3 H,
HPc), 4.52 (dq, J = 8.26, 0.67 Hz, 2 H, CH2CF3), 6.46 (dd, J = 7.9,
1.8 Hz, 1 H, Pc-HAr), 6.51 (d, J = 1.7 Hz, 1 H, Pc-HAr), 6.57–6.59
(m, 1 H, Pc-HAr), 6.59–6.63 (m, 3 H, Pc-HAr), 6.65–6.67 (m, 1 H,
Pc-HAr), 6.68–6.71 (m, 1 H, Pc-HAr), 7.76 (d, J = 1.8 Hz, 1 H, Pc-
(300 MHz, CDCl3): δ = 2.69–282 (m, 1 H, HPc), 2.88–3.15 (m, 6 H,
HPc), 3.75–3.86 (m, 1 H, HPc), 6.51–6.56 (m, 6 H, Pc-HAr), 6.92 (s,
1 H, Pc-HAr), 7.24 (d, J = 5.17 Hz, 1 H, Pc-HAr), 7.43–7.53 (m,
3 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 34.7, 35.2,
35.3, 35.5 (–, 4ϫ CH2), 118.8, 128.3 (2ϫ), 128.7 (2ϫ), 130.7, 131.0,
132.5, 132.6, 133.0, 133.4, 134.5, 136.3 (+, 13ϫ CH), 138.2, 138.3,
139.0, 139.4, 139.6, 140.1 (6ϫ Cquat), 157.2 (+, CH), 164.5, 166.0
(2ϫ Cquat) ppm. IR (DRIFT): ν = 3006 (vw), 2922 (w), 2849 (w),
˜
1896 (vw), 1738 (vw), 1674 (vw), 1585 (w), 1559 (w), 1536 (w), 1499
(w), 1456 (w), 1430 (w), 1404 (w), 1369 (w), 1324 (w), 1296 (w),
1238 (w), 1171 (w), 1156 (w), 1096 (vw), 1068 (vw), 1047 (vw), 1025
(w), 986 (vw), 938 (vw), 904 (w), 883 (vw), 865 (w), 849 (w), 798
(w), 765 (w), 731 (w), 712 (w), 696 (w), 672 (w), 649 (w), 634 (w),
578 (w), 512 (w), 497 (w), 463 (vw), 437 (vw) cm–1. MS (70 eV, EI):
m/z (%) = 362 (29) [M+], 259 (6) [C19H17N+], 258 (35) [C18H14N2+],
104 (43) [C8H8+], 103 (2) [C7H5N+]. HRMS: calcd. for C26H22N2
362.1781; found 362.1783.
H
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.2, 35.0, 35.1, 35.4
(–, 4ϫ CH2), 49.7 (–, q, J = 35.0 Hz, CH2), 107.1 (+, CH), 122.8
(q, J = 280.7 Hz, Cquat), 129.0 (Cquat), 129.9, 132.4, 132.4, 133.4,
134.0, 134.8, 135.5 (+, 7ϫ CH), 137.4, 139.2, 139.7, 140.8 (4ϫ
C
quat), 140.9 (+, CH), 148.8 (Cquat) ppm. 19F NMR (400 MHz,
CDCl ): δ = –70.4 (CF ) ppm. IR (DRIFT): ν = 2915 (vw), 2854
˜
3
3
(vw), 1594 (vw), 1503 (vw), 1464 (vw), 1414 (w), 1380 (w), 1317
(w), 1269 (w), 1255 (w), 1186 (w), 1146 (w), 1073 (w), 1010 (vw),
926 (w), 908 (w), 882 (vw), 835 (w), 790 (w), 724 (w), 708 (vw), 674
(vw), 661 (w), 646 (w), 587 (w), 532 (vw), 417 (w), 499 (w), 405
(vw) cm–1. MS (70 eV, EI): m/z (%) = 356 (37) [M+], 252 (18)
[C13H11F3N2+], 183 (3) [C12H11N2+], 104 (31) [C8H8+], 69 (11)
[CF3+]. HRMS: calcd. for C21H19F3N2 356.1500; found 356.1501.
Compound 6: A high-pressure vessel was charged with 4-acetyl[2.2]-
paracyclophane (4; 1.54 g, 6.16 mmol) and DMF-DMA (5;
2.56 mL, 2.20 g, 18.5 mmol) snd the mixture was heated to 120 °C
overnight. The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 6 (1.23 g, 65%) as a
light-yellow solid. Rf = 0.26 (cyclohexane/ethyl acetate, 1:1). 1H
Compound 8d: According to general procedure C with 6 (46.0 mg,
NMR (300 MHz, CDCl3): δ = 2.83–3.23 (m, 13 H, HPc and 2ϫ 150 μmol). The crude product was purified by column chromatog-
Me), 3.63–3.82 (m, 1 H, HPc), 5.32 (d, J = 12.6 Hz, 1 H, Pc-HAr),
6.40 (d, J = 7.3 Hz, 1 H, Pc-HAr), 6.45 (d, J = 7.8 Hz, 1 H, Pc-
HAr), 6.49–6.57 (m, 3 H, Pc-HAr), 6.71–6.79 (m, 2 H, Pc-HAr), 7.58
(d, J = 12.5 Hz, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3):
δ = 35.1, 35.2, 35.3, 35.6 (–, 4ϫ CH2), 37.1, 44.9 (+, 2ϫ CH3),
96.8, 131.9, 132.3, 132.3, 132.5, 132.6, 134.4, 135.6 (+, 8ϫ CH),
raphy (cyclohexane/ethyl acetate, 20:1) to give 8d (17 mg, 32%) as
a white crystalline solid. Rf = 0.53 (cyclohexane/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 0.93–1.05 (m, 1 H, cHex), 1.14–
1.26 (m, 2 H, cHex), 1.32–1.38 (m, 1 H, cHex), 1.53–1.62 (m, 3 H,
cHex), 1.87–1.92 (m, 1 H, cHex), 2.05–2.11 (m, 1 H, cHex), 2.15–
2.23 (m, 1 H, cHex), 2.83–3.05 (m, 5 H, CH, HPc), 3.08–3.17 (m,
139.1, 139.4, 139.5, 140.2, 140.5 (5ϫ Cquat), 153.4 (+, CH), 191.9 3 H, HPc), 3.87–3.95 (m, 1 H, HPc), 6.46 (dd, J = 7.9, 1.8 Hz, 1 H,
(CO, Cquat) ppm. IR (DRIFT): ν = 2924 (vw), 2849 (vw), 2325 Pc-HAr), 6.49 (d, J = 1.8 Hz, 1 H, Pc-HAr), 6.50 (s, Pc-HAr), 6.56–
˜
(vw), 2039 (vw), 1977 (vw), 1892 (vw), 1643 (w), 1567 (w), 1501
(vw), 1431 (vw), 1348 (vw), 1292 (vw), 1237 (vw), 1179 (vw), 1108
6.57 (m, 2 H, Pc-HAr), 6.61 (dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 6.67
(dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 6.71 (dd, J = 7.9, 1.8 Hz, 1 H,
(vw), 1086 (vw), 1034 (vw), 978 (vw), 935 (vw), 893 (vw), 854 (vw), Pc-HAr), 7.68 (d, J = 1.7 Hz, 1 H, Pc-HAr) ppm. 13C NMR
805 (w), 770 (vw), 752 (vw), 719 (w), 670 (vw), 621 (w), 508 (w), (100 MHz, CDCl3): δ = 24.2, 24.4, 24.8, 30.76, 32.2, 32.8, 34.1
407 (vw) cm–1. MS (70 eV, EI): m/z (%) = 305 (28) [M+], 201 (36)
(2ϫ), 34.4 (–, 9ϫ CH2), 56.7 (+, NCH), 104.7, 128.9 (–, 2ϫ CH2),
[C13H15N2O+], 157 (4) [C11H9O+], 104 (42) [C8H8+], 103 (23) 129.3 (Cquat), 131.1, 131.5, 132.3, 132.8, 133.1, 134.0 (–, 6ϫ CH2),
[C8H7+], 98 (4) [C5H8NO+]. HRMS: calcd. for C21H23NO
305.1780; found 305.1783.
137.4 (Cquat), 137.7 (–,CH2), 138.4, 138.5, 139.1, 142.1 (4ϫ
Cquat) ppm. IR (DRIFT): ν = 3088 (vw), 2916 (w), 2846 (w), 1678
˜
Eur. J. Org. Chem. 2013, 6108–6123
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6115

M. Busch, M. Cayir, M. Nieger, W. R. Thiel, S. Bräse
FULL PAPER
(w), 1591 (vw), 1527 (vw), 1500 (vw), 1450 (w), 1396 (w), 1359 (w),
1324 (w), 1260 (w), 1186 (w), 1127 (w), 1099 (w), 1064 (w), 1010
(400 MHz, [D6]DMSO): δ = 2.65–2.72 (m, 1 H, HPC), 2.81–3.03
[m, 8 H, HPC + N(CH3)2], 3.14–3.21 (m, 4 H, HPC), 3.69–3.77 (m,
(vw), 999 (w), 956 (vw), 928 (w), 895 (w), 857 (vw), 839 (w), 816 1 H, HPC), 5.34 (d, J = 12.2 Hz, 1 H, COCH), 6.23 (d, J = 7.6 Hz,
(w), 800 (w), 767 (w), 760 (w), 722 (w), 672 (w), 643 (w), 891 (w), 1 H, Pc-HAr), 6.28 (dd, J = 17.7, 1.4 Hz, 1 H, Pc-HAr), 6.39–6.46
637 (w), 510 (m), 484 (w), 462 (w), 406 (w) cm–1. MS (70 eV, EI): (m, 2 H, Pc-HAr), 6.60 (dd, J = 7.8, 1.4 Hz, 1 H, Pc-HAr), 6.85 (dd,
m/z (%) = 256 (100) [C25H28N2+], 274 (93) [C19H17N2+], 252 (28)
J = 7.7, 1.5 Hz, 1 H, Pc-HAr), 7.78 (d, J = 12.2 Hz, 1 H, CHN),
[M+], 169 (93) [C11H9N2+], 104 (41) [C8H8+]. HRMS: calcd. for 13.47 (br. s, 1 H, OH) ppm. 13C NMR (100 MHz, DMSO): δ =
C17H20N2 356.2252; found 356.2254.
29.5, 33.3, 34.6, 36.6 (–, 4ϫ CH2), 37.2, 44.8 (+, 2ϫ CH3), 96.0
(+, COCH), 123.7 (Cquat), 126.2, 127.0, 130.7, 131.8, 132.7, 136.9
(+, 6ϫ CH), 138.0, 139.1, 140.5 (3ϫ Cquat), 154.3 (+, NCH), 160.1
Compound 8f: According to general procedure C with 6 (46.0 mg,
150 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 10:1) to give 8f (33.5 mg, 61%) as
a light-yellow crystalline solid. Rf = 0.86 (cyclohexane/ethyl acetate,
1:1). 1H NMR (400 MHz, CDCl3): δ = 2.87–3.14 (m, 8 H, HPc),
5.05 (d, J = 15.0 Hz, 1 H, CH2-Ph), 5.20 (d, J = 15.0 Hz, 1 H, CH2-
Ph), 6.46–6.49 (m, 2 H, Pc-HAr), 6.56 (d, J = 1.8 Hz, 1 H, Pc-HAr),
6.63 (dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 6.73 (dd, J = 7.8, 1.8 Hz,
1 H, Pc-HAr), 6.74 (dd, J = 7.9, 1.8 Hz, 1 H, Pc-HAr), 6.81–6.86
(m, 2 H, Pc-HAr), 7.12–7.15 (m, 3 H, Pc-HAr), 7.69 (d, J = 1.8 Hz,
1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.6, 35.1,
35.2, 35.4 (–, 4ϫ CH2), 52.9 (–, CH2Ph), 106.2, 127.4, 128.3, 128.6,
128.8 (+, 5ϫ CH), 129.0 (Cquat), 129.8, 130.0 (+, 2ϫ CH), 130.1
(Cquat), 132.3, 132.4, 133.3, 134.0, 134.3, 135.2 (+, 6ϫ CH), 137.0,
138.3, 139.5 (3ϫ Cquat), 139.5 (+, CH), 140.3, 144.4 (2ϫ
(Cquat, COH), 190.5 (Cquat, CO) ppm. IR (DRIFT): ν = 2941 (vw),
˜
1879 (vw), 1623 (m), 1567 (w), 1538 (w), 1491 (vw), 1423 (w), 1400
(m), 1358 (w), 1329 (w), 1269 (w), 1230 (m), 1156 (w), 1082 (m),
1018 (w), 976 (w), 937 (w), 856 (w), 794 (w), 756 (w), 734 (w), 715
(w), 715 (w), 655 (w), 602 (w), 573 (w), 535 (w), 505 (w), 461 (vw),
402 (vw) cm–1. MS (70 eV, EI): m/z (%) = 321 (70) [M+], 217 (58)
[C13H15NO2+], 104 (100) [C8H8+], 98 (8) [C5H8NO]. C21H23NO2
(321.17): calcd. C 78.47, H 7.21, N 4.36; found C 77.78, H 7.09, N
4.08.
Compound 11a: According to general procedure B with 10 (1.17 g,
3.64 mmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 3:1) to give 11a (1.00 g, 95%) as
a white solid; m.p. = 155.4 °C. Rf = 0.59 (cyclohexane/ethyl acetate,
1:1). 1H NMR (400 MHz, CDCl3): δ = 2.55–2.65 (m, 2 H, HPc),
2.80–2.87 (m, 1 H, HPc), 2.95–3.09 (m, 2 H, HPc), 3.17–3.24 (m,
1 H, HPc), 3.45–3.52 (m, 1 H, HPc), 3.68–3.74 (m, 1 H, HPc), 6.31
(dd, J = 7.7, 1.9 Hz, 1 H, Pc-HAr), 6.32 (d, J = 7.6 Hz, 1 H, Pc-
Cquat) ppm. IR (DRIFT): ν = 3089 (w), 3064 (m), 3030 (m), 3009
˜
(m), 2928 (s), 2891 (m), 2852 (m), 1894 (vw), 1736 (m), 1701 (w),
1626 (w), 1595 (m), 1533 (w), 1497 (m), 1455 (s), 1434 (m), 1399
(s), 1359 (w), 1297 (m), 1270 (m), 1241 (m), 1204 (m), 1181 (w),
1129 (w), 1102 (m), 1061 (w), 1029 (w), 1011 (w), 928 (m), 906 (m),
842 (m), 781 (s), 727 (s), 695 (s), 673 (w), 641 (m), 593 (w), 577
(w), 518 (m), 498 (m), 457 (w) cm–1. MS (70 eV, EI): m/z (%) = 364
(1) [M+], 104 (3) [C8H8+], 103 (2) [C8H7+], 91 (85) [C7H7+], 78 (9)
[C5H4N+], 77 (48) [C6H5+]. HRMS: calcd. for C26H24N2 364.1939;
found 364.1942.
H
Ar), 6.42 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.48 (dd, J = 7.9, 1.8 Hz,
1 H, Pc-HAr), 6.57 (d, J = 2.5 Hz, 1 H, HPy), 6.58–6.60 (m, 1 H,
Ar), 7.03 (dd, J = 7.8, 1.9 Hz, 1 H, HAr), 7.63 (d, J = 2.5 Hz, 1 H,
H
HPy), 10.23 (br. s, 1 H, NH), 10.70 (br. s, 1 H, OH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 30.8, 34.0, 34.3, 35.2 (–, 4ϫ CH2), 106.4
(+, NHCHCH), 118.7 (Cquat), 126.6, 127.5 (+, 2ϫ CH), 127.6
(Cquat), 129.0, 129.9, 132.1, 132.9, 134.4 (+, 5ϫ CH), 138.2, 139.4,
139.9 (3ϫ Cquat), 151.0 (Cquat, NHNC), 154.6 (Cquat, CO) ppm. IR
Compound 8g: According to general procedure C with 6 (48.0 mg,
160 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 20:1) to give 8g (51 mg, 74%) as
a light-yellow crystalline solid. Rf = 0.53 (cyclohexane/ethyl acetate,
3:1). 1H NMR (400 MHz, CDCl3): δ = 2.41–2.54 (m, 2 H, HPc),
2.74–2.78 (m, 2 H, HPc), 3.04–3.13 (m, 4 H, HPc), 6.32 (d, J =
7.8 Hz, 1 H, Pc-HAr), 6.47 (dd, J = 7.9, 1.9 Hz, 1 H, Pc-HAr), 6.51–
6.56 (m, 2 H, Pc-HAr), 6.59 (d, J = 1.8 Hz, 1 H, Pc-HAr), 6.62 (dd,
J = 7.8, 1.9 Hz, 1 H, Pc-HAr), 6.69 (dd, J = 7.3, 1.8 Hz, 2 H, Pc-
HAr), 6.96–7.00 (m, 2 H, Pc-HAr), 7.29–7.33 (m, 2 H, Pc-HAr), 7.83
(d, J = 1.8 Hz, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3):
δ = 33.6, 34.8, 35.1, 35.4 (–, 4ϫ CH2), 108.2 (+, CH), 120.4 (Cquat),
128.88 (2ϫ), 129.6 (+, 3ϫ CH), 129.7 (Cquat), 131.5 (2ϫ), 132.2,
132.3, 133.0, 133.3, 134.5, 135.4 (+, 8ϫ CH), 138.7, 139.2, 139.4,
139.6, 140.2 (5ϫ Cquat), 140.77 (+, CH), 143.9 (Cquat) ppm. IR
(DRIFT): ν = 3363 (vw), 2940 (w), 1851 (vw), 1608 (vw), 1567
˜
(vw), 1524 (vw), 1501 (vw), 1429 (w), 1278 (vw), 1238 (w), 1182
(w), 1146 (vw), 1088 (w), 1061 (vw), 1012 (w), 985 (vw), 958 (vw),
936 (vw), 925 (vw), 875 (vw), 801 (w), 770 (w), 750 (w), 709 (w),
667 (w), 600 (vw), 566 (w), 513 (w), 466 (vw) cm–1. MS (70 eV, EI):
m/z (%)
=
290 (22) [M+], 223 (5) [C16H15O+], 186 (27)
[C11H10N2O+], 104 (16) [C8H8+], 68 (14) [C3H3N2+ + H], 42 (100).
HRMS: calcd. for C19H18N2O 290.1419; found 290.1420.
Compound 11b: Hydroxy-pyrazolyl[2.2]paracyclophane (11a;
100 mg, 340 μmol) was dissolved in anhydrous THF (1 mL), and
NaH (13; 17.0 mg, 690 μmol) was added at 0 °C. In a period of 2 h,
the mixture was warmed to room temperature. MeI (14; 40.0 μL,
690 μmol) in anhydrous THF (1 mL) was added slowly and the
mixture was stirred for 12 h at room temperature. The solvent was
removed under reduced pressure and the residue was dissolved in
ethyl acetate and NaHCO3 was added. The aqueous phase was
extracted with ethyl acetate (3ϫ 20 mL) and the combined organic
layers were dried with MgSO4 and purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 3:1) to give 11b (50.5 mg, 49%) as
(DRIFT): ν = 2920 (vw), 2849 (vw), 1589 (vw), 1531 (vw), 1488
˜
(w), 1453 (w), 1403 (w), 1377 (w), 1097 (vw), 1072 (w), 1010 (w),
991 (w), 924 (w), 898 (w), 865 (vw), 827 (m), 782 (m), 721 (w), 704
(w), 675 (vw), 638 (w), 589 (w), 552 (vw), 515 (w), 486 (vw), 467
(vw), 454 (w), 411 (vw), 309 (vw) cm–1. MS (70 eV, EI): m/z (%) =
428 (82) [M+], 349 (73) [C25H21N2+], 324 (36) [C17H13BrN2+], 245
(73) [C17H13N2+], 104 (55) [C8H8+], 78 (10) [Br]. HRMS: calcd. for
C25H21BrN2 428.0888; found 428.0886.
1
a white solid. Rf = 0.81 (cyclohexane/ethyl acetate, 2:1). H NMR
(400 MHz, CDCl3): δ = 2.57–2.67 (m, 2 H, HPc), 2.78–2.86 (m, 1 H,
HPc), 2.95–3.09 (m, 2 H, HPc), 3.17–3.24 (m, 1 H, HPc), 3.45–3.52
(m, 1 H, HPc), 3.70–3.76 (m, 1 H, HPc), 3.99 (s, 3 H, Me), 3.29 (d,
J = 7.7 Hz, 1 H, HPc), 6.33 (dd, J = 7.7, 1.9 Hz, 1 H, Pc-HAr), 6.41
(d, J = 7.7 Hz, 1 H, Pc-HAr), 6.48 (d, J = 2.3 Hz, 1 H, HPy), 6.49
(dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 6.59 (dd, J = 7.8, 1.8 Hz, 1 H,
HAr), 7.05 (dd, J = 7.7, 1.9 Hz, 1 H, HAr), 7.40 (d, J = 2.3 Hz,
Compound 10: A high-pressure vessel was charged with AHPC (9;
0.470 g, 1.75 mmol) and DMF–DMA (5; 0.610 mL, 0.520 g,
4.37 mmol). The mixture was heated to 90 °C for 20 min, then the
crude product was purified by column chromatography (cyclohex-
ane/ethyl acetate, 1:1) to give 10 (523 mg, 93%) as a yellow solid;
m.p. 220.2 °C. Rf = 0.37 (cyclohexane/ethyl acetate, 1:1). 1H NMR 1 H, HPy-NMe), 10.89 (br. s, 1 H, OH) ppm. 13C NMR (100 MHz,
6116
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Eur. J. Org. Chem. 2013, 6108–6123

Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
CDCl3): δ = 30.8, 34.1, 34.2, 35.3 (–, 4ϫ CH2), 39.0 (+, CH3), 129.8, 132.2, 132.9, 134.9 (+, 5ϫ CH), 138.2 (Cquat), 139.0 (+,CH),
106.7 (+, CH), 119.0 (Cquat), 126.5, 127.6 (+, 2ϫ CH), 127.6 139.8, 139.9 (2ϫ Cquat), 148.3 (+,CH), 153.2, 154.7 (2ϫ
(Cquat), 129.8, 130.7, 132.1, 132.9, 134.1 (+, 5ϫ CH), 138.2, 139.1,
Cquat) ppm. IR (DRIFT): ν = 3147 (vw), 3013 (vw), 2925 (w), 2850
˜
139.9, 150.7, 154.7 (5ϫ Cquat) ppm. IR (DRIFT): ν = 2920 (vw), (w), 1742 (vw), 1594 (m), 1577 (m), 1521 (m), 1470 (m), 1447 (s),
˜
2848 (vw), 1604 (vw), 1570 (vw), 1518 (vw), 1491 (vw), 1433 (w),
1412 (w), 1341 (vw), 1309 (vw), 1290 (w), 1225 (w), 1147 (vw), 1127
1413 (m), 1348 (m), 1293 (m), 1236 (w), 1147 (w), 1123 (w), 1087
(w), 1055 (m), 1018 (m), 992 (w), 969 (w), 954 (w), 931 (w), 907
(vw), 1076 (vw), 1016 (vw), 962 (vw), 931 (vw), 877 (vw), 772 (w), (w), 878 (w), 771 (s), 730 (m), 715 (s), 662 (m), 620 (w), 582 (m),
688 (w), 665 (w), 598 (vw), 578 (vw), 564 (vw), 540 (vw), 512 (w),
512 (m), 464 (w), 405 (w) cm–1. MS (70 eV, EI): m/z (%) = 367
464 (vw), 435 (vw) cm–1. MS (70 eV, EI): m/z (%) = 304 (75) [M+],
(100) [M+], 263 (100) [C16H13N3O+], 185 (10) [C11H9N2O+], 119
200 (100) [C12H12N2O+], 104 (7) [C8H8+], 81 (6) [C4H5N2+]. (5) [C8H7O+], 104 (56) [C8H8+], 78 (16) [C5H4N+], 77 (6) [C6H5+].
HRMS: calcd. for C20H20N2O 304.1576; found 304.1578.
HRMS: calcd. for C24H21N3O 367.1685; found 367.1682.
Compound 11h: According to general procedure B with 10 (250 mg,
780 μmol). The crude product was purified by column chromatog-
Compound 11k: In a high-pressure vessel, 11a (127 mg, 440 μmol)
was dissolved in anhydrous DMF (2 mL), and NaH (13; 12.0 mg,
raphy (pentane/ethyl acetate, 5:1) to give 11h (127 mg, 47%) as a 480 μmol) and MOMCl (50.0 μL, 660 μmol) were added. The mix-
yellow crystalline solid. Rf = 0.74 (pentane/ethyl acetate, 4:1). 1H
ture was stirred at room temperature for 30 min and quenched with
NMR (400 MHz, CDCl3): δ = 1.70 (s, 9 H, tBu), 2.56–2.66 (m, water. The solution was extracted with ethyl acetate (3ϫ 20 mL)
2 H, HPc), 2.77–2.84 (m, 1 H, HPc), 2.96–3.11 (m, 2 H, HPc), 3.18– and dried with MgSO4. The crude product was purified by column
3.26 (m, 1 H, HPc), 3.44–3.53 (m, 1 H, HPc), 3.71–3.80 (m, 1 H, chromatography (cyclohexane/ethyl acetate, 3:1) to give 11k
HPc), 6.25 (dd, J = 7.7, 1.8 Hz, 1 H, Pc-HAr), 6.31 (d, J = 7.7 Hz,
1 H, Pc-HAr), 6.43 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.47–6.49 (m, 2 H, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.56–2.65 (m, 2 H, HPc),
Pc-HAr), 6.58 (dd, J = 8.0, 1.7 Hz, 1 H, Pc-HAr), 7.06 (dd, J = 7.7, 2.80–2.87 (m, 1 H, HPc), 2.97–3.10 (m, 2 H, HPc), 3.17–3.24 (m,
1.8 Hz, 1 H, Pc-HAr), 7.07 (d, J = 1.8 Hz, 1 H, Pc-HAr), 11.25 (br. s, 1 H, HPc), 3.44 (s, 3 H, Me), 3.46–3.53 (m, 1 H, HPc), 3.68–3.74 (m,
(80 mg, 55%) as a white solid. Rf = 0.50 (cyclohexane/ethyl acetate,
1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.7 (+, 3ϫ
CH3), 31.0, 34.0, 34.1, 35.4 (–, 4ϫ CH2), 58.6 [C(CH3), Cquat],
105.7 (+,CH), 119.3 (Cquat), 126.4, 126.5, 127.3 (+, 3ϫ CH), 127.6
(Cquat), 129.6, 132.0, 133.0, 133.8 (+, 4ϫ CH), 138.2, 139.1, 139.8,
1 H, HPc), 5.48 (q, J = 10.9, 6.1 Hz, 2 H, OCH2), 6.30 (dd, J = 7.8,
1.8 Hz, 1 H, Pc-HAr), 6.32 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.43 (d, J
= 7.7 Hz, 1 H, Pc-HAr), 6.49 (dd, J = 7.9, 1.6 Hz, 1 H, Pc-HAr),
6.59 (dd, J = 8.8, 2.5 Hz, 2 H, Pc-HAr), 7.05 (dd, J = 7.7, 1.7 Hz,
1 H, Pc-HAr), 7.62 (d, J = 2.5 Hz, 1 H, Pc-HAr), 10.76 (br. s, 1 H,
150.0, 154.8 (5ϫ Cquat) ppm. IR (DRIFT): ν = 2972 (w), 2928 (m),
˜
1676 (vw), 1601 (w), 1568 (w), 1498 (w), 1475 (w), 1420 (m), 1364 OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.8, 34.0, 34.3, 35.3
(m), 1343 (m), 1288 (m), 1231 (m), 1147 (w), 1124 (m), 1099 (w), (–, 4ϫ CH2), 57.0 (+, OCH3), 81.9 (–, CH2), 108.2 (+, CH), 118.6
1065 (w), 1019 (m), 960 (w), 935 (w), 878 (w), 796 (w), 771 (m), (Cquat), 126.6, 127.5 (+, 2ϫ CH), 127.7 (Cquat), 129.7, 130.6, 132.1,
714 (m), 663 (m), 643 (m), 611 (m), 593 (w), 576 (w), 512 (m), 465
133.0, 134.4 (+, 5ϫ CH), 138.1, 139.4, 139.9, 151.5, 154.7 (5ϫ
(w), 419 (vw) cm–1. MS (70 eV, EI): m/z (%) = 346 (1) [M+], 268
Cquat) ppm. IR (DRIFT): ν = 2930 (w), 1733 (vw), 1598 (w), 1567
˜
(23) [C23H26N2O+], 104 (27) [C8H8+], 77 (4) [C6H5+], 57 (8) (w), 1516 (w), 1498 (w), 1484 (w), 1412 (m), 1327 (w), 1291 (w),
[C4H9+]. HRMS: calcd. for C23H26N2O 346.2045; found 346.2044.
1240 (w), 1214 (w), 1188 (w), 1149 (w), 1108 (m), 1059 (m), 1042
(w), 1018 (w), 989 (w), 962 (vw), 940 (w), 919 (w), 880 (w), 778
(m), 740 (m), 715 (m), 687 (m), 659 (m), 624 (w), 601 (w), 579 (w),
563 (w), 513 (m), 437 (vw) cm–1. MS (70 eV, EI): m/z (%) = 334
(53) [M+], 230 (46) [C13H14N2O2+], 185 (18) [C11H9N2O+], 104 (25)
[C8H8+], 45 (100) [C2H5O+]. HRMS: calcd. for C21H22N2O2
334.1681; found 334.1682.
Compound (Sp)-11h: According to general procedure B with (Sp)-
10 (402 mg, 1.25 mmol). The crude product was purified by column
chromatography (ethyl acetate/cyclohexane, 50:1) to give (Sp)-11h
(190 mg, 44%) as a yellow crystalline solid; [α]2D0 = –208 (c =
1
1.6 mg/mL, EtOAc); Rf = 0.47 (ethyl acetate/cyclohexane, 5:1). H
NMR (400 MHz, CDCl3): δ = 1.70 (s, 9 H, tBu), 2.51–2.64 (m,
2 H, HPc), 2.72–2.83 (m, 1 H, HPc), 2.91–3.10 (m, 2 H, HPc), 3.14– Compound 12b: According to general procedure B with 10 (965 mg,
3.24 (m, 1 H, HPc), 3.43–3.50 (m, 1 H, HPc), 3.68–3.81 (m, 1 H, 300 μmol). The reaction gave 12b (869 mg, 95%) as a white crystal-
HPc), 6.24 (dd, J = 7.7, 1.5 Hz, 1 H, Pc-HAr), 6.29 (d, J = 7.7 Hz,
line solid. 1H NMR (400 MHz, CDCl3): δ = 2.45–2.54 (m, 1 H,
1 H, Pc-HAr), 6.41 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.44–6.48 (m, 2 H, HPc), 2.61–2.73 (m, 1 H, HPc), 2.82–2.92 (m, 3 H, HPc), 3.10–3.17
Pc-HAr), 6.54–6.57 (m, 1 H, Pc-HAr), 7.01–7.04 (m, 1 H, Pc-HAr), (m, 2 H, HPc), 3.37–3.45 (m, 1 H, HPc), 3.59 (s, 3 H, Me), 5.41
7.56 (d, J = 2.45 Hz, 1 H, Pc-HAr), 11.22 (br. s, 1 H, OH) ppm.
(br. s, 1 H, OH), 6.33 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.52 (d, J =
7.7 Hz, 1 H, Pc-HAr), 6.60–6.70 (m, 4 H, Pc-HAr), 6.91–6.95 (m,
1 H, Pc-HAr), 7.73 (d, J = 1.9 Hz, 1 H, Pc-HAr) ppm. IR (DRIFT):
Compound 11i: According to general procedure B with 10 (168 mg,
520 μmol). The crude product was purified by column chromatog-
raphy (pentane/ethyl acetate, 5:1) to give 11i (7.7 mg, 4%) as an
ν = 2924 (w), 2851 (vw), 1591 (vw), 1566 (vw), 1500 (vw), 1459
˜
(vw), 1433 (vw), 1410 (w), 1386 (w), 1283 (vw), 1243 (vw), 1175
(w), 1138 (vw), 1087 (vw), 1046 (vw), 1011 (vw), 979 (vw), 931
(vw), 876 (vw), 843 (vw), 780 (w), 710 (w), 680 (vw), 651 (w), 581
(vw), 515 (w), 566 (vw), 438 (vw) cm–1. MS (70 eV, EI): m/z (%) =
304 (80) [M+], 199 (100) [C12H12N2O+], 104 (15) [C8H8+]. HRMS:
calcd. for C20H20N2O 304.1576; found 304.1577.
1
orange crystalline solid. Rf = 0.90 (pentane/ethyl acetate, 2:1). H
NMR (400 MHz, CDCl3): δ = 2.60–2.68 (m, 2 H, HPc), 2.84–2.92
(m, 1 H, HPc), 2.98–3.11 (m, 2 H, HPc), 3.19–3.26 (m, 1 H, HPc),
3.46–3.53 (m, 1 H, HPc), 3.70–3.77 (m, 1 H, HPc), 6.35 (d, J =
7.7 Hz, 1 H, Pc-HAr), 6.38 (dd, J = 7.8, 1.9 Hz, 1 H, Pc-HAr), 6.47
(d, J = 7.7 Hz, 1 H, Pc-HAr), 6.50 (dd, J = 7.8, 1.6 Hz, 1 H, Pc-
HAr), 6.60 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.73 (d, J = 2.7 Hz, Compound 12c: According to general procedure B with 10 (300 mg,
1 H, Pc-HAr), 7.76 (dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 7.24–7.27 930 μmol). The crude product was purified by column chromatog-
(m, 1 H, Pc-HAr), 7.89–7.94 (m, 1 H, Pc-HAr), 8.01 (d, J = 8.2 Hz, raphy (pentane/ethyl acetate, 5:1) to give 12c (12 mg, 90%) as a
1 H, Pc-HAr), 8.47–8.48 (m, 1 H, Pc-HAr), 8.65 (d, J = 2.7 Hz, 1 H, yellow crystalline solid. Rf = 0.80 (pentane/ethyl acetate, 2:1). 1H
Pc-HAr), 10.71 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ
NMR (400 MHz, CDCl3): δ = 2.39–2.47 (m, 1 H, HPc), 2.66–2.74
= 30.8, 34.0, 34.3, 35.4 (–, 4ϫ CH2), 109.3, 112.0 (+, 2ϫ CH), (m, 1 H, HPc), 2.83–2.89 (m, 3 H, HPc), 3.10–3.17 (m, 2 H, HPc),
118.3 (Cquat), 121.6, 126.7, 127.4 (+, 3ϫ CH), 127.7 (Cquat), 127.8, 3.36–3.46 (m, 1 H, HPc), 4.47 (m, 2 H, CH2), 5.36 (br. s, 1 H, OH),
Eur. J. Org. Chem. 2013, 6108–6123
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6117

M. Busch, M. Cayir, M. Nieger, W. R. Thiel, S. Bräse
FULL PAPER
6.35 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.56 (d, J = 7.9 Hz, 1 H, Pc-
HAr), 6.64–6.71 (m, 3 H, Pc-HAr), 6.74 (d, J = 1.8 Hz, 1 H, Pc-
HAr), 6.92–6.94 (m, 1 H, Pc-HAr), 7.85 (d, J = 1.8 Hz, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.6, 32.8, 34.0, 34.8
(–, 4ϫ CH2), 49.5 (q, J = 35 Hz, CH2CF3), 106.6 (+, CH), 115.3
(Cquat), 122.8 (q, J = 280 Hz, CF3), 126.8 (+, CH), 126.9 (Cquat),
128.0, 129.6, 132.7, 133.7, 137.6 (+, 5ϫ CH), 138.4, 139.4, 140.1,
140.5 (4ϫ Cquat), 141.3 (+, CH), 152.1 (Cquat) ppm. IR (DRIFT):
m/z (%) = 366 (64) [M+], 262 (68) [C17H14N2O+], 261 (100)
[C17H13N2O+], 245 (3) [C17H13N2+], 104 (20) [C8H8+], 102 (1)
[C8H6+], 77 (5) [C6H5+]. HRMS: calcd. for C25H22N2O 366.1732;
found 366.1733.
Compound 12f: According to general procedure B with 10 (158 mg,
490 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 10:1) to give 12f (80 mg, 43%) as
a yellow crystalline solid. Rf = 0.32 (cyclohexane/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 2.41–2.49 (m, 1 H, HPc), 2.61–
2.68 (m, 1 H, HPc), 2.70–2.77 (m, 1 H, HPc), 2.78–2.86 (m, 2 H,
ν = 2929 (w), 2854 (w), 1596 (w), 1568 (w), 1501 (w), 1460 (w),
˜
1411 (m), 1382 (m), 1318 (m), 1251 (s), 1181 (m), 1151 (s), 1104
(m), 1030 (m), 994 (w), 927 (m), 834 (w), 781 (m), 718 (m), 670
(m), 642 (m), 582 (m), 515 (m), 438 (w), 402 (w) cm–1. MS (70 eV,
EI): m/z (%) = 372 (58) [M+], 268 (23) [C13H11F3N2O+], 267 (60)
[C13H10F3N2O+], 185 (3) [C11H9N2O+], 104 (100) [C8H8+], 83 (2)
[C2H2F3+], 77 (7) [C6H5+]. HRMS: calcd. for C21H19F3N2O
372.1449; found 372.1447.
HPc), 3.08–3.16 (m, 2 H, HPc), 3.33–3.43 (m, 1 H, HPc), 4.93 (d, J
= 14.8 Hz, 1 H, CH2-Ph), 5.09 (d, J = 14.8 Hz, 1 H, CH2-Ph), 5.27
(s, 1 H, OH), 6.33 (d, J = 7.8 Hz, 1 H, Pc-HAr), 6.52 (d, J = 7.7 Hz,
1 H, Pc-HAr), 6.63 (dq, J = 7.8, 1.7 Hz, 2 H, Ph), 6.66 (d, J =
1.9 Hz, 1 H, Pc-HAr), 6.71 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.85–
6.89 (m, 2 H, Pc-HAr), 6.92 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr),
7.14–7.14 (m, 3 H, Pc-HAr), 7.77 (d, J = 1.8 Hz, 1 H, Pc-HAr) ppm.
13C NMR (100 MHz, CDCl3): δ = 30.7, 33.1, 34.0, 34.8, 53.0 (–,
5ϫ CH2), 105.3 (+, CH), 116.3, 126.4 (2ϫ Cquat), 126.5, 127.6,
128.0, 129.7, 132.6, 133.6 (+, 10ϫ CH), 136.4 (Cquat), 137.2 (+,
CH), 137.3, 138.6 (2ϫ Cquat), 139.8 (+, CH), 140.4, 140.9, 151.8
(3ϫ Cquat), 148.3 (+, CH), 153.2, 154.7 (2ϫ Cquat) ppm. IR
Compound 12d: According to general procedure
B with 10
(55.0 mg, 170 μmol). The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 10:1) to give 12d
(36 mg, 57%) as a yellow crystalline solid. Rf = 0.38 (cyclohexane/
ethyl acetate, 5:1). 1H NMR (400 MHz, CDCl3): δ = 0.92–1.07 (m,
1 H, cHex), 1.13–1.26 (m, 2 H, cHex), 1.35–1.43 (m, 1 H, cHex),
1.51–1.66 (m, 3 H, cHex), 1.79–1.87 (m, 1 H, cHex), 1.95–2.09 (m,
2 H, cHex), 2.47–2.59 (m, 1 H, cHex), 2.62–2.72 (m, 1 H, HPc),
2.78–2.92 (m, 3 H, HPc), 3.08–3.16 (m, 2 H, HPc), 3.34–3.45 (m,
1 H, HPc), 3.67–3.80 (m, 1 H, HPc), 5.34 (s, 1 H, OH), 6.32 (d, J =
7.7 Hz, 1 H, Pc-HAr), 6.52 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.61–6.71
(m, 4 H, Pc-HAr), 6.91 (d, J = 7.9 Hz, 1 H, Pc-HAr), 7.77 (d, J =
1.6 Hz, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.1,
25.4, 25.7, 30.7 (–, 4ϫ CH2), 32.0, 32.9, 33.6, 34.1, 34.9 (–, 4ϫ
CH2, cHex), 57.6 (+, CH, cHex), 104.4 (+, CH), 116.4, 126.2 (2ϫ
Cquat), 126.3, 128.0, 129.8, 132.5, 133.7 (+, 5ϫ CH), 135.9 (Cquat),
137.1 (+, CH), 138.5 (Cquat), 139.3 (+, CH), 140.4, 141.0, 151.7
(DRIFT): ν = 2920 (w), 2849 (w), 1886 (vw), 1640 (w), 1567 (w),
˜
1497 (w), 1454 (w), 1432 (w), 1410 (w), 1297 (w), 1275 (w), 1241
(w), 1207 (w), 1144 (w), 1098 (vw), 1083 (w), 1032 (w), 998 (vw),
979 (vw), 933 (w), 873 (vw), 842 (vw), 778 (w), 707 (m), 694 (w),
663 (w), 588 (w), 516 (w), 467 (w), 436 (vw) cm–1. MS (70 eV, EI):
m/z (%) = 380 (41) [M+], 289 (2) [C19H17N2O+], 276 (65)
[C18H16N2O+], 185 (13) [C11H9N2O+], 157 (1) [C10H9N2+], 104 (60)
[C8H8+], 91 (18) [C7H7+], 78 (12) [C5H4N+], 77 (11) [C6H5+].
HRMS: calcd. for C26H24N2O 380.1889; found 380.1887.
Compound 12j: According to general procedure B with 10 (62.0 mg,
190 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 2:1) to give 12j (45.7 mg, 63%) as
a yellow crystalline solid. Rf = 0.13 (cyclohexane/ethyl acetate, 2:1).
1H NMR (400 MHz, CDCl3): δ = 2.59–2.67 (m, 2 H, HPc), 2.77–
2.84 (m, 1 H, HPc), 2.68–2.95 (m, 2 H, HPc), 3.04–3.18 (m, 2 H,
(3ϫ Cquat) ppm. IR (DRIFT): ν = 3502 (vw), 2924 (w), 2851 (w),
˜
1596 (vw), 1567 (vw), 1500 (vw), 1449 (w), 1409 (w), 1356 (vw),
1319 (vw), 1261 (vw), 1206 (vw), 1167 (vw), 1142 (vw), 1121 (vw),
1098 (vw), 1029 (vw), 994 (vw), 979 (vw), 929 (vw), 893 (vw), 875
(vw), 781 (w), 760 (vw), 717 (vw), 684 (vw), 661 (vw), 581 (vw),
518 (w), 446 (vw), 422 (vw), 401 (vw) cm–1. MS (70 eV, EI): m/z
H
Pc), 3.33–3.43 (m, 1 H, HPc), 5.07 (dd, J = 15.7 Hz, 2 H, CH2Py),
6.27 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.46 (d, J = 7.7 Hz, 1 H, Pc-
Ar), 6.61 (dd, J = 7.8, 1.7 Hz, 1 H, Pc-HAr), 6.67 (dd, J = 7.8,
(%)
=
372 (100) [M+], 268 (27) [C17H20N2O+], 289 (3)
H
[C19H17N2O+], 185 (74) [C11H9N2O+], 104 (12) [C8H8+], 83 (100)
[C6H11+]. HRMS: calcd. for C25H28N2O 372.2202; found 372.2201.
1.8 Hz, 1 H, Pc-HAr), 6.72 (d, J = 1.8 Hz, 1 H, Pc-HAr), 6.77 (dd,
J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.82 (d, J = 7.8 Hz, 1 H, Pc-HAr),
6.91 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 7.06–7.11 (m, 1 H, Pc-HAr),
7.52 (dt, J = 15.4, 7.7, 1.8 Hz, 1 H, Pc-HAr), 7.78 (d, J = 1.8 Hz,
1 H, Pc-HAr), 8.39 (d, J = 4.8 Hz, 1 H, Pc-HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 30.4, 33.0, 34.2, 35.0 (–, 4ϫ CH2), 54.0
(–, CH2Py), 105.5 (+, CH), 117.4 (Cquat), 121.7, 122.6, 126.4 (+,
3ϫ CH), 127.3 (Cquat), 128.3, 130.0, 132.5, 133.5, 136.9, 137.1 (+,
6ϫ CH), 138.5, 139.0 (2ϫ Cquat), 140.3 (+, CH), 140.4, 141.0 (2ϫ
Cquat), 149.0 (+, CH), 152.5, 156.1 (2ϫ Cquat) ppm. IR (DRIFT):
Compound 12e: According to general procedure B with 10 (300 mg,
930 μmol). The crude product was purified by column chromatog-
raphy (pentane/ethyl acetate, 10:1) to give 12e (268 mg, 79%) as an
1
orange crystalline solid. Rf = 0.72 (pentane/ethyl acetate, 2:1). H
NMR (400 MHz, CDCl3): δ = 2.25–2.33 (m, 1 H, HPc), 2.35–2.42
(m, 1 H, HPc), 2.61–2.80 (m, 3 H, HPc), 3.06–3.20 (m, 2 H, HPc),
3.36–3.46 (m, 1 H, HPc), 5.47 (br. s, 1 H, OH), 6.04 (d, J = 7.7 Hz,
1 H, Pc-HAr), 6.45 (d, J = 7.7 Hz, 1 H, Pc-HAr), 6.58 (s, 2 H, Pc-
HAr), 6.70 (d, J = 8.0 Hz, 1 H, Pc-HAr), 6.84 (d, J = 1.8 Hz, 1 H,
Pc-HAr), 6.94 (d, J = 8.0 Hz, 1 H, Pc-HAr), 7.03–7.08 (m, 2 H, Pc-
HAr), 7.16–7.20 (m, 3 H, Pc-HAr), 7.93 (d, J = 1.8 Hz, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.7, 33.0, 34.1, 34.6
(–, 4ϫ CH2), 106.5 (+,CH), 116.3 (Cquat), 124.77 (+, 2ϫ CH),
126.1 (Cquat), 126.5, 127.2, 128.0, 128.4, 129.4, 132.5, 133.7, 137.1
(+, 9ϫ CH), 137.4, 138.7, 139.5, 140.2 (4ϫ Cquat), 140.8 (+,CH),
ν = 3015 (vw), 2961 (vw), 2936 (w), 1597 (vw), 1559 (w), 1527 (vw),
˜
1503 (vw), 1477 (w), 1435 (w), 1415 (w), 1396 (w), 1300 (w), 1271
(w), 1243 (vw), 1211 (w), 1192 (w), 1104 (w), 1091 (w), 1072 (vw),
1053 (vw), 1004 (vw), 995 (w), 978 (w), 942 (w), 926 (w), 884 (w),
868 (w), 840 (vw), 818 (w), 795 (w), 776 (w), 757 (w), 744 (w), 720
(w), 672 (w), 632 (w), 594 (w), 585 (w), 524 (w), 508 (w), 467 (vw),
442 (vw), 407 (vw), 2855 (vw), 1891 (vw) cm–1. MS (70 eV, EI): m/z
(%) = 381 (100) [M+], 303 (3) [C20H19N2O+], 289 (2) [C19H17N2O+],
199 (59) [C12H11N2O+], 185 (11) [C11H9N2O+], 104 (9) [C8H8+], 92
(2) [C6H6N2+], 80 (3) [C4H4N2+], 78 (3) [C5H4N+]. HRMS: calcd.
for C25H23N3O 381.1841; found 381.1840.
141.2, 151.3 (2ϫ Cquat) ppm. IR (DRIFT): ν = 3503 (w), 2936 (w),
˜
1744 (vw), 1597 (w), 1568 (vw), 1497 (w), 1453 (vw), 1433 (vw),
1408 (w), 1380 (w), 1308 (w), 1253 (vw), 1197 (w), 1161 (w), 1143
(w), 1087 (w), 1069 (vw), 1047 (vw), 1016 (w), 989 (vw), 972 (vw),
921 (w), 874 (vw), 834 (vw), 803 (w), 765 (m), 720 (w), 693 (w), Compound 15: Hydroxy-pyrazolyl[2.2]paracyclophane (11a;
651 (w), 583 (w), 514 (w), 448 (m), 420 (w) cm–1. MS (70 eV, EI): 76.0 mg, 260 μmol) was dissolved in anhydrous THF (1 mL), and
6118
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Eur. J. Org. Chem. 2013, 6108–6123

Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
NaH (13; 35.0 mg, 1.44 mmol) was added at 0 °C. In a period of
2 h, the mixture was warmed to room temperature. MeI (14;
30.0 μL, 520 μmol) in anhydrous THF (1 mL) was added slowly
and the mixture was stirred for 12 h at room temperature. The sol-
vent was removed under reduced pressure and the residue was dis-
solved in ethyl acetate and NaHCO3 was added. The aqueous
phase was extracted with ethyl acetate (3ϫ 20 mL) and the com-
bined organic layers were dried with MgSO4 and purified by col-
umn chromatography (cyclohexane/ethyl acetate, 3:1) to give 15
(80.9 mg, 98%) as a white solid. Rf = 0.19 (cyclohexane/ethyl acet-
added and the mixture was extracted with ethyl acetate (3ϫ
20 mL). The combined organic layers were dried with MgSO4 and
purified by column chromatography (cyclohexane/ethyl acetate,
5:1) to give 17 (200 mg, 34%) as a yellow solid. Rf = 0.26 (cyclohex-
ane/ethyl acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.59–2.66
(m, 1 H, HPc), 2.72–2.80 (m, 1 H, HPc), 2.83–2.90 (m, 1 H, HPc),
2.95–3.02 (m, 2 H, HPc), 3.04–3.12 (m, 1 H, HPc), 3.19–3.28 (m,
1 H, HPc), 3.71 (m, 1 H, HPc), 6.45 (d, J = 8.4 Hz, 1 H, Pc-HAr),
6.54–6.58 (m, 1 H, HAr), 6.60–6.65 (m, 2 H, HAr), 6.70 (d, J =
7.9 Hz, 1 H, Pc-HAr), 6.75 (dd, J = 7.8, 1.7 Hz, 1 H, Pc-HAr), 6.92–
ate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.62–2.75 (m, 2 H, HPc), 6.96 (m, 1 H, HAr), 7.04 (d, J = 2.5 Hz, 1 H, Pc-HAr), 7.15–7.22
2.76–2.82 (m, 1 H, HPc), 2.85–2.09 (m, 1 H, HPc), 3.00–3.06 (m, (m, 2 H, HAr), 7.44–7.52 (m, 2 H, HAr), 7.60–7.65 (m, 1 H, HAr),
1 H, HPc), 3.13–3.20 (m, 1 H, HPc), 3.30–3.36 (m, 1 H, HPc), 3.38 7.71 (d, J = 7.7 Hz, 1 H, Pc-HAr), 7.87 (dd, J = 8.0, 1.2 Hz, 1 H,
(s, 3 H, NMe), 3.60–3.67 (m, 1 H, HPc), 3.96 (s, 3 H, OMe), 6.45
(q, J = 7.8 Hz, 2 H, Pc-HAr), 6.54–6.60 (m, 2 H, Pc-HAr), 6.66–6.68
(m, 1 H, Pc-HAr), 6.67 (d, J = 2.2 Hz, 1 H, HPy), 6.86 (dd, J = 7.9,
1.6 Hz, 1 H, Pc-HAr), 7.63 (d, J = 2.2 Hz, 1 H, HPy-NMe) ppm.
13C NMR (100 MHz, CDCl3): δ = 29.8, 33.2, 33.5 (–, 4ϫ CH2),
37.9 (+, NCH3), 59.5 (+, OCH3), 106.5 (+, CH), 127.1 (Cquat),
128.1, 128.8, 129.2, 129.8 (+, 4ϫ CH), 130.4 (Cquat), 131.6, 131.7,
133.6 (+, 3ϫ CH), 138.4, 138.6, 140.4, 147.4, 156.0 (5ϫ
Pc-HAr), 7.91 (dd, J = 8.2, 1.6 Hz, 1 H, Pc-HAr) ppm. MS (70 eV,
EI): m/z (%) = 532 (87) [M+], 306 (10) [C17H12N3O3+], 104 (9)
[C8H8+]. HRMS: calcd. for C31H24N4O5 532.1747; found 532.1750.
Compound 18: A high-pressure vessel was charged with 12b
(40.0 mg, 0.130 mmol), methyl bromoacetate (25.0 μL, 40.0 mg,
260 μmol), potassium carbonate (36.0 mg, 260 μmol) and DMF
(1 mL). The mixture was stirred for 2 d at room temperature, then
the crude product was purified by column chromatography (cyclo-
hexane/ethyl acetate, 3:1) to give 18 (98%) as a yellow compound.
Rf = 0.42 (cyclohexane/ethyl acetate, 3:1). 1H NMR (300 MHz,
CDCl3): δ = 2.50–2.60 (m, 1 H, HPc), 2.69–2.92 (m, 4 H, HPc),
3.07–3.21 (m, 2 H, HPc), 3.44–3.55 (m, 1 H, HPc), 3.61 (s, 3 H,
NMe), 3.62 (s, 3 H, OMe), 3.91 (q, J = 15.1 Hz, 2 H, OCH2), 6.40–
6.47 (m, 1 H, Pc-HAr), 6.51–6.57 (m, 1 H, Pc-HAr), 6.62–6.63 (m,
2 H, Pc-HAr, HPy), 6.68–6.72 (m, 2 H, Pc-HAr), 6.84–6.91 (m, 1 H,
Pc-HAr), 7.61–7.66 (m, 1 H, HPy) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.3, 33.0, 34.4, 34.7 (–, 4ϫ CH2), 36.7 (+, NCH3),
51.8 (+, OCH3), 70.1 (–, OCH2), 107.7, 129.6, 129.9, 130.4, 132.1
(+, 5ϫ CH), 132.5 (Cquat), 133.3, 136.8, 138.3 (+, 3ϫ CH), 138.7,
139.1, 140.2, 141.9, 155.4 (5ϫ Cquat), 169.4 (Cquat, CO) ppm. IR
Cquat) ppm. IR (DRIFT): ν = 2923 (m), 2850 (w), 1596 (vw), 1558
˜
(vw), 1511 (w), 1501 (w), 1460 (w), 1432 (w), 1407 (m), 1386 (m),
1330 (w), 1302 (vw), 1240 (m), 1223 (m), 1183 (w), 1145 (w), 1123
(w), 1073 (w), 1035 (m), 997 (w), 987 (w), 956 (vw), 928 (w), 892
(w), 873 (w), 801 (m), 772 (m), 757 (m), 715 (m), 690 (w), 672 (w),
610 (w), 581 (w), 520 (m), 468 (w), 450 (vw), 408 (vw) cm–1. MS
(70 eV, EI): m/z (%) = 318 (100) [M+], 214 (20) [C13H14N2O+], 81
(26) [C4H5N2+]. HRMS: calcd. for C21H22N2O 318.1732; found
318.1734.
Compound 16: A high-pressure vessel was charged with 11b
(320 mg, 1.05 mmol), 1-fluoro-2-nitrobenzene (170 μL, 1.58 mmol),
anhydrous K2CO3 (436 mg, 3.16 mmol) and anhydrous DMSO
(2 mL). The mixture was heated at 180 °C for 5 h, then water was
added and the mixture was extracted with ethyl acetate (3ϫ
20 mL). The combined organic layers were dried with MgSO4 and
purified by column chromatography (cyclohexane/ethyl acetate,
5:1) to give 16 (360 mg, 81%) as a brown solid. Rf = 0.23 (cyclohex-
ane/ethyl acetate, 5:1). 1H NMR (400 MHz, CDCl3): δ = 2.57–2.68
(DRIFT): ν = 2929 (w), 2853 (w), 1762 (m), 1678 (vw), 1595 (vw),
˜
1557 (vw), 1500 (w), 1459 (w), 1428 (m), 1400 (m), 1282 (w), 1261
(w), 1174 (m), 1103 (w), 1079 (m), 1011 (w), 993 (w), 964 (w), 948
(w), 926 (m), 896 (w), 848 (w), 795 (m), 764 (w), 714 (m), 664 (w),
651 (w), 605 (w), 585 (w), 519 (m), 474 (w), 420 (w) cm–1. MS
(70 eV, EI): m/z (%) = 376 (100) [M+], 272 (4) [C15H16N2O3+], 257
(m, 2 H, HPc), 2.81–2.92 (m, 2 H, HPc), 2.94–3.02 (m, 1 H, HPc), (5) [C14H13N2O3+], 198 (6) [C12H10N2O+], 183 (7) [C12H11N2+], 104
3.03–3.14 (m, 1 H, HPc), 3.18–3.28 (m, 1 H, HPc), 3.71–3.81 (m,
1 H, HPc), 3.85 (s, 3 H, Me), 6.42–6.48 (m, 1 H, Pc-HAr), 6.54–6.64
(m, 3 H, Pc-HAr), 6.65–6.74 (m, 2 H, Pc-HAr), 6.75–6.79 (m, 1 H,
Pc-HAr), 6.89–6.95 (m, 1 H, Pc-HAr), 7.12–7.17 (m, 1 H, Pc-HAr),
7.18–7.23 (m, 1 H, Pc-HAr), 7.28–7.33 (m, 1 H, Pc-HAr), 7.86–7.93
(m, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.2,
34.2, 34.3, 34.4 (–, 4ϫ CH2), 38.9 (+, NCH3), 107.6, 116.6, 120.7,
125.4 (+, 4ϫ CH), 128.8 (Cquat), 129.7, 130.1, 130.3 (+, 3ϫ CH),
132.1 (Cquat), 132.7, 132.9, 133.0, 134.1, 134.9 (+, 5ϫ CH), 138.5,
139.3, 139.6, 142.7, 147.0, 148.9, 151.5 (7ϫ Cquat) ppm. IR
(37) [C8H8+]. HRMS: calcd. for C23H24N2O3 376.1787; found
376.1789.
Compound 20: Compound 10 (200 mg, 620 μmol) was solved in an-
hydrous dichloromethane (2 mL) and added to a high-pressure ves-
sel charged with conc. HCl (1.5 mL). The mixture was heated to
40 °C for1 h, then quenched with distilled H2O (3 mL). The mix-
ture was extracted with dichloromethane (3ϫ 5 mL) and the or-
ganic layers were dried with MgSO4. The solvent was removed un-
der reduced pressure to give 20 (165 mg, 97%). Rf = 0.48 (cyclohex-
ane/ethyl acetate, 1:1). 1H NMR (400 MHz, CDCl3): δ = 2.79–2.88
(m, 2 H, HPC), 2.97–3.05 (m, 1 H, HPC), 3.07–3.12 (m, 2 H, HPC),
3.15–3.20 (m, 1 H, HPC), 3.56–3.63 (m, 1 H, HPC), 4.57–4.62 (m,
1 H, HPC), 6.23–6.27 (m, 2 H, Pc-HAr), 6.38–6.40 (m, 1 H, Pc-HAr),
6.42–6.44 (m, 1 H, Pc-HAr), 6.54–6.56 (m, 1 H, Pc-HAr), 6.63 (d, J
= 7.6 Hz, 1 H, COCH), 6.79 (d, J = 7.6 Hz, 1 H, OCH), 7.80 (d, J
= 5.8 Hz, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
30.4, 33.9, 34.0, 35.4 (–, 4ϫ CH2), 114.1 (+, CHCO), 126.7 (Cquat),
126.8 (+, CH), 128.8 (Cquat), 130.5, 131.5, 133.1, 133.7, 137.6 (+,
5ϫ CH), 138.8, 139.9, 143.4 (3ϫ Cquat), 152.9 (+, CHOC), 156.5
(DRIFT): ν = 2928 (w), 2852 (vw), 1734 (vw), 1603 (w), 1519 (m),
˜
1476 (w), 1451 (w), 1414 (w), 1389 (w), 1344 (m), 1307 (w), 1250
(m), 1232 (m), 1159 (w), 1145 (w), 1122 (w), 1088 (w), 1040 (w),
1010 (w), 967 (w), 938 (w), 884 (w), 858 (w), 830 (w), 796 (w), 770
(w), 740 (m), 715 (w), 675 (w), 635 (w), 582 (w), 518 (w), 467 (vw),
429 (vw) cm–1. MS (70 eV, EI): m/z (%) = 425 (100) [M+], 321 (3)
[C18H15N3O3+], 275 (44) [C18H15N2O+], 199 (17) [C12H11N2O+],
104 (9) [C8H8+]. HRMS: calcd. for C26H23N3O3 425.1739; found
425.1736.
Compound 17: A high-pressure vessel was charged with 11a
(320 mg, 1.10 mmol), 1-fluoro-2-nitrobenzene (170 μL, 1.65 mmol),
anhydrous K2CO3 (457 mg, 3.31 mmol) and anhydrous DMSO
(2 mL). The mixture was heated at 180 °C for 4 h, then water was
(Cquat, CHOC), 179.2 (Cquat, CO) ppm. IR (DRIFT): ν = 2923 (m),
˜
2851 (w), 1632 (s), 1578 (m), 1499 (w), 1474 (s), 1430 (m), 1410
(m), 1391 (m), 1342 (s), 1300 (m), 1240 (m), 1210 (m), 1122 (w),
1056 (m), 999 (w), 981 (w), 941 (m), 893 (w), 867 (m), 827 (m), 797
Eur. J. Org. Chem. 2013, 6108–6123
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6119

M. Busch, M. Cayir, M. Nieger, W. R. Thiel, S. Bräse
FULL PAPER
(s), 718 (m), 663 (m), 618 (w), 593 (m), 555 (m), 539 (w), 540 (m), 1.8 Hz, 1 H, Pc-HAr), 6.99 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 8.16
456 (w), 439 (w) cm–1. MS (70 eV, EI): m/z (%) = 276 (20) [M+], (s, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.5, 35.2,
172 (35) [C11H8O2+], 104 (18) [C8H8+], 43 (100). HRMS: calcd. for 35.2, 35.3 (–, 4ϫ CH2), 49.0 (q, J = 36 Hz, CH2CF3), 122.4 (q, J
C19H16O2 276.1150; found 276.1152. C19H16O2 (276.12): calcd. C
82.58, H 5.84; found C 81.39, H 5.99.
= 280 Hz, CF3), 125.9 (Cquat), 132.0, 132.2, 132.7, 133.3, 133.8,
135.6, 135.8 (+, 7ϫ CH), 138.7, 139.1, 139.4, 141.0 (4ϫ Cquat),
152.2 (+, CH), 156.8 (Cquat) ppm. 19F NMR (400 MHz, CDCl3): δ
= –70.05 ppm. MS (70 eV, EI): m/z (%) = 357 (53) [M+], 253 (100)
[C12H10F3N3+], 104 (28) [C8H8+], 103 (6) [C8H7+]. HRMS: calcd.
for C20H18F3N3 357.1453; found 357.1454.
Compound 22: A high-pressure vessel was charged with 9 (1.06 g,
3.99 mmol) and N,N-dimethylacetamide-dimethylacetal (21;
1.75 mL, 1.60 g, 12.0 mmol) and the mixture was heated to 120 °C
overnight. The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 22 (131 mg, 11%) as
a yellow solid. Rf = 0.70 (cyclohexane/ethyl acetate, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 2.43 (s, 3 H, Me), 2.78–2.87 (m, 2 H, HPc),
2.99–3.20 (m, 4 H, HPc), 3.58–3.68 (m, 1 H, HPc), 4.52–4.64 (m,
1 H, HPc), 6.10 (s, 1 H, Pc-HAr), 6.27 (d, J = 6.9 Hz, 1 H, Pc-HAr),
6.38 (t, J = 8.4 Hz, 2 H, Pc-HAr), 6.54 (d, J = 7.9 Hz, 1 H, Pc-HAr),
6.62 (d, J = 7.6 Hz, 1 H, Pc-HAr), 6.78 (d, J = 7.6 Hz, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.2 (+, CH3), 30.6,
33.9, 34.0, 35.3 (–, 4ϫ CH2), 111.6 (+, CH), 125.3 (Cquat), 127.0
(+, CH), 128.4 (Cquat), 130.4, 131.2, 133.1, 133.6, 137.3 (+, 5ϫ
Compound 25d: According to general procedure D with 24
(33.0 mg, 110 μmol). The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give 25d
(25.3 mg, 64%) as a white solid. Rf = 0.70 (cyclohexane/ethyl acet-
ate, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.01–1.08 (m, 1 H,
HcHex), 1.10–1.29 (m, 3 H, HcHex), 1.46–1.51 (m, 1 H, HcHex), 1.59–
1.72 (m, 3 H, HcHex), 1.83–1.90 (m, 1 H, HcHex), 1.98–2.11 (m, 2 H,
HcHex), 2.86–2.94 (m, 2 H, HPc), 2.97–3.06 (m, 3 H, HPc), 3.14–3.22
(m, 2 H, HPc), 3.85–3.96 (m, 1 H, HPc), 6.55–6.60 (m, 4 H, Pc-HAr),
6.62 (d, J = 1.7 Hz, 1 H, Pc-HAr), 6.73 (d, J = 1.7 Hz, 1 H, Pc-
CH), 138.7, 139.9, 143.2, 156.5, 163.4 (5ϫ Cquat), 179.9 (Cquat
,
HAr), 6.93 (dd, J = 7.9, 1.8 Hz, 1 H, Pc-HAr), 8.07 (s, 1 H, Pc-
CO) ppm. IR (DRIFT): ν = 2925 (vw), 2850 (vw), 1639 (w), 1617
˜
HAr) ppm. IR (DRIFT): ν = 3109 (w), 3011 (m), 2930 (s), 2855 (s),
˜
(w), 1580 (w), 1568 (w), 1499 (vw), 1474 (w), 1429 (vw), 1405 (vw),
1386 (w), 1362 (w), 1290 (vw), 1249 (vw), 1290 (vw), 1249 (vw),
1224 (vw), 1180 (vw), 1159 (vw), 1127 (vw), 1034 (vw), 1017 (vw),
959 (vw), 935 (w), 878 (w), 865 (w), 822 (vw), 793 (vw), 768 (vw),
714 (w), 679 (vw), 659 (w), 592 (w), 567 (vw), 539 (vw), 502 (w),
463 (vw), 439 (vw), 3058 (vw) cm–1. MS (70 eV, EI): m/z (%) = 290
(100) [M+], 186 (37) [C12H10O2+], 104 (1) [C8H8+]. HRMS: calcd.
for C20H18O2 290.1307; found 290.1309.
2238 (w), 1896 (w), 1869 (w), 1728 (s), 1683 (s), 1595 (m), 1557 (w),
1502 (m), 1454 (s), 1385 (s), 1358 (m), 1325 (m), 1279 (s), 1240 (s),
1179 (s), 1100 (m), 1086 (m), 1047 (m), 1029 (m), 1000 (m), 974
(m), 939 (m), 902 (m), 845 (m), 817 (m), 794 (m), 761 (m), 760 (s),
678 (m), 643 (m), 595 (w), 512 (m), 488 (w) cm–1. 13C NMR
(100 MHz, CDCl3): δ = 25.0, 25.3, 25.5, 31.9, 33.4 (–, 4ϫ CH2),
33.5, 35.2, 35.3, 35.4 (–, 4ϫ CH2), 57.4 (+, CH), 127.7 (Cquat),
131.8, 132.3, 132.7, 133.4, 133.8, 135.2, 135.2 (–, 7ϫ CH2), 139.0,
139.1, 139.4, 140.4 (4ϫ Cquat), 151.0 (+, CH), 153.8 (Cquat) ppm.
MS (70 eV, EI): m/z (%) = 357 (3) [M+], 253 (1) [C16H19N3+], 104
(2) [C8H8+], 83 (100) [C6H11+]. HRMS: calcd. for C24H27N3
357.2205; found 357.2203.
Compound 24: A high-pressure vessel was charged with 23 (560 mg,
2.23 mmol) and DMF-DMA (5; 5.10 mL, 4.38 g, 2.23 mmol) and
the mixture was heated to 130 °C for 24 h. The reaction gave 24
(280 mg, 41%) as a white solid.
Compound 25e: According to general procedure D with 24
(40.0 mg, 130 μmol). The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give 25e
(26.8 mg, 59%) as a white solid. Rf = 0.68 (cyclohexane/ethyl acet-
ate, 1:1). 1H NMR (400 MHz, CDCl3): δ = 2.44–2.51 (m, 1 H, HPc),
2.61–2.66 (m, 1 H, HPc), 2.76–2.89 (m, 2 H, HPc), 2.99–3.05 (m,
2 H, HPc), 3.07–3.21 (m, 2 H, HPc), 6.32 (d, J = 7.8 Hz, 1 H, Pc-
HAr), 6.50 (dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 6.54–6.60 (m, 3 H,
Pc-HAr), 6.83 (dd, J = 7.5, 1.4 Hz, 1 H, Pc-HAr), 6.86 (d, J =
1.8 Hz, 1 H, Pc-HAr), 7.11–7.13 (m, 1 H, Pc-HAr), 7.13 (d, J =
2.2 Hz, 1 H, Pc-HAr), 7.26–7.23 (m, 3 H, Pc-HAr), 8.22 (s, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.8, 35.1, 35.2, 35.4
(–, 4ϫ CH2), 115.5, 124.3 (+, 2ϫ CH), 127.3 (Cquat), 128.0, 128.8,
129.6, 131.8, 131.9, 132.7, 133.2, 133.7, 135.3, 135.5 (+, 10ϫ CH),
137.9, 139.2, 139.2, 139.3, 140.3 (5ϫ Cquat), 151.8 (+, CH), 154.3
Compound 25b: According to general procedure D with 24
(39.1 mg, 130 μmol). The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give 25b
(20.0 mg, 53%) as a white solid. Rf = 0.30 (cyclohexane/ethyl acet-
ate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.85–2.91 (m, 1 H, HPc),
2.94–2.98 (m, 2 H, HPc), 3.02–3.09 (m, 3 H, HPc), 3.12–3.22 (m,
2 H, HPc), 3.70 (s. 3 H, Me), 6.57–6.64 (m, 5 H, Pc-HAr), 6.81–6.83
(m, 1 H, Pc-HAr), 6.83–6.86 (m, 1 H, Pc-HAr), 8.08 (s, 1 H, Pc-
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.8, 35.2, 35.3, 35.4
(–, 4ϫ CH2), 35.8 (+, CH3), 127.2 (Cquat), 131.9, 132.0, 132.8,
133.4, 133.8, 135.3, 135.4 (+, 7ϫ CH), 139.0, 139.0, 139.4, 140.7
(4ϫ Cquat), 151.0 (+, CH), 155.1 (Cquat) ppm. IR (DRIFT): ν =
˜
2925 (w), 2850 (w), 1896 (vw), 1718 (vw), 1670 (vw), 1593 (w), 1518
(vw), 1490 (w), 1443 (w), 1411 (w), 1369 (w), 1278 (w), 1175 (w),
1153 (w), 1093 (w), 1047 (vw), 1004 (w), 976 (w), 942 (vw), 903
(w), 870 (w), 847 (w), 794 (w), 734 (w), 711 (m), 684 (w), 664 (m),
640 (m), 588 (w), 516 (w), 505 (w), 462 (vw), 3109 (vw), 3012
(vw) cm–1. MS (70 eV, EI): m/z (%) = 289 (37) [M+], 185 (100)
[C11H11N3+], 170 (1) [C10H8N3+], 104 (25) [C8H8+], 103 (6) [C8H7+].
HRMS: calcd. for C19H19N3 289.1579; found 289.1577.
(Cquat) ppm. IR (DRIFT): ν = 2926 (w), 2852 (w), 1734 (w), 1596
˜
(w), 1498 (m), 1451 (m), 1372 (m), 1240 (m), 1174 (w), 1133 (w),
1105 (w), 1068 (w), 1045 (w), 1005 (m), 970 (w), 902 (w), 843 (m),
794 (w), 762 (m), 733 (m), 719 (m), 692 (m), 668 (m), 640 (m), 591
(w), 558 (w), 514 (m) cm–1. MS (70 eV, EI): m/z (%) = 351 (1) [M+],
247 (1) [C16H13N3+], 104 (1) [C8H8+]. HRMS: calcd. for C24H21N3
351.1735; found 351.1737.
Compound 25c: According to general procedure D with 24
(41.0 mg, 130 μmol). The crude product was purified by column
chromatography (cyclohexane/ethyl acetate, 5:1) to give 25c
(21.0 mg, 45%) as a white solid. Rf = 0.42 (cyclohexane/ethyl acet-
Compound 25g: According to general procedure D with 24 (41 mg,
130 μmol). The crude product was purified by column chromatog-
ate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.79–2.86 (m, 1 H, HPc), raphy (cyclohexane/ethyl acetate, 10:1) to give 25g (26 mg, 47%) as
1
2.94–3.10 (m, 5 H, HPc), 3.12–3.26 (m, 2 H, HPc), 4.51 (q, J =
8.0 Hz, 2 H, CH2CF3), 6.53 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.59
(d, J = 7.9 Hz, 1 H, Pc-HAr), 6.61 (qd, J = 16.1, 7.8, 1.7 Hz, 2 H,
Pc-HAr), 6.66 (dd, J = 7.9, 1.8 Hz, 1 H, Pc-HAr), 6.70 (d, J =
a white solid. Rf = 0.45 (cyclohexane/ethyl acetate, 3:1). H NMR
(400 MHz, CDCl3): δ = 2.51–2.61 (m, 2 H, HPc), 2.77–2.93 (m, 2 H,
HPc), 2.98–3.07 (m, 2 H, HPc), 3.11–3.19 (m, 2 H, HPc), 6.37 (d, J
= 7.8 Hz, 1 H, Pc-HAr), 6.51–6.53 (m, 1 H, Pc-HAr), 6.59 (d, J =
6120
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Eur. J. Org. Chem. 2013, 6108–6123

Roadmap towards N-Heterocyclic [2.2]Paracyclophanes
8.1 Hz, 3 H, Pc-HAr), 6.79–6.83 (m, 1 H, Pc-HAr), 6.85–6.86 (m,
HAr), 7.71 (d, J = 15.7 Hz, 1 H, COCHCH), 12.37 (br. s, 1 H,
1 H, Pc-HAr), 7.02 (d, J = 8.6 Hz, 2 H, Pc-HAr), 7.38 (d, J = 8.7 Hz, OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.3, 33.9, 35.4, 37.5
2 H, Pc-HAr), 8.24 (s, 1 H, Pc-HAr) ppm. 13C NMR (100 MHz, (–, 4ϫ CH2), 116.2, 116.4 (+, 2ϫ CH), 123.2 (Cquat), 126.7, 126.7,
CDCl3): δ = 33.9, 35.1, 35.1, 35.3 (–, 4ϫ CH2), 115.4 (+, CH), 127.0, 127.8 (+, 4ϫ CH), 129.1 (Cquat), 130.4, 130.5 (+, 2ϫ CH),
121.9 (Cquat), 125.7 (+, CH), 126.9 (Cquat), 129.7, 131.8, 131.9,
131.0 (Cquat), 131.2, 132.2, 132.8 (+, 3ϫ CH), 137.8 (Cquat), 139.9
132.0, 132.7, 133.2, 133.6, 135.5, 135.7 (+, 9ϫ CH), 168.8, 139.1, (+, CH), 140.1, 142.3 (2ϫ Cquat), 161.9 (Cquat, COH), 165.4 (Cquat
,
139.1, 139.4, 140.6 (+, 5ϫ CH),151.9 (+, CH), 154.4 (Cquat) ppm.
IR (DRIFT): ν = 3012 (m), 2928 (s), 2853 (m), 1897 (vw), 1736
CF), 194.5 (Cquat, CO) ppm. IR (DRIFT): ν = 2921 (w), 2851 (vw),
1889 (vw), 1630 (w), 1597 (w), 1569 (w), 1556 (w), 1505 (w), 1453
˜
˜
(m), 1593 (m), 1492 (s), 1406 (m), 1374 (s), 1242 (s), 1174 (m), 1046 (w), 1433 (w), 1409 (w), 1339 (w), 1292 (w), 1213 (w), 1155 (w),
(m), 1001 (s), 970 (w), 901 (m), 844 (m), 829 (s), 755 (m), 736 (s), 1099 (w), 1073 (w), 1018 (w), 991 (w), 935 (w), 872 (vw), 856 (vw),
719 (m), 693 (w), 670 (m), 641 (m), 592 (w), 556 (vw), 512 (m), 826 (w), 979 (w), 915 (w), 689 (w), 660 (w), 596 (vw), 580 (w), 529
457 (w) cm–1. MS (70 eV, EI): m/z (%) = 429 (11) [M+], 350 (23) (w), 496 (w), 452 (w), 428 (vw) cm–1. MS (70 eV, EI): m/z (%) =
[C24H20N3+], 325 (15) [C16H12BrN3+], 104 (7) [C8H8+]. HRMS: 372 (33) [M+], 268 (27) [C17H13FO2+], 104 (100) [C8H8+]. HRMS:
calcd. for C24H20BrN3 429.0841; found 429.0841.
calcd. for (C25H21FO2) 372.1526; found 372.1523. C25H21FO2
(372.15): calcd. C 80.62, H 5.68; found C 80.03, H 5.72.
Compound 25i: According to general procedure D with 24 (33.0 mg,
110 μmol). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 5:1) to give 25i (18.9 mg, 49%) as
a white solid. Rf = 0.20 (cyclohexane/ethyl acetate, 3:1). H NMR
(400 MHz, CDCl3): δ = 2.47–2.56 (m, 1 H, HPc), 2.74–2.93 (m, 3 H,
Compound 27c: According to general procedure A with AHPC (9;
200 mg, 750 μmol), yield 49.8 mg (16%). Rf = 0.4 (cyclohexane/
ethyl acetate, 10:1). 1H NMR (400 MHz, CDCl3): δ = 2.54–2.61
(m, 1 H, HPC), 2.70–2.78 (m, 1 H, HPC), 3.01–3.09 (m, 3 H, HPC),
1
HPc), 2.97–3.06 (m, 2 H, HPc), 3.10–3.22 (m, 2 H, HPc), 6.36 (d, J 3.17–3.23 (m, 1 H, HPC), 3.40–3.54 (m, 2 H, HPC), 6.30 (d, J =
= 7.8 Hz, 1 H, Pc-HAr), 6.50–6.53 (m, 1 H, Pc-HAr), 6.55–6.60 (m, 7.6 Hz, 1 H, Pc-HAr), 6.31 (dd, J = 7.8, 1.9 Hz, 1 H, Pc-HAr), 6.42
3 H, Pc-HAr), 6.81–6.84 (m, 1 H, Pc-HAr), 6.86 (d, J = 1.7 Hz, 1 H, (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.54 (m, 2 H, Pc-HAr), 6.95 (dd,
Pc-HAr), 7.07 (d, J = 8.1 Hz, 1 H, Pc-HAr), 7.22–7.25 (m, 1 H, Pc-
Ar), 7.63 (td, J = 15.6, 7.7, 1.8 Hz, 1 H, Pc-HAr), 8.26 (s, 1 H,
Pc-HAr), 8.43 (dd, J = 4.7, 1.4 Hz, 1 H, Pc-HAr) ppm. 13C NMR
J = 7.8, 1.9 Hz, 1 H, Pc-HAr), 7.23 (d, J = 15.9 Hz, 1 H, COCH),
7.67–7.72 (m, 4 H, HAr), 7.73 (d, J = 15.9 Hz, 1 H, COCHCH),
H
12.25 (br. s, 1 H, OH) ppm. IR (DRIFT): ν = 2929 (w), 2854 (w),
˜
(100 MHz, CDCl3): δ = 33.8, 35.1, 35.4, 35.4 (–, 4ϫ CH2), 119.0, 1639 (w), 1574 (m), 1449 (vw), 1409 (m), 1319 (m), 1254 (w), 1218
123.3 (+, 2ϫ CH), 127.5 (Cquat), 131.8, 132.0, 132.7, 133.2, 133.7,
135.2, 135.4, 138.0 (+, 8ϫ CH), 139.3, 139.3, 139.3, 140.2 (4ϫ
C
(w), 1159 (m), 1104 (m), 1060 (m), 1015 (m), 982 (m), 953 (w), 937
(w), 877 (w), 836 (m), 824 (m), 798 (m), 732 (m), 718 (w), 694 (w),
quat), 149.0 (+, CH), 150.5 (Cquat), 152.1 (+, CH), 154.8 663 (w), 592 (w), 580 (w), 534 (w), 513 (w), 472 (w), 411 (vw) cm–1.
(Cquat) ppm. IR (DRIFT): ν = 2920 (w), 2852 (w), 1631 (vw), 1591
MS (70 eV, EI): m/z (%) = 422 (5) [M+], 318 (4) [C18H13F3O2+],
˜
(w), 1572 (w), 1519 (vw), 1473 (m), 1463 (m), 1434 (m), 1410 (w), 104 (100) [C8H8+]. HRMS: calcd. for C26H21F3O2 422.1494; found
1391 (w), 1375 (m), 1261 (w), 1211 (w), 1170 (w), 1149 (w), 1136 422.1494.
(w), 1083 (w), 1045 (vw), 1014 (w), 999 (w), 971 (w), 956 (vw), 942
Compound 27d: According to general procedure A with AHPC (9;
2.0 g, 7.50 mmol) in 2-propanol (20 mL), yield 456 mg (15%); m.p.
(vw), 901 (w), 888 (w), 842 (w), 789 (m), 734 (m), 717 (m), 670 (w),
638 (w), 619 (w), 590 (w), 561 (w), 514 (m), 491 (w), 411 (w) cm–1.
159.6 °C. Rf = 0.72 (cyclohexane/ethyl acetate, 1:1). 1H NMR
MS (70 eV, EI): m/z (%) = 352 (7) [M+], 248 (38) [C15H12N4+], 104
(400 MHz, CDCl3): δ = 1.35 [s, 9 H, C(CH3)3], 2.54–2.61 (m, 1 H,
(38) [C8H8+], 103 (2) [C8H7+], 78 (1) [C5H4N+]. HRMS: calcd. for
HPC), 2.68–2.77 (m, 1 H, HPC), 2.98–3.08 (m, 3 H, HPC), 3.16–3.25
C23H20N4 352.1688; found 352.1690.
(m, 1 H, HPC), 3.41–3.48 (m, 1 H, HPC), 3.55–3.61 (m, 1 H, HPC),
Compound 27a: According to general procedure A with AHPC (9;
300 mg, 1.13 mmol), to give 27a (111 mg, 28%). Rf = 0.74 (cyclo-
6.36 (d, J = 7.6 Hz, 1 H, Pc-HAr), 6.39 (dd, J = 7.8, 1.9 Hz, 1 H,
Pc-HAr), 6.48 (dd, J = 7.8, 7.1 Hz, 1 H, Pc-HAr), 6.57 (d, J =
hexane/ethyl acetate, 1:1). 13C NMR (100 MHz, CDCl3): δ = 30.3, 7.6 Hz, 1 H, Pc-HAr), 6.61 (dd, J = 7.9, 2.0 Hz, 1 H, Pc-HAr), 7.04
33.4, 33.9, 36.24 (–, 4ϫ CH2), 123.3 (Cquat), 126.9, 127.0, 127.3,
(dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr), 7.13 (d, J = 15.7 Hz, 1 H,
127.8, 128.6, 128.7, 128.9 (+, 7ϫ CH), 129.0 (Cquat), 130.1 (+, CH), COCH), 7.45 (d, J = 8.4 Hz, 2 H, HAr), 7.55 (d, J = 8.4 Hz, 2 H,
130.1 (Cquat), 130.7, 131.2, 132.2, 132.8 (+, 4ϫ CH), 132.8, 139.5 HAr), 7.72 (d, J = 15.8 Hz, 1 H, COCHCH), 12.43 (br. s, 1 H,
(2ϫ Cquat), 143.1 (+, CH), 145.4 (Cquat), 161.9 (Cquat, COH), 194.7
(Cquat, CO) ppm. IR (DRIFT): ν = 3058 (vw), 3027 (w), 2926 (w),
OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 30.2 (–, CH2), 31.2
[+, C(CH3)3], 33.9 (–, CH2), 35.0 [Cquat, C(CH3)3], 35.4, 37.5 (–,
˜
2851 (w), 1734 (w), 1663 (w), 1632 (m), 1570 (m), 1494 (w), 1448 2ϫ CH2), 123.3 (Cquat), 126.1, 126.2, 126.9, 127.8, 128.5 (+, 5ϫ
(w), 1433 (w), 1409 (m), 1336 (m), 1218 (m), 1154 (w), 1100 (w), CH), 129.0 (Cquat), 131.2 (+, CH), 132.0 (Cquat), 132.15, 132.8 (+,
1073 (m), 1021 (m), 990 (w), 935 (w), 910 (w), 861 (w), 795 (m), 2ϫ CH), 137.9 (Cquat), 139.8 (+, CH), 140.1, 142.4 (2ϫ Cquat),
751 (m), 694 (m), 664 (m), 585 (w), 565 (m), 546 (w), 511 (m), 483
(w), 461 (w) cm–1. MS (70 eV, EI): m/z (%) = 354 (2) [M+], 43 (100).
HRMS: calcd. for C25H22O2 354.1620; found 354.1622.
143.2 (+, CH), 154.4 (Cquat), 161.8 (Cquat, COH), 194.9 (Cquat,
CO) ppm. IR (DRIFT): ν = 2962 (vw), 2927 (vw), 1626 (w), 1571
˜
(w), 1556 (w), 1502 (vw), 1455 (vw), 1410 (w), 1333 (w), 1269 (vw),
1218 (w), 1152 (vw), 1100 (vw), 1070 (w), 994 (w), 935 (vw), 876
(vw), 832 (w), 793 (w), 753 (vw), 716 (vw), 668 (w), 595 (vw), 581
(vw), 555 (w), 535 (vw), 509 (w), 475 (vw), 453 (vw) cm–1. MS
Compound 27b: According to general procedure A with AHPC (9;
1.5 g, 5.63 mmol) in 2-propanol (20 mL), yield 234 mg (11%); m.p.
154.7 °C. Rf = 0.67 (cyclohexane/ethyl acetate, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 2.54–2.60 (m, 1 H, HPC), 2.69–2.79 (m,
1 H, HPC), 3.02–3.08 (m, 3 H, HPC), 3.16–3.23 (m, 1 H, HPC), 3.41–
3.48 (m, 1 H, HPC), 3.52–3.57 (m, 1 H, HPC), 6.35 (d, J = 7.6 Hz,
1 H, Pc-HAr), 6.40 (dd, J = 7.8, 1.9 Hz, 1 H, Pc-HAr), 6.49 (dd, J
(70 eV, EI): m/z (%) = 410 (94) [M+], 305 (100) [C21H22O2 – H],
+
104 (64) [C8H8+]. HRMS: calcd. for C29H30O2 410.2246; found
410.2245. C29H30O2 (410.22): calcd. C 84.84, H 7.37; found C
83.39, H 7.50.
= 7.9, 1.7 Hz, 1 H, Pc-HAr), 6.58 (d, J = 7.6 Hz, 1 H, Pc-HAr), 6.63 Compound 27e: According to general procedure A with AHPC (9;
(dd, J = 7.9, 1.9 Hz, 1 H, Pc-HAr), 7.04 (dd, J = 7.8, 1.8 Hz, 1 H, 200 mg, 750 μmol), yield 59.3 mg (19%). Rf = 0.40 (cyclohexane/
Pc-HAr), 7.07–7.14 (m, 3 H, HAr + COCH), 7.58–7.62 (m, 2 H, ethyl acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 2.54–2.61 (m,
Eur. J. Org. Chem. 2013, 6108–6123
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6121

M. Busch, M. Cayir, M. Nieger, W. R. Thiel, S. Bräse
FULL PAPER
1 H, HPc), 2.68–2.77 (m, 1 H, HPc), 2.99–3.07 (m, 3 H, HPc), 3.16– X-ray Crystallographic Data: Crystallographic Data (excluding
3.23 (m, 1 H, HPc), 3.41–3.47 (m, 1 H, HPc), 3.52–3.57 (m, 1 H, structure factors) for the structures reported in this work have been
HPc), 3.84 (s, 6 H, 2ϫ OCH3), 6.36 (d, J = 7.6 Hz, 1 H, Pc-HAr),
6.39 (dd, J = 7.9, 1.8 Hz, 1 H, Pc-HAr), 6.49 (dd, J = 7.9, 1.5 Hz,
1 H, Pc-HAr), 6.54 [t, J = 2.2 Hz, 1 H, CH(COCH3)2], 6.58 (d, J =
7.6 Hz, 1 H, Pc-HAr), 6.61 (dd, J = 7.9, 1.8 Hz, 1 H, Pc-HAr), 6.74
(d, J = 2.2 Hz, 2 H, HAr), 7.03 (dd, J = 7.9, 1.7 Hz, 1 H, Pc-HAr),
deposited with the Cambridge Crystallographic Data Centre under
registration numbers CCDC-919988 (for 10), -918989 (for 27a),
-918990 (for 27b), -918991 (for 27d), -918992 (for 27e), -918993 (for
11b), -918994 (for 11k), -918995 (for 12e), -918996 (for 12c),
-918997 (for 11h), -918998 (for 11i), -918999 (for 22), -919000 (for
7.12 (d, J = 15.7 Hz, 1 H, COCH), 7.65 (d, J = 15.7 Hz, 1 H, 12j), -919001 (for 18), -919002 (for 12f), -919003 (for 2a), -919004
COCHCH), 12.34 (br. s, 1 H, OH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 30.2, 33.8, 35.4, 37.5 (–, 4ϫ CH2), 55.5 (+, 2ϫ CH3),
102.8 [+, C(COCH3)2], 106.5 [+, 2ϫ CO(CH2)2C(CH)2], 123.2
(for 25i), -919005 (for 25e), -919006 (for 25d), -919007 (for 8c),
-919008 (for 8g), -919009 (for 29a), and -919010 (for 8b). These
data can be obtained free of charge from The Cambridge Crystallo-
(Cquat), 126.9, 127.5, 127.8 (+, 3ϫ CH), 129.0 (Cquat), 131.2, 132.2, graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
132.8 (+, 3ϫ CH), 136.6, 137.9 (2ϫ Cquat), 139.9 (+, CH), 140.1,
Supporting Information (see footnote on the first page of this arti-
142.5 (2ϫ Cquat), 143.1 (+, CH), 161.1 (Cquat, 2ϫ COCH3), 161.9
cle): Crystal structure determinations and NMR spectra.
(Cquat, COH), 194.7 (Cquat, CO) ppm. IR (DRIFT): ν = 3005 (vw),
˜
2935 (w), 2845 (vw), 1636 (w), 1585 (w), 1498 (vw), 1448 (w), 1404
(w), 1357 (w), 1324 (w), 1294 (w), 1245 (w), 1199 (w), 1151 (w),
1101 (w), 1059 (w), 981 (w), 935 (w), 921 (vw), 873 (vw), 825 (w),
772 (w), 714 (w), 693 (vw), 674 (w), 658 (w), 645 (vw), 594 (w), 530
(vw), 511 (w), 486 (vw), 443 (vw) cm–1. MS (70 eV, EI): m/z (%) =
414 (100) [M+], 309 (50) [C19H18O4+ – H], 279 (9) [C18H15O3+], 104
(18) [C8H8+]. HRMS: calcd. for C27H26O4 414.1831; found
414.1828.
Acknowledgments
This research was funded by the Collaborative Research Center
(SFB/TRR 88 3MET). Further funding received from the Feasibil-
ity Study for Young Scientists (FYS). The authors would like to
thank the Science and Management Program of the Karlsruhe In-
stitute of Technology (KIT) in cooperation with the Collège des
Ingénieurs (CDI) in Paris, Andreas Hafner for fruitful discussions
and Alexander Braun for the synthesis of some compounds.
Compound 27f: According to general procedure A with AHPC (9;
200 mg, 750 μmol), yield 12.4 mg (3%). Rf = 0.70 (cyclohexane/
1
ethyl acetate 3:1). H NMR (400 MHz, CDCl3): δ = 2.56–2.71 (m,
2 H, HPc), 2.94–3.24 (m, 11 H, HPc), 3.41–3.55 (m, 2 H, HPc), 3.64–
3.77 (m, 1 H, HPc), 6.30–6.32 (m, 1 H, Pc-HAr), 6.37–6.40 (m, 2 H,
Pc-HAr), 6.45–6.48 (m, 2 H, Pc-HAr), 6.52–6.55 (m, 3 H, Pc-HAr),
6.60–6.63 (m, 3 H, Pc-HAr), 6.70–6.72 (m, 1 H, Pc-HAr), 6.96 (d, J
= 15.5 Hz, 1 H, COCH), 7.05 (dd, J = 7.8, 1.8 Hz, 1 H, Pc-HAr),
7.91 (d, J = 15.5 Hz, 1 H, COCHCH), 12.49 (br. s, 1 H, OH) ppm.
13C NMR (100 MHz, CDCl3): δ = 30.3, 33.8, 33.8, 35.1, 35.3 (–,
5ϫ CH2), 35.4 (–, 2ϫ CH2), 37.5 (–,CH2), 123.6 (Cquat), 126.6,
126.9, 127.8 (+, 3ϫ CH), 129.1 (Cquat), 131.2, 131.2, 131.3, 131.8,
132.2, 132.8, 132.9, 133.1 (+, 8ϫ CH), 134.8 (Cquat), 135.0, 135.4
(+, 2ϫ CH), 137.9, 139.2, 139.3 (3ϫ Cquat), 139.8 (+, CH), 140.1
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(Cquat), 140.5 (+, CH), 140.6, 141.9, 142.4 (3ϫ Cquat), 161.8 (Cquat
,
COH), 194.6 (Cquat, CO) ppm. MS (70 eV, EI): m/z (%) = 484 (11)
[M+], 277 (11) [C19H16O2+ + H], 206 (16) [C16H14+], 119 (25)
[C8H7O+], 104 (100) [C8H8+], 103 (13) [C8H7+]. HRMS: calcd. for
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Compound 31: A high-pressure vessel was charged with hydroxy-
pyrazolyl[2.2]paracyclophane (156 mg, 540 μmol), [PdCl2(PhCN)2]
(30; 103 mg, 270 μmol) and dichloromethane (2 mL). The mixture
was stirred at 45 °C for 1 h then the organic precipitate was filtered
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in accordance with the experimental spectrum (see the Supporting
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room temperature. The mixture was cooled to –25 °C and cinnam-
aldehyde (0.08 mL, 640 μmol) was added. After one day, the reac-
tion was quenched at room temperature with 2 m aqueous HCl
(1 mL). The crude product was purified by column chromatog-
raphy (cyclohexane/ethyl acetate, 20:1) to give the secondary
alcohol (R)-34 (98 mg, 95%). Rf = 0.09 (cyclohexane/ethyl acetate,
5:1). 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H,
CH3), 1.18–1.26 (m, 1 H, CH2), 1.60–1.62 (m, 1 H, CH2), 4.08–4.21
(m, 1 H, CHCOH), 6.13 (dd, J = 15.9, 6.8 Hz, Ph-CH-CH), 6.50
(d, J = 15.9 Hz, Ph-CH), 7.16–7.33 (m, 5 H, Ph) ppm. See the Sup-
porting Information for chiral phase HPLC analytics for determin-
ing the ee of 24%.
3981.
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obtained from racemic mixtures. Mostly they crystallized in
centrosymmetric space groups. Some samples crystallized in
non-centrosymmetic space groups that possess a rotoinversion
axis (glide plane) and therefore both enantiomers are present
in the crystal structure (27d, 11h, 8b and 2a). Only one sample
crystallized in the chiral space group P212121 (22), for which
the absolute configuration could not be determined reliably.
This is a spontaneous resolution of the racemic sample.
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6108–6123

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Received: April 9, 2013
Published Online: August, 2, 2013
Eur. J. Org. Chem. 2013, 6108–6123
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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